Glucose oxidase variants

Abstract

The present disclosure concerns a glucose oxidase variant derived from the amino acid sequence of SEQ ID NO: 1. The glucose oxidase variant comprises an amino acid substitution at any one of positions 159, 411, 443, 468, and / or 491 and optionally at any one of positions 92, 433, 440, and / or 503. The glucose oxidase variants exhibit enzymatic activity both at room temperature as well as at elevated temperatures.

Description

[0001] GLUCOSE OXIDASE VARIANTS

[0002] CROSS-REFERENCE TO RELATED APPLICATION(S) AND DOCUMENT(S)

[0003] This patent application claims priority to U.S. provisional patent application 63 / 582,640 filed on September 14, 2023 which is herewith incorporated in its entirety. This patent application also comprises a sequence listing in electronic format also incorporated herewith in its entirety.

[0004] TECHNOLOGICAL FIELD

[0005] The present disclosure concerns glucose oxidase variants exhibiting activity at elevated temperatures while maintaining activity at room temperature.

[0006] BACKGROUND

[0007] Glucose oxidase is a flavin adenine dinucleotide (FAD)-dependent enzyme which oxidizes p- D-glucose to D-glucono-w-lactone and hydrogen peroxide in the presence of molecular oxygen. It is utilized as an oxidizing agent in industries including pharmaceutical, medical, textile, and food sectors. In baking applications, by virtue of the hydrogen peroxide it releases in situ, glucose oxidase facilitates the formation of an ordered gluten matrix in bread dough, improving its machinability, loaf volume, and crumb consistency.

[0008] Catalytically, glucose oxidase is considered a near-ideal enzyme owing to its rapid and highly specific mechanism of action (on the order of 106M'1S'1). Thermodynamically, the enzyme is susceptible to variability in conditions such as temperature, pH, or ionic strength. A glucose oxidase which maintains its full catalytic power but also has higher thermodynamic stability is desirable in biotechnological and other industrial applications.

[0009] SUMMARY

[0010] The present disclosure provides glucose oxidase variants having enzymatic activity which differ from the parental (wildtype) glucose oxidase.

[0011] According to a first aspect, the present disclosure provides a glucose oxidase variant (i) having at least 90% identity with the amino acid sequence of SEQ ID NO: 1 , and (ii) comprising an amino acid substitution at any one of positions 159, 411 , 443, 468, and / or 491 . In some embodiments, the glucose oxidase variant can comprise the amino acid substitution at position 159. In additional embodiments, the amino acid substitution at position 159 can be A159F, A159L, A159K, A159R, A159Y, A159T, A159V, or A159S. In some embodiments, the glucose oxidase variant can comprise the amino acid substitution at position 411. In additional embodiments, the amino acid substitution at position 411 can be T411 V, T411 S, T411A, T41 1 Q, T41 1 E, or T411 K. In some embodiments, the glucose oxidase variant can comprise the amino acid substitution at position 443. In additional embodiments, the amino acid substitution at position 443 can be A443I, A443L, A443F, A443M, A443Y, or A443V. In some embodiments, the glucose oxidase variant can comprise the amino acid substitution at position 468. In additional embodiments, the amino acid substitution at position 468 can be H468R, H468A, H468K, H468G, or H468S. In some embodiments, the glucose oxidase variant can comprise the amino acid substitution at position 491 . In additional embodiments, the amino acid substitution at position 491 can be Q491 K, Q491 R, or Q491 E. In another embodiment, the glucose oxidase variant can further comprise one or more additional amino acid substitution at any one of positions 92, 433, 440, and / or 503. In some embodiments, the glucose oxidase variant can comprise the amino acid substitution at position 92. In additional embodiments, the amino acid substitution at position 92 can be D92E, D92Q, D92A, D92K, D92R, D92S, or D92Y. In some embodiments, the glucose oxidase variant can comprise the amino acid substitution at position 433. In additional embodiments, the amino acid substitution at position 433 can be S433A, S433V, S433L, S433G, S433F, S433Y, or S433I. In some embodiments, the glucose oxidase variant can comprise the amino acid substitution at position 440. In additional embodiments, the amino acid substitution at position 440 can be A440G, A440E, A440D, A440S, A440F, or A440K. In some embodiments, the glucose oxidase variant can comprise the amino acid substitution at position 503. In additional embodiments, the amino acid substitution at position 503 can be 503K, Q503A, Q503R, Q503S, or Q503E.

[0012] According to a second aspect, the present disclosure provides a heterologous nucleic acid molecule comprising an open reading frame encoding the glucose oxidase variant described herein. In an embodiment, the heterologous nucleic acid molecule further comprises at least one promoter operably associated with the open reading frame.

[0013] According to a third aspect, the present disclosure provides a vector comprising the heterologous nucleic acid molecule described herein.

[0014] According to a fourth aspect, the present disclosure provides an expression cassette comprising the heterologous nucleic acid molecule described herein.

[0015] According to a fifth aspect, the present disclosure provides a recombinant microbial host cell expressing the glucose oxidase variant described herein. In an embodiment, the recombinant microbial host cell comprises the heterologous nucleic acid molecule described herein, the vector described herein, or the expression cassette described herein. In an embodiment, the recombinant microbial host cell is a yeast. In a further embodiment, the recombinant microbial host cell is from Saccharomyces sp. In still a further embodiment, the recombinant microbial host cell is from Saccharomyces cerevisiae. In a further embodiment, the recombinant microbial is from Komagataella sp. In yet a further embodiment, the recombinant microbial host cell is from Komagataella phaffii.

[0016] According to a sixth aspect, the present disclosure provides a method for making the glucose oxidase variant described herein. The process comprises expressing the heterologous nucleic acid molecule described herein, the vector described herein, or the expression cassette described herein in the recombinant microbial host cell described herein. In an embodiment, the glucose oxidase variant is an intracellular polypeptide or a secreted polypeptide. In another embodiment, the secreted polypeptide is in a free form or is associated to the surface of the recombinant microbial host cell. In yet another embodiment, the polypeptide associated to the surface of the recombinant yeast host cell is a tethered polypeptide. In an embodiment, the method further comprises, after step (i), (ii) substantially separating the glucose oxidase variant from the recombinant microbial host cell. In still a further embodiment, the method further comprises, after step (i) or (ii), drying the glucose oxidase variant.

[0017] According to a seventh aspect, the present disclosure provides composition comprising the glucose oxidase variant described herein, and a carrier. In an embodiment, the glucose oxidase variant is obtainable or obtained by the method described herein. In yet further embodiments, the composition further comprises another enzyme.

[0018] According to an eighth aspect, the present disclosure provides a process for preparing a dough or a baked product prepared from the dough, the process comprising adding an effective amount of the glucose oxidase variant described herein, optionally in combination with a fermenting yeast, to the dough. In an embodiment, the process further comprises, prior to, during and / or after the addition, leavening the dough. In another embodiment, the process further comprises, after the addition, baking the dough. In a further embodiment, the process is for increasing the softness and / or the resilience of the baked product. In additional embodiments, the process is for increasing the strength of the dough and can, in other embodiments, be used to reduce, at least in part, the amount of a chemical dough strengthener in the dough.

[0019] DETAILED DESCRIPTION OF THE DRAWINGS

[0020] Having thus generally described the nature of the invention, reference will now be made to the accompanying drawings, showing by way of illustration, a preferred embodiment thereof, and in which:

[0021] Figure 1 provides the relative glucose oxidase activity after incubation for ten minutes at 25°C (solid bars) or 65°C (striped bars) for enzyme variants expressed in Saccharomyces cerevisiae. The 25°C activities are reported as percentages of the wildtype activity. The 65°C activities are reported as percentages of each variant’s baseline level of activity at 25°C. Each data point is the average of two technical replicates. The assay was carried out twice.

[0022] Figure 2 provides the absolute glucose oxidase activity (absorbance measured at 510 nm) at 25°C for enzyme variants expressed in S. cerevisiae. Each data point is the average of three technical replicates. The assay was carried out twice. The error bars denote the standard deviation of the mean.

[0023] Figure 3 provides the temperature activity profiles for enzyme variants expressed in S. cerevisiae. Results are shown for wildtype or WT (black squares, dotted and dashed trend line ■); GOx variants v15 (gray rhombi, solid gray trend line 0); v16 (gray crossed squares, solid light gray trend line □); v24 (gray circles, long dashed gray trend line o); and v26 (gray triangles, close-spaced gray trend line A).

[0024] Figure 4 provides the relative glucose oxidase activity after incubation for ten minutes at 25°C (solid bars) or 65°C (striped bars) for enzyme variants expressed in Komagataella phaffii. The 25°C activities are reported as percentages of the wildtype activity. The 65°C activities are reported as percentages of each variant’s baseline level of activity at 25°C. Each data point is the average of two technical replicates. The assay was carried out twice.

[0025] Figure 5 provides the absolute glucose oxidase activity at 25°C for enzyme variants expressed in K. phaffii. Each data point is the average of three technical replicates. The assay was carried out twice. The error bars denote the standard deviation of the mean.

[0026] Figure 6 provides the temperature activity profiles for enzyme variants expressed in K. phaffii. Results are shown for wildtype or WT (black squares, dotted and dashed trend line ■); GOx variant v29 (gray rhombi, solid gray trend line 0); v16 (gray crossed squares, solid light gray trend line □); v24 (gray circles, long dashed gray trend line o); and v26 (gray triangles, closespaced gray trend line A).

[0027] Figure 7 provides baking application tests comparing the wildtype (WT) glucose oxidase and the GOx variants v24 and v26 expressed in K. phaffii. The solid bars on the left and the striped bars on the right of the graph depict data from two separate bake tests. Glucose oxidase enzymes were dosed into dough from spray-dried samples of enzyme produced in bioreactors. The enzyme dose is denoted under each bar in glucose oxidase units (GODU) per kilogram flour. No enzyme was added to the control dough. The volume of the final bread loaves is plotted.

[0028] DETAILED DESCRIPTION

[0029] The present disclosure provides polypeptides having glucose oxidase activity which belong to Enzyme Commission # 1.1.3.4. The polypeptides are derived from a naturally occurring glucose oxidase from Aspergillus niger having the GenBank accession number P13006 or the Uniprot accession number P13006.1 (which corresponds to the amino acid sequence of SEQ ID NO: 1). The glucose oxidase from Aspergillus niger having the GenBank accession number P13006 or the Uniprot accession number P13006.1 (which corresponds to the amino acid sequence of SEQ ID NO: 1) can be referred to as the parental glucose oxidase or the wildtype (WT) glucose oxidase. In the context of the present disclosure, polypeptides are considered being “derived from a naturally occurring glucose oxidase from Aspergillus niger3’ when they can be obtained from modifying (adding, deleting, and / or substituting) at least one amino acid residue which is present in the amino acid sequence of SEQ ID NO: 1. In the context of the present disclosure, polypeptides derived from the naturally occurring glucose oxidase from A. niger can be referred to as glucose oxidase variants. In some embodiments, the glucose oxidase variants exhibit at least 70% identity to the amino acid sequence of SEQ ID NO: 1. The term “% identity”, as known in the art, is a relationship between two or more polypeptide sequences, as determined by comparing the sequences. The level of identity can be determined conventionally using known computer programs. Identity can be readily calculated by known methods, including but not limited to those described in: Computational Molecular Biology (Lesk, A. M., ed.) Oxford University Press, NY (1988); Biocomputing: Informatics and Genome Projects (Smith, D. W., ed.) Academic Press, NY (1993); Computer Analysis of Sequence Data, Part I (Griffin, A. M., and Griffin, H. G., eds.) Humana Press, NJ (1994); Sequence Analysis in Molecular Biology (von Heinje, G., ed.) Academic Press (1987); and Sequence Analysis Primer (Gribskov, M. and Devereux, J., eds.) Stockton Press, NY (1991). Preferred methods to determine identity are designed to give the best match between the sequences tested. Methods to determine identity and similarity are codified in publicly available computer programs. Sequence alignments and percent identity calculations may be performed using the Megalign program of the LASERGENE bioinformatics computing suite (DNASTAR Inc., Madison, Wis.) or Geneious Prime. Multiple alignments of the sequences disclosed herein were performed using the Clustal Omega alignment method, which employs a Hidden Markov Model-based algorithm, using default parameters (including a cluster size = 100).

[0030] The variants of the present disclosure exhibit glucose oxidase activity. It is well known in the art how to determine if a polypeptide exhibits glucose oxidase activity. For example, in a first step, the polypeptide suspected of having glucose oxidase activity can be placed in the presence of a substrate known to be acted upon by the enzyme (p-D-glucose for example). If the tested polypeptide exhibits glucose oxidase activity, it will, in the presence of oxygen, generate hydrogen peroxide (H2O2) and a lactone (D-glucono-6-lactone for example). The presence / amount of hydrogen peroxide released can be determined in a further step by using a peroxidase to generate a detectable dye (quinoneimine for example which can be detected at 510 nm; or O-dianiside dihydrocloride for example which can be detected at 540 nm). In this further step, when the detectable dye can be used with the peroxidase to determine glucose oxidase activity.

[0031] The variants of the present disclosure exhibit glucose oxidase activity at room temperature e.g., at a temperature between 20°C and 30°C and, in some embodiments, at a temperature of about 25°C). In the context of the present disclosure, the polypeptides exhibiting “glucose oxidase activity at room temperature” refer to polypeptides having at least 10% of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In some embodiments, the glucose oxidase variants exhibit at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 20% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 25% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 30% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 35% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 40% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 45% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 50% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 55% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 60% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 65% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 70% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 75% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 80% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 85% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 90% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In additional embodiments, the glucose oxidase variants exhibit at least 95% or more of the activity of the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In some additional embodiments, the glucose oxidase variants exhibit substantially the same activity (e.g., between 95-105%) as the wildtype glucose oxidase when measured at the same temperature under similar assay conditions. In yet some further embodiments, exhibit at more activity (e.g., more than 100%, 105%, 1 10%, 115%, 120%, or higher) than the wildtype glucose oxidase when measured at the same temperature under similar assay conditions.

[0032] In addition to exhibiting activity at room temperature, the variants of the present disclosure also exhibit higher activity at elevated temperatures (e.g., at a temperature equal to or higher than 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 71 °C, 72°C, 73°C, 74°C, 75°C, 76°C, 1 C, 78°C, or 79°C) than the wildtype glucose oxidase. In some embodiments, this means that the variants of the present disclosure exhibit 50% or more residual activity. The expression “residual activity” refers to the percentage of the ratio of the activity of a glucose oxidase variant after having been submitted to a heat challenge when compared to the activity of the glucose oxidase variant that has not been submitted to the heat challenge. The heat challenge is applied at elevated temperatures (65°C for example) for a defined amount of time (10 minutes for example). In some embodiments, the residual activity of the glucose oxidase variant can be equal to or greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more (when measured, for example after a heat challenge of 10 minutes at 65°C for example). In some additional embodiments, the residual activity of the glucose oxidase variant can be equal to or greater than 50% or more (when measured, for example after a heat challenge of 10 minutes at 65°C for example). In some additional embodiments, the residual activity of the glucose oxidase variant can be equal to or greater than 55% or more (when measured, for example after a heat challenge of 10 minutes at 65°C for example). In some additional embodiments, the residual activity of the glucose oxidase variant can be equal to or greater than 60% or more (when measured, for example after a heat challenge of 10 minutes at 65°C for example). In some additional embodiments, the residual activity of the glucose oxidase variant can be equal to or greater than 65% or more (when measured, for example after a heat challenge of 10 minutes at 65°C for example). In some additional embodiments, the residual activity of the glucose oxidase variant can be equal to or greater than 70% or more (when measured, for example after a heat challenge of 10 minutes at 65°C for example). In some additional embodiments, the residual activity of the glucose oxidase variant can be equal to or greater than 75% or more (when measured, for example after a heat challenge of 10 minutes at 65°C for example). In some additional embodiments, the residual activity of the glucose oxidase variant can be equal to or greater than 80% or more (when measured, for example after a heat challenge of 10 minutes at 65°C for example). In some additional embodiments, the residual activity of the glucose oxidase variant can be equal to or greater than 85% or more (when measured, for example after a heat challenge of 10 minutes at 65°C for example). In some additional embodiments, the residual activity of the glucose oxidase variant can be equal to or greater than 90% or more (when measured, for example after a heat challenge of 10 minutes at 65°C for example). In some additional embodiments, the residual activity of the glucose oxidase variant can be equal to or greater than 95% or more (when measured, for example after a heat challenge of 10 minutes at 65°C for example).

[0033] The glucose oxidase variants of the present disclosure can have an inactivation temperature that is higher than the wildtype glucose oxidase. The inactivation temperature, which is also referred to as T5o, is the temperature at which an enzyme loses 50% of its activity. The inactivation temperature can be measured, for example, by generating a temperature activity profile for the glucose oxidase variant and by fitting each temperature activity curve to a sum of squares model. In some embodiments, the inactivation temperature of the glucose oxidase variant is higher by at least 1 °C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or more when compared to the inactivation temperature of the wildtype glucose oxidase. In some additional embodiments, the inactivation temperature of the glucose oxidase variant is higher by at least 6°C, 7°C, 8°C, 9°C, or more when compared to the inactivation temperature of the wildtype glucose oxidase. In some further embodiments, the inactivation temperature of the glucose oxidase variant is higher by at least 8°C, 9°C, or more when compared to the inactivation temperature of the wildtype glucose oxidase.

[0034] The glucose oxidase variants of the present disclosure can have a melting temperature that is higher than the wildtype glucose oxidase. The melting temperature, which is also referred to as Tm, is the temperature at which the enzyme folded and unfolded state distributions are equally populated (e.g., the midpoint of the denaturation curve of the protein). The melting temperature can be measured, for example, by using differential scanning fluorimetry using a fluorescent dye. In some embodiments, the melting temperature of the glucose oxidase variant is higher by at least 1 °C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or more when compared to the melting temperature of the wildtype glucose oxidase. In some additional embodiments, the melting temperature of the glucose oxidase variant is higher by at least 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or more when compared to the melting temperature of the wildtype glucose oxidase. In some further embodiments, the melting temperature of the glucose oxidase variant is higher by at least 7°C, 8°C, 9°C, or more when compared to the melting temperature of the wildtype glucose oxidase.

[0035] The glucose oxidase variants of the present disclosure can have increased stability during storage (at specific temperatures) than the wildtype glucose oxidase. Stability during storage can be assessed by methods known in the art. For example, the activity before and after storage can be determined to calculate the activity that is lost during storage. Storage can be performed at room temperature (between about 20-30°C), at cold temperatures (between about 0-20°C), at freezing temperatures (below 0°C), or at elevated temperatures (above 30°C for example). In some embodiments, the stability of the glucose oxidase variant and of the wildtype enzyme is determined at elevated temperatures (between about 35-55°C, and in some embodiments, at about 45°C). The stability of the glucose oxidase variant and of the wildtype enzyme is determined after a specific amount of storage time (hours, days, months). In some embodiments, the stability of the glucose oxidase variant and of the wildtype enzyme is determined after a storage time of 1 , 2, 3, and / or 4 weeks. After an incubation at 45°C for one week, some of the glucose oxidase will exhibit a loss in activity below about 15% of the initial activity of 0-day incubated samples that are kept frozen (and in some additional embodiments, a loss in activity equal to or below about 14, 13, 12, 11 , 10, 9, 8, 7, or 6%). After an incubation at 45°C for two weeks, some of the glucose oxidase will exhibit a loss in activity below about 18% of the initial activity of 0-day incubated samples that are kept frozen (and in some additional embodiments, a loss in activity equal to or below about 17, 16, 15, or 14%). After an incubation at 45°C for three weeks, some of the glucose oxidase will exhibit a loss in activity below about 26% of the initial activity of 0-day incubated samples that are kept frozen (and in some additional embodiments, a loss in activity equal to or below about 25, 24, 23, 22, 21 , 20, 19, 18, 17, 16, or 15%). After an incubation at 45°C for four weeks, some of the glucose oxidase will exhibit a loss in activity below about 31 % of the initial activity of 0-day incubated samples that are kept frozen (and in some additional embodiments, a loss in activity equal to or below about 30, 29, 28, 27, 26, 25, 24, 23, or 22%).

[0036] Glucose oxidase variants

[0037] As indicated herein, the glucose oxidase variants of the present disclosure are derived from a naturally occurring glucose oxidase from Aspergillus niger having the GenBank accession number P13006 or the Uniprot accession number P13006.1 (which corresponds to the amino acid sequence of SEQ ID NO: 1). The wildtype glucose oxidase, when expressed natively in Aspergillus niger, is believed to have a signal sequence which can be cleaved when the enzyme is secreted in a mature form. However, the prediction of the exact domain boundary of the signal sequence is ambiguous, and therefore of the amino acid sequence of the mature wildtype glucose oxidase can vary. In some embodiments, the signal sequence of the wildtype glucose oxidase includes the first 16 amino acid residues of the amino acid sequence of SEQ ID NO: 1. In such embodiments, the mature (secreted) form of the wild-type glucose oxidase and of the glucose oxidase variants would comprise the amino acid residues 17 to 605 of the amino acid sequence of SEQ ID NO: 1 . In some further embodiments, the signal sequence of the wildtype and of the glucose oxidase variants includes the first 22 amino acid residues of the amino acid sequence of SEQ ID NO: 1. In such embodiments, the mature (secreted) form of the wild-type glucose oxidase and of the glucose oxidase variants would comprise the amino acid residues 23 to 605 of the amino acid sequence of SEQ ID NO: 1. In some additional embodiments, the signal sequence of the wildtype and of the glucose oxidase variants includes the first 24 amino acid residues of the amino acid sequence of SEQ ID NO: 1. In such embodiments, the mature (secreted) form of the wild-type glucose oxidase and of the glucose oxidase variants would comprise the amino acid residues 25 to 605 of the amino acid sequence of SEQ ID NO: 1.

[0038] In the context of the present disclosure, the numbering of the amino acid residues which are modified in the glucose oxidase variants are provided with respect to the full length of the amino acid sequence of SEQ ID NO: 1 , even though the glucose oxidase variants (especially in their mature / secreted form) may lack some of N-terminal residues which are cleaved upon secretion. For example, as indicated herein, some of the glucose oxidase variants include a substitution at position 159 of the amino acid sequence of SEQ ID NO: 1 . In embodiments in which the signal sequence has not yet been cleaved (prior to secretion for example), this will correspond to position 159 in the glucose oxidase variant. In embodiments in which the first 16 amino acid residues are cleaved upon secretion (or in a cell-free production system), this will correspond to position 143 in the mature form of the glucose oxidase variant. In embodiments in which the first 22 amino acid residues are cleaved upon secretion (or in a cell- free production system), this will correspond to position 137 in the secreted glucose oxidase variant. In embodiments in which the first 24 amino acid residues are cleaved upon secretion (or in a cell-free production system), this will correspond to position 135 in the mature form of the glucose oxidase variant. In another example, as indicated herein, some of the glucose oxidase variants include a substitution at position 411 of the amino acid sequence of SEQ ID NO: 1 . In embodiments in which the signal sequence has not yet been cleaved (prior to secretion for example), this will correspond to position 41 1 in the glucose oxidase variant. In embodiments in which the first 16 amino acid residues are cleaved upon secretion, this will correspond to position 395 in the mature form of the glucose oxidase variant. In embodiments in which the first 22 amino acid residues are cleaved upon secretion, this will correspond to position 389 in the secreted glucose oxidase variant. In embodiments in which the first 24 amino acid residues are cleaved upon secretion (or in a cell-free production system), this will correspond to position 387 in the mature form of the glucose oxidase variant. In yet another example, as indicated herein, some of the glucose oxidase variants include a substitution at position 443 of the amino acid sequence of SEQ ID NO: 1 . In embodiments in which the signal sequence has not yet been cleaved (prior to secretion for example), this will correspond to position 443 in the glucose oxidase variant. In embodiments in which the first 16 amino acid residues are cleaved upon secretion, this will correspond to position 427 in the mature form of the glucose oxidase variant. In embodiments in which the first 22 amino acid residues are cleaved upon secretion, this will correspond to position 421 in the secreted glucose oxidase variant. In embodiments in which the first 24 amino acid residues are cleaved upon secretion (or in a cell-free production system), this will correspond to position 419 in the mature form of the glucose oxidase variant. In still another example, as indicated herein, some of the glucose oxidase variants include a substitution at position 468 of the amino acid sequence of SEQ ID NO: 1 . In embodiments in which the signal sequence has not yet been cleaved (prior to secretion for example), this will correspond to position 468 in the glucose oxidase variant. In embodiments in which the first 16 amino acid residues are cleaved upon secretion, this will correspond to position 452 in the mature form of the glucose oxidase variant. In embodiments in which the first 22 amino acid residues are cleaved upon secretion, this will correspond to position 446 in the secreted glucose oxidase variant. In embodiments in which the first 24 amino acid residues are cleaved upon secretion (or in a cell-free production system), this will correspond to position 444 in the mature form of the glucose oxidase variant. In a further example, as indicated herein, some of the glucose oxidase variants include a substitution at position 491 of the amino acid sequence of SEQ ID NO: 1 . In embodiments in which the signal sequence has not yet been cleaved (prior to secretion for example), this will correspond to position 491 in the glucose oxidase variant. In embodiments in which the first 16 amino acid residues are cleaved upon secretion, this will correspond to position 475 in the mature form of the glucose oxidase variant. In embodiments in which the first 22 amino acid residues are cleaved upon secretion, this will correspond to position 469 in the secreted glucose oxidase variant. In embodiments in which the first 24 amino acid residues are cleaved upon secretion (or in a cell-free production system), this will correspond to position 467 in the mature form of the glucose oxidase variant. In yet a further example, as indicated herein, some of the glucose oxidase variants include a substitution at position 92 of the amino acid sequence of SEQ ID NO: 1 . In embodiments in which the signal sequence has not yet been cleaved (prior to secretion for example), this will correspond to position 92 in the glucose oxidase variant. In embodiments in which the first 16 amino acid residues are cleaved upon secretion, this will correspond to position 76 in the mature form of the glucose oxidase variant. In embodiments in which the first 22 amino acid residues are cleaved upon secretion, this will correspond to position 70 in the secreted glucose oxidase variant. In embodiments in which the first 24 amino acid residues are cleaved upon secretion (or in a cell-free production system), this will correspond to position 68 in the mature form of the glucose oxidase variant. In still another example, as indicated herein, some of the glucose oxidase variants include a substitution at position 433 of the amino acid sequence of SEQ ID NO: 1 . In embodiments in which the signal sequence has not yet been cleaved (prior to secretion for example), this will correspond to position 433 in the glucose oxidase variant. In embodiments in which the first 16 amino acid residues are cleaved upon secretion, this will correspond to position 417 in the mature form of the glucose oxidase variant. In embodiments in which the first 22 amino acid residues are cleaved upon secretion, this will correspond to position 411 in the secreted glucose oxidase variant. In embodiments in which the first 24 amino acid residues are cleaved upon secretion (or in a cell-free production system), this will correspond to position 409 in the mature form of the glucose oxidase variant. In still another example, as indicated herein, some of the glucose oxidase variants include a substitution at position 440 of the amino acid sequence of SEQ ID NO: 1 . In embodiments in which the signal sequence has not yet been cleaved (prior to secretion for example), this will correspond to position 440 in the glucose oxidase variant. In embodiments in which the first 16 amino acid residues are cleaved upon secretion, this will correspond to position 424 in the mature form of the glucose oxidase variant. In embodiments in which the first 22 amino acid residues are cleaved upon secretion, this will correspond to position 418 in the secreted glucose oxidase variant. In embodiments in which the first 24 amino acid residues are cleaved upon secretion (or in a cell-free production system), this will correspond to position 416 in the mature form of the glucose oxidase variant. In still another example, as indicated herein, some of the glucose oxidase variants include a substitution at position 503 of the amino acid sequence of SEQ ID NO: 1 . In embodiments in which the signal sequence has not yet been cleaved (prior to secretion for example), this will correspond to position 503 in the glucose oxidase variant. In embodiments in which the first 16 amino acid residues are cleaved upon secretion, this will correspond to position 487 in the mature form of the glucose oxidase variant. In embodiments in which the first 22 amino acid residues are cleaved upon secretion, this will correspond to position 481 in the secreted glucose oxidase variant. In embodiments in which the first 24 amino acid residues are cleaved upon secretion (or in a cell-free production system), this will correspond to position 479 in the mature form of the glucose oxidase variant.

[0039] The glucose oxidase variants of the present disclosure have at least 70% identity and less than 100% identity to the amino acid sequence of SEQ ID NO: 1 . As such, the glucose oxidase variants include amino acid modifications with respect to the amino acid sequence of SEQ ID NO: 1. The amino modifications can include at least one amino acid addition, at least one amino acid deletion and / or at least one amino acid substitution. In some specific embodiments, the glucose oxidase variants include amino acid substitutions with respect to the amino acid sequence of SEQ ID NO: 1 . In some additional embodiments, the glucose oxidase variants include at least two, three, four, five, six, seven, eight, nine, or more amino acid substitutions with respect to the amino acid sequence of SEQ ID NO: 1 .

[0040] In some further embodiments, the glucose oxidase variants include at least one amino acid substitution at any one of positions 159, 411 , 443, 468, and / or 491 . In additional embodiments, the glucose oxidase variants include at least two amino acid substitutions at any combinations of positions 159, 41 1 , 443, 468, and / or 491. In additional embodiments, the glucose oxidase variants include at least three amino acid substitutions at any combinations of positions 159, 411 , 443, 468, and / or 491. In further embodiments, the glucose oxidase variants include at least four amino acid substitutions at any combinations of positions 159, 411 , 443, 468, and / or 491. In yet additional embodiments, the glucose oxidase variants include amino acid substitutions at positions 159, 41 1 , 443, 468, and 491. Embodiments of glucose oxidase variants comprising at least one amino acid substitution at any one of positions 159, 411 , 443, 468, and / or 491 are provided in Table 1 .

[0041] The present disclosure provides variants of glucose oxidase variants including at least one amino acid substitution at any one of positions 159, 411 , 443, 468, and / or 491 . Such variants include at least one amino acid substitution at any one of positions 159, 41 1 , 443, 468, and / or 491 as well as other modifications. As used in the context of the present disclosure, a “variant” of a glucose oxidase variant includes at least one amino acid difference (e.g., at least one amino acid addition, deletion or substitution) when compared to the amino acid sequence of the original glucose oxidase variant. Variants exhibit a substantially similar biological activity when compared to the biological activity of the original glucose oxidase variant. In some embodiments, the variants (including the fragments) can also have at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more biological activity when compared to the biological activity of the original glucose oxidase variant. In some specific embodiments, the variants (including the fragments) can also have more biological activity when compared to the biological activity of the original glucose oxidase variant. The at least one amino acid difference can referto an amino acid residue that has been added, substituted, or deleted. As used in the context of the present disclosure, a “fragment” is a type of variant which includes at least one deleted amino acid residues when compared to the amino acid sequence of the original polypeptide. In some embodiments, fragments can refer to the mature form of a secreted glucose oxidase fragment (from which the signal sequence has been cleaved). In some embodiments, the variants (including the fragments) can also have at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of the glucose oxidase variant.

[0042] The variants of glucose oxidase variants described herein may be (i) one in which one or more of the amino acid residues are substituted with a conservative or non-conservative (preferably a conservative) amino acid residue and such substituted amino acid residue may or may not be one encoded by the genetic code, or (ii) one in which one or more of the amino acid residues includes a substituent group, or (iii) one in which the mature polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (for example, polyethylene glycol), or (iv) one in which the additional amino acids are fused to the mature polypeptide for purification of the polypeptide. Conservative substitutions typically include the substitution of one amino acid for another with similar characteristics, e.g., substitutions of an amino acid by another one belonging to same category determined by its side chain: within amino acids presenting hydrophobic side chain (alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, or tryptophan); within amino acids presenting positively charged side chain (arginine, histidine, or lysine); negatively charged side chain (aspartic acid or glutamic acid) and polar-uncharged side chain (serine, threonine, asparagine, or glutamine); or substitutions within the following groups: valine, glycine; glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid; asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. Other conservative amino acid substitutions are known in the art and are included herein. Non-conservative substitutions, such as replacing a basic amino acid with a hydrophobic one, are also well-known in the art.

[0043] A variant of a glucose oxidase variant can also be a conservative variant or an allelic variant. As used herein, a conservative variant refers to alterations in the amino acid sequence that do not adversely affect the biological function(s) of the polypeptide. A substitution, insertion, or deletion is said to adversely affect the polypeptide when the altered sequence prevents or disrupts a biological function associated with the polypeptide. For example, the overall charge, structure, or hydrophobic-hydrophilic properties of the polypeptide can be altered without adversely affecting a biological activity. Accordingly, the amino acid sequence can be altered, for example to render the polypeptide more hydrophobic or hydrophilic, without adversely affecting the biological activities of the polypeptide.

[0044] A fragment can correspond to the polypeptides to which the signal peptide sequence has been removed. In additional embodiments, the fragment can be, for example, a truncation of one or more, two or more, three or more, four, five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more at the amino terminus of the non-truncated polypeptide or variant. In additional embodiments, the fragment can be, for example, a truncation of one or more, two or more, three or more, four, five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 1 1 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more at the carboxyl terminus of the non-truncated polypeptide or variant. Alternatively, or in combination, the fragment can be generated from removing one or more internal amino acid residues. In an embodiment, the polypeptide fragment can have at least 100, 150, 200, 250, 300, 350, 400, 450, or more consecutive amino acid residues of the original amino acid sequence or the polypeptide variant. The present disclosure also provides variants of glucose oxidase variants including at least one amino acid substitution at any one of positions 159, 41 1 , 443, 468, and / or 491 . Such variants include the at least one amino acid substitution at any one of positions 159, 411 , 443, 468, and / or 491 as well as other modifications. The glucose oxidase variants having at least one amino acid substitution at any one of positions 159, 411 , 443, 468, and / or 491 can further include at least one amino acid substitution at any one of positions 92, 433, 440, and / or 503. In additional embodiments, the glucose oxidase variants having at least one amino acid substitution at any one of positions 159, 411 , 443, 468, and / or 491 can also include at least two amino acid substitutions at any combinations of positions 92, 433, 440, and / or 503. In additional embodiments, the glucose oxidase variants having at least one amino acid substitution at any one of positions 159, 411 , 443, 468, and / or 491 can also include at least three amino acid substitutions at any combinations of positions 92, 433, 440, and / or 503. In additional embodiments, the glucose oxidase variants having at least one amino acid substitution at any one of positions 159, 411 , 443, 468, and / or 491 can also include substitutions at positions 92, 433, 440, and 503. Embodiments of glucose oxidase variants comprising at least one at least one amino acid substitution at any one of positions 159, 411 , 443, 468, and / or 491 as well as at least one further amino acid substitution at any one of 92, 433, 440, and / or 503 are provided in Table 1 . The glucose oxidase variants of the present disclosure can have the amino acid sequence of SEQ ID NO: 19.

[0045] Table 1. Embodiments of the combinations of amino acid identity at positions 92, 159, 411 , 433, 440, 443, 468, 491 , and 503 of the glucose oxidase variants of the present disclosure. The amino acid numbering is based on the amino acid sequence of SEQ ID NO: 1. X1 (at position 92) refers to any natural occurring amino acid residue which is not D; in some embodiments it can be E, Q, A, K, R, S, or Y; in some further embodiments, it can be E. X2 (at position 159) refers to any natural occurring amino acid residue which is not A; in some embodiments it can be F, L, K, R, Y, T, V, or S; in some further embodiments, it can be F. X3 (at position 411) refers to any natural occurring amino acid residue which is not T; in some embodiments it can be V, S, A, Q, E, or K; in some further embodiments, it can be V. X4 (at position 433) refers to any natural occurring amino acid residue which is not S; in some embodiments it can be A, V, L, G, F, Y, or I; in some further embodiments, it can be A. X5 (at position 440) refers to any natural occurring amino acid residue which is not A; in some embodiments it can be G, E, D, S, F, or K; in some further embodiments, it can be G. X6 (at position 443) refers to any natural occurring amino acid residue which is not A; in some embodiments it can be I, L, F, M, Y, or V; in some further embodiments, it can be I. X7 (at position 468) refers to any natural occurring amino acid residue which is not H; in some embodiments it can be R, A, K, G, or S; in some further embodiments, it can be R. X8 (at position 491) refers to any natural occurring amino acid residue which is not Q; in some embodiments it can be K, R, or E; in some further embodiments, it can be K. X9 (at position 3) refers to any natural occurring amino acid residue which is not Q; in some embodiments can be K, A, R, S, or E; in some further embodiments, it can be K.

[0046]

[0047] In some embodiments, the glucose oxidase variant comprises, at position 159, a naturally occurring amino acid residue that is different from A. The glucose oxidase variant comprising a substitution at position 159 can include, in some embodiments, at least one further substitution at any one of positions 411 , 443, 468, and / or 491. The glucose oxidase variant comprising a substitution at position 159 can include, in some embodiments, at least two further substitutions at any one of positions 411 , 443, 468, and / or 491. The glucose oxidase variant comprising a substitution at position 159 can include, in some embodiments, at least three further substitutions at any one of positions 411 , 443, 468, and / or 491. The glucose oxidase variant comprising a substitution at position 159 can include, in some embodiments, substitutions at positions 411 , 443, 468, and 491. For example, the glucose oxidase variant can include, at position 159, one of the following amino acid residue: R (A159R), N (A159N), or V (A159V). For example, the glucose oxidase variant can include, at position 159, one of the following amino acid residue: R (A159R), L (A159L), K (A159K), F (A159F), S (A159S), T (A159T), Y (A159Y), or V (A159V). In another example, the glucose oxidase variant can include, at position 159, one of the following amino acid residue: K (A159K), F (A159F), S (A159S), T (A159T), Y (A159Y), or V (A159V). In a further example, the glucose oxidase variant can include, at position 159, one of the following amino acid residue: L (A159L), or F (A159F). In yet a further example, the glucose oxidase variant can include, at position 159, F (A159F). In some embodiments, the glucose oxidase variant does not include, at position 159, Q (D159Q). In some embodiments, the glucose oxidase variant does not include, at position 159, L (A159L). Specific embodiments of the glucose oxidase comprising, at position 159, a substitution include, without limitation, a polypeptide comprising the amino acid sequence of SEQ ID NO: 5 or 7 or a variant thereof (including fragments thereof comprising, in some embodiments, the amino acid residues 25-605 of the amino acid sequence of SEQ ID NO: 5 or 7).

[0048] In some embodiments, the glucose oxidase variant comprises, at position 411 , a naturally occurring amino acid residue that is different from T. The glucose oxidase variant comprising a substitution at position 411 can include, in some embodiments, at least one further substitution at any one of positions 159, 443, 468, and / or 491. The glucose oxidase variant comprising a substitution at position 41 1 can include, in some embodiments, at least two further substitutions at any one of positions 159, 443, 468, and / or 491. The glucose oxidase variant comprising a substitution at position 411 can include, in some embodiments, at least three further substitutions at any one of positions 159, 443, 468, and / or 491. The glucose oxidase variant comprising a substitution at position 41 1 can include, in some embodiments, substitutions at positions 159, 443, 468, and 491. For example, the glucose oxidase variant can include, at position 411 , one of the following amino acid residue: A (T411A), R (T411 R), N (T411 N), D (T411 D), C (T411 C), E (T411 E), Q (T41 1 Q), G (T411 G), H (T411 H), I (T411 I), L (T411 L), K (T411 K), M (T41 1 M), F (T411 F), P (T411 P), S (T41 1 S), W (T411 W), Y (T411 Y), or V (T41 1V). For example, the glucose oxidase variant can include, at position 411 , one of the following amino acid residues: A (T411A), E (T411 E), Q (T41 1 Q), K (T411 K), S (T411 S), or V (T411V). In another example, the glucose oxidase variant can include, at position 411 , one of the following amino acid residues: Q (T411 Q), K (T411 K), S (T41 1 S), or V (T411 V). In a further example, the glucose oxidase variant can include, at position 411 , one of the following amino acid residues: S (T41 1 S), or V (T411V). In yet a further example, the glucose oxidase variant can include, at position 411 , V (T41 1V). In some embodiments, the glucose oxidase variant does not include, at position 41 1 , A (T41 1A). In some embodiments, the glucose oxidase variant does not include, at position 411 , E (T411 E). In some embodiments, the glucose oxidase variant does not include, at position 411 , A (T41 1A) or E (T411 E). Specific embodiments of the glucose oxidase comprising, at position 41 1 , a substitution include, without limitation, a polypeptide comprising the amino acid sequence of SEQ ID NO: 5 or 7 or a variant thereof (including fragments thereof comprising, in some embodiments, the amino acid residues 25-605 of the amino acid sequence of SEQ ID NO: 5 or 7).

[0049] In some embodiments, the glucose oxidase variant comprises, at position 443, a naturally occurring amino acid residue that is different from A. The glucose oxidase variant comprising a substitution at position 443 can include, in some embodiments, at least one further substitution at any one of positions 159, 411 , 468, and / or 491. The glucose oxidase variant comprising a substitution at position 443 can include, in some embodiments, at least two further substitutions at any one of positions 159, 411 , 468, and / or 491. The glucose oxidase variant comprising a substitution at position 443 can include, in some embodiments, at least three further substitutions at any one of positions 159, 411 , 468, and / or 491. The glucose oxidase variant comprising a substitution at position 443 can include, in some embodiments, substitutions at positions 159, 411 , 468, and 491. For example, the glucose oxidase variant can include, at position 443, one of the following amino acid residue: R (A443R), N (A443N), D (A443D), C (A443C), E (A443E), Q (A443Q), G (A443G), H (A443H), I (A443I), L (A443L), K (A443K), M (A443M), F (A443F), P (A443P), S (A443S), T (A443T), W (A443W), Y (A443Y), or V (A443V). For example, the glucose oxidase variant can include, at position 443, one of the following amino acid residues: I (A443I), L (A443L), M (A443M), F (A443F), Y (A443Y), or V (A443V). In another example, the glucose oxidase variant can include, at position 443, one of the following amino acid residues: M (A443M), F (A443F), Y (A443Y), or V (A443V). In a further example, the glucose oxidase variant can include, at position 443, one of the following amino acid residues: I (A443I), or L (A443L). In yet a further example, the glucose oxidase variant can include, at position 443, I (A443I). In some embodiments, the glucose oxidase variant does not include, at position 443, 1 (A443I). In some embodiments, the glucose oxidase variant does not include, at position 443, L (A443L). In some embodiments, the glucose oxidase variant does not include, at position 443, 1 (A443I) or L (A443L). Specific embodiments of the glucose oxidase comprising, at position 443, a substitution include, without limitation, a polypeptide comprising the amino acid sequence of SEQ ID NO: 5 or 7 or a variant thereof (including fragments thereof comprising, in some embodiments, the amino acid residues 25- 605 of the amino acid sequence of SEQ ID NO: 5 or 7).

[0050] In some embodiments, the glucose oxidase variant comprises, at position 468, a naturally occurring amino acid residue that is different from H. The glucose oxidase variant comprising a substitution at position 468 can include, in some embodiments, at least one further substitution at any one of positions 159, 411 , 443, and / or 491. The glucose oxidase variant comprising a substitution at position 468 can include, in some embodiments, at least two further substitutions at any one of positions 159, 411 , 443, and / or 491. The glucose oxidase variant comprising a substitution at position 468 can include, in some embodiments, at least three further substitutions at any one of positions 159, 411 , 443, and / or 491 . The glucose oxidase variant comprising a substitution at position 468 can include, in some embodiments, substitutions at positions 159, 411 , 443, and 491. For example, the glucose oxidase variant can include, at position 468, one of the following amino acid residue: A (H468A), R (H468R), N (H468N), D (H468D), C (H468C), E (H468E), Q (H468Q), G (H468G), I (H468I), L (H468L), K (H468K), M (H468M), F (H468F), P (H468P), S (H468S), T (H468T), W (H468W), Y (H468Y), or V (H468V). For example, the glucose oxidase variant can include, at position 468, one of the following amino acid residues: A (H468A), R (H468R), (H468G), K (H468K), or S (H468S). In another example, the glucose oxidase variant can include, at position 468, one of the following amino acid residues: A (H468A), (H468G), K (H468K), or S (H468S). In a further example, the glucose oxidase variant can include, at position 468, one of the following amino acid residues: A (H468A), R (H468R), or K (H468K). In yet a further example, the glucose oxidase variant can include, at position 468, R (H468R). In some embodiments, the glucose oxidase variant does not include, at position 468, R (H468R). Specific embodiments of the glucose oxidase comprising, at position 468, a substitution include, without limitation, a polypeptide comprising the amino acid sequence of SEQ ID NO: 5 or 7 or a variant thereof (including fragments thereof comprising, in some embodiments, the amino acid residues 25- 605 of the amino acid sequence of SEQ ID NO: 5 or 7).

[0051] In some embodiments, the glucose oxidase variant comprises, at position 491 , a naturally occurring amino acid residue that is different from Q. The glucose oxidase variant comprising a substitution at position 491 can include, in some embodiments, at least one further substitution at any one of positions 159, 411 , 443, and / or 468. The glucose oxidase variant comprising a substitution at position 491 can include, in some embodiments, at least two further substitutions at any one of positions 159, 411 , 443, and / or 468. The glucose oxidase variant comprising a substitution at position 491 can include, in some embodiments, at least three further substitutions at any one of positions 159, 411 , 443, and / or 468. The glucose oxidase variant comprising a substitution at position 491 can include, in some embodiments, substitutions at positions 159, 411 , 443, and 468. For example, the glucose oxidase variant can include, at position 491 , one of the following amino acid residue: A (Q491A), R (Q491 R), N (Q491 N), D (Q491 D), C (Q491 C), E (Q491 E), G (Q491 G), H (Q491 H), I (Q4911), L (Q491 L), K (Q491 K), M (Q491 M), F (Q491 F), P (Q491 P), S (Q491 S), T (Q491T), W (Q491W), Y (Q491Y), or V (Q491 V). For example, the glucose oxidase variant can include, at position 491 , one of the following amino acid residues: R (Q491 R), E (Q491 E), or K (Q491 K). In another example, the glucose oxidase variant can include, at position 491 , one of the following amino acid residues: R (Q491 R), or E (Q491 E). In yet a further example, the glucose oxidase variant can include, at position 491 , K (Q491 K). In some embodiments, the glucose oxidase variant does not include, at position 491 , K (Q491 K). Specific embodiments of the glucose oxidase comprising, at position 491 , a substitution include, without limitation, a polypeptide comprising the amino acid sequence of SEQ ID NO: 5 or 7 or a variant thereof (including fragments thereof comprising, in some embodiments, the amino acid residues 25-605 of the amino acid sequence of SEQ ID NO: 5 or 7).

[0052] Glucose oxidase variants having amino acid substitutions at positions 159, 411 , 443, 468, and 491 include, but are not limited to, those having the following combinations of substitutions: A159F,T411V,A443I,H468R,Q491 K;A159F,T411V,A443I,H468R,Q491 R;A159F,T411V,A443 l,H468R,Q491 E;A159F,T411 V,A443I,H468A,Q491 K;A159F.T41 1 V,A443I,H468A,Q491 R;A1 59F.T41 1 V,A443I,H468A,Q491 E;A159F.T41 1 V,A443I,H468K,Q491 K;A159F.T411 V,A443I,H 468K.Q491 R;A159F.T411 V,A443I,H468K,Q491 E;A159F,T41 1 V,A443I,H468G,Q491 K;A159 F,T411 V,A443I,H468G,Q491 R;A159F.T411 V,A443I,H468G,Q491 E;A159F.T41 1 V,A443I,H4 68S.Q491 K;A159F.T411 V,A443I,H468S,Q491 R;A159F.T411 V,A443I,H468S,Q491 E;A159F, T41 1 V,A443L,H468R,Q491 K;A159F,T411 V,A443L,H468R,Q491 R;A159F,T411 V,A443L,H46 8R.Q491 E;A159F.T411 V,A443L,H468A,Q491 K;A159F.T411 V,A443L,H468A,Q491 R;A159F, T41 1 V,A443L,H468A,Q491 E;A159F,T41 1 V,A443L,H468K,Q491 K;A159F,T41 1 V,A443L,H46 8K.Q491 R;A159F.T411 V,A443L,H468K,Q491 E;A159F.T411 V,A443L,H468G,Q491 K;A159F, T41 1 V,A443L,H468G,Q491 R;A159F,T41 1 V,A443L,H468G,Q491 E;A159F,T411 V,A443L,H46 8S.Q491 K;A159F.T411 V,A443L,H468S,Q491 R;A159F.T411 V,A443L,H468S,Q491 E;A159F, T41 1 V,A443F,H468R,Q491 K;A159F,T411 V,A443F,H468R,Q491 R;A159F,T411 V,A443F,H4 68R.Q491 E;A159F.T41 1 V,A443F,H468A,Q491 K;A159F.T411 V,A443F,H468A,Q491 R;A159 F,T411 V,A443F,H468A,Q491 E;A159F.T411 V,A443F,H468K,Q491 K;A159F,T41 1 V,A443F,H 468K.Q491 R;A159F.T411 V,A443F,H468K,Q491 E;A159F.T411 V,A443F,H468G,Q491 K;A15 9F,T411 V,A443F,H468G,Q491 R;A159F.T41 1 V,A443F,H468G,Q491 E;A159F.T411 V.A443F, H468S.Q491 K;A159F.T41 1 V,A443F,H468S,Q491 R;A159F,T41 1 V,A443F,H468S,Q491 E;A1 59F.T41 1 V,A443M,H468R,Q491 K;A159F.T41 1 V,A443M,H468R,Q491 R;A159F,T411 V,A443 M,H468R,Q491 E;A159F.T41 1 V,A443M,H468A,Q491 K;A159F.T41 1 V,A443M,H468A,Q491 R; A159F.T411 V,A443M,H468A,Q491 E;A159F.T41 1 V,A443M,H468K,Q491 K;A159F,T411 V,A4 43M,H468K,Q491 R;A159F.T411 V,A443M,H468K,Q491 E;A159F.T411 V,A443M,H468G,Q49

[0053] I K;A159F.T41 1 V,A443M,H468G,Q491 R;A159F.T411 V,A443M,H468G,Q491 E;A159F.T41 1 V ,A443M,H468S,Q491 K;A159F.T411 V,A443M,H468S,Q491 R;A159F.T411 V,A443M,H468S,Q 491 E;A159F.T411 V,A443Y,H468R,Q491 K;A159F.T41 1 V,A443Y,H468R,Q491 R;A159F.T41 1 V,A443Y,H468R,Q491 E;A159F,T411V,A443Y,H468A,Q491 K;A159F,T411V,A443Y,H468A, Q491 R;A159F.T411 V,A443Y,H468A,Q491 E;A159F.T411 V,A443Y,H468K,Q491 K;A159F,T4

[0054] I I V,A443Y,H468K,Q491 R;A159F.T41 1 V,A443Y,H468K,Q491 E;A159F,T411 V,A443Y,H468 G.Q491 K;A159F.T411 V,A443Y,H468G,Q491 R;A159F.T41 1 V,A443Y,H468G,Q491 E;A159F, T41 1 V,A443Y,H468S,Q491 K;A159F.T411 V,A443Y,H468S,Q491 R;A159F.T411 V,A443Y,H4 68S.Q491 E;A159F.T411 V,A443V,H468R,Q491 K;A159F.T411 V,A443V,H468R,Q491 R;A159

[0055] F.T411 V,A443V,H468R,Q491 E;A159F.T411 V,A443V,H468A,Q491 K;A159F.T411 V,A443V,H 468A.Q491 R;A159F.T411 V,A443V,H468A,Q491 E;A159F.T41 1 V,A443V,H468K,Q491 K;A15 9F.T411 V,A443V,H468K,Q491 R;A159F.T411 V,A443V,H468K,Q491 E;A159F.T411 V.A443V, H468G.Q491 K;A159F.T41 1 V,A443V,H468G,Q491 R;A159F.T411 V,A443V,H468G,Q491 E;A 159F.T411 V,A443V,H468S,Q491 K;A159F.T41 1 V,A443V,H468S,Q491 R;A159F.T41 1 V.A443 V,H468S,Q491 E;A159F.T411 S,A443I,H468R,Q491 K;A159F.T411 S,A443I,H468R,Q491 R;A1 59F.T41 1 S,A443I,H468R,Q491 E;A159F.T411 S,A443I,H468A,Q491 K;A159F.T411 S.A443I.H 468A.Q491 R;A159F.T411 S,A443I,H468A,Q491 E;A159F.T411 S,A443I,H468K,Q491 K;A159F ,T411 S,A443I,H468K,Q491 R;A159F.T411 S,A443I,H468K,Q491 E;A159F.T411 S.A443I.H468

[0056] G.Q491 K;A159F.T411 S,A443I,H468G,Q491 R;A159F.T41 1 S,A443I,H468G,Q491 E;A159F,T 411 S,A443I,H468S,Q491 K;A159F.T411 S,A443I,H468S,Q491 R;A159F.T411 S.A443I.H468S, Q491 E;A159F.T411 S,A443L,H468R,Q491 K;A159F.T411 S,A443L,H468R,Q491 R;A159F.T41 1 S,A443L,H468R,Q491 E;A159F.T411 S,A443L,H468A,Q491 K;A159F.T41 1 S,A443L,H468A, Q491 R;A159F.T411 S,A443L,H468A,Q491 E;A159F.T411 S,A443L,H468K,Q491 K;A159F.T41

[0057] I S,A443L,H468K,Q491 R;A159F.T411 S,A443L,H468K,Q491 E;A159F.T411 S,A443L,H468G, Q491 K;A159F.T411 S,A443L,H468G,Q491 R;A159F.T411 S,A443L,H468G,Q491 E;A159F.T4

[0058] I I S,A443L,H468S,Q491 K;A159F.T41 1 S,A443L,H468S,Q491 R;A159F.T41 1 S,A443L,H468S ,Q491 E;A159F.T411 S,A443F,H468R,Q491 K;A159F.T411 S,A443F,H468R,Q491 R;A159F.T4 11 S,A443F,H468R,Q491 E;A159F.T411 S,A443F,H468A,Q491 K;A159F.T41 1 S,A443F,H468A ,Q491 R;A159F.T411 S,A443F,H468A,Q491 E;A159F.T411 S,A443F,H468K,Q491 K;A159F.T4 11 S,A443F,H468K,Q491 R;A159F.T411 S,A443F,H468K,Q491 E;A159F.T41 1 S,A443F,H468 G.Q491 K;A159F.T411 S,A443F,H468G,Q491 R;A159F.T41 1 S,A443F,H468G,Q491 E;A159F, T41 1 S,A443F,H468S,Q491 K;A159F.T411 S,A443F,H468S,Q491 R;A159F.T41 1 S,A443F,H46 8S.Q491 E;A159F.T41 1 S,A443M,H468R,Q491 K;A159F.T411 S,A443M,H468R,Q491 R;A159 F.T411 S,A443M,H468R,Q491 E;A159F.T411 S,A443M,H468A,Q491 K;A159F.T411 S.A443M, H468A.Q491 R;A159F.T411 S,A443M,H468A,Q491 E;A159F.T41 1 S,A443M,H468K,Q491 K;A

[0059] 159F.T411 S,A443M,H468K,Q491 R;A159F.T411 S,A443M,H468K,Q491 E;A159F.T41 1 S,A44 3M,H468G,Q491 K;A159F.T411 S,A443M,H468G,Q491 R;A159F.T411 S,A443M,H468G,Q491 E;A159F.T41 1 S,A443M,H468S,Q491 K;A159F.T411 S,A443M,H468S,Q491 R;A159F.T411 S, A443M,H468S,Q491 E;A159F.T411 S,A443Y,H468R,Q491 K;A159F.T411 S,A443Y,H468R,Q4 91 R;A159F.T411 S,A443Y,H468R,Q491 E;A159F.T411 S,A443Y,H468A,Q491 K;A159F.T411 S,A443Y,H468A,Q491 R;A159F.T411 S,A443Y,H468A,Q491 E;A159F.T411 S,A443Y,H468K, Q491 K;A159F.T411 S,A443Y,H468K,Q491 R;A159F.T411 S,A443Y,H468K,Q491 E;A159F.T4 11 S,A443Y,H468G,Q491 K;A159F.T411 S,A443Y,H468G,Q491 R;A159F.T41 1 S,A443Y,H468 G.Q491 E;A159F.T411 S,A443Y,H468S,Q491 K;A159F.T411 S,A443Y,H468S,Q491 R;A159F, T41 1 S,A443Y,H468S,Q491 E;A159F.T411 S,A443V,H468R,Q491 K;A159F.T41 1 S,A443V,H4 68R.Q491 R;A159F.T411 S,A443V,H468R,Q491 E;A159F.T41 1 S,A443V,H468A,Q491 K;A159

[0060] F.T411 S,A443V,H468A,Q491 R;A159F.T411 S,A443V,H468A,Q491 E;A159F.T411 S,A443V,H 468K.Q491 K;A159F.T41 1 S,A443V,H468K,Q491 R;A159F.T41 1 S,A443V,H468K,Q491 E;A15 9F.T411 S,A443V,H468G,Q491 K;A159F.T411 S,A443V,H468G,Q491 R;A159F.T411 S.A443V, H468G.Q491 E;A159F.T41 1 S,A443V,H468S,Q491 K;A159F.T41 1 S,A443V,H468S,Q491 R;A1 59F.T41 1 S,A443V,H468S,Q491 E;A159F.T411 A,A443I,H468R,Q491 K;A159F.T411 A.A443I, H468R.Q491 R;A159F.T411 A,A443I,H468R,Q491 E;A159F.T411 A,A443I,H468A,Q491 K;A15 9F.T411 A,A443I,H468A,Q491 R;A159F.T41 1 A,A443I,H468A,Q491 E;A159F.T411 A.A443I.H4 68K.Q491 K;A159F,T411 A,A443I,H468K,Q491 R;A159F,T411 A,A443I,H468K,Q491 E;A159F, T41 1 A,A443I,H468G,Q491 K;A159F.T411 A,A443I,H468G,Q491 R;A159F.T411 A.A443I.H468

[0061] G,Q491 E;A159F,T411 A,A443I,H468S,Q491 K;A159F,T41 1 A,A443I,H468S,Q491 R;A159F,T4 11 A,A443I,H468S,Q491 E;A159F,T411 A,A443L,H468R,Q491 K;A159F,T411 A,A443L,H468R, Q491 R;A159F.T411 A,A443L,H468R,Q491 E;A159F.T41 1 A,A443L,H468A,Q491 K;A159F.T41 1 A,A443L,H468A,Q491 R;A159F.T411 A,A443L,H468A,Q491 E;A159F.T411 A,A443L,H468K, Q491 K;A159F.T411 A,A443L,H468K,Q491 R;A159F.T411 A,A443L,H468K,Q491 E;A159F.T41 1A,A443L,H468G,Q491 K;A159F,T411A,A443L,H468G,Q491 R;A159F,T411A,A443L,H468G, Q491 E;A159F.T411 A,A443L,H468S,Q491 K;A159F.T411 A,A443L,H468S,Q491 R;A159F.T41

[0062] I A,A443L,H468S,Q491 E;A159F.T41 1 A,A443F,H468R,Q491 K;A159F,T411 A,A443F,H468R, Q491 R;A159F.T411 A,A443F,H468R,Q491 E;A159F.T411 A,A443F,H468A,Q491 K;A159F.T4

[0063] I I A,A443F,H468A,Q491 R;A159F.T41 1 A,A443F,H468A,Q491 E;A159F.T41 1 A,A443F,H468K ,Q491 K;A159F.T411 A,A443F,H468K,Q491 R;A159F.T411 A,A443F,H468K,Q491 E;A159F.T4 11 A,A443F,H468G,Q491 K;A159F,T41 1 A,A443F,H468G,Q491 R;A159F.T411 A,A443F,H468 G.Q491 E;A159F.T411 A,A443F,H468S,Q491 K;A159F.T41 1 A,A443F,H468S,Q491 R;A159F,T 411 A,A443F,H468S,Q491 E;A159F.T411 A,A443M,H468R,Q491 K;A159F.T411 A,A443M,H46 8R.Q491 R;A159F.T41 1 A,A443M,H468R,Q491 E;A159F.T41 1 A,A443M,H468A,Q491 K;A159 F.T411 A,A443M,H468A,Q491 R;A159F.T411 A,A443M,H468A,Q491 E;A159F.T411 A.A443M, H468K.Q491 K;A159F.T41 1 A,A443M,H468K,Q491 R;A159F.T411 A,A443M,H468K,Q491 E;A 159F.T411 A,A443M,H468G,Q491 K;A159F,T411 A,A443M,H468G,Q491 R;A159F,T41 1 A,A44 3M,H468G,Q491 E;A159F,T411A,A443M,H468S,Q491 K;A159F,T411A,A443M,H468S,Q491 R;A159F.T41 1 A,A443M,H468S,Q491 E;A159F,T411 A,A443Y,H468R,Q491 K;A159F,T411 A, A443Y,H468R,Q491 R;A159F.T411 A,A443Y,H468R,Q491 E;A159F.T411 A,A443Y,H468A,Q4 91 K;A159F,T411 A,A443Y,H468A,Q491 R;A159F.T41 1 A,A443Y,H468A,Q491 E;A159F,T41 1 A ,A443Y,H468K,Q491 K;A159F,T411A,A443Y,H468K,Q491 R;A159F,T411A,A443Y,H468K,Q4 91 E;A159F.T411 A,A443Y,H468G,Q491 K;A159F.T411 A,A443Y,H468G,Q491 R;A159F.T411 A,A443Y,H468G,Q491 E;A159F.T411 A,A443Y,H468S,Q491 K;A159F.T411 A,A443Y,H468S, Q491 R;A159F.T411 A,A443Y,H468S,Q491 E;A159F.T411 A,A443V,H468R,Q491 K;A159F.T4 11 A,A443V,H468R,Q491 R;A159F.T411 A,A443V,H468R,Q491 E;A159F.T411 A,A443V,H468 A.Q491 K;A159F.T41 1 A,A443V,H468A,Q491 R;A159F,T411 A,A443V,H468A,Q491 E;A159F,T 411 A,A443V,H468K,Q491 K;A159F.T41 1 A,A443V,H468K,Q491 R;A159F.T411 A,A443V,H46 8K.Q491 E;A159F.T411 A,A443V,H468G,Q491 K;A159F.T411 A,A443V,H468G,Q491 R;A159F ,T411 A,A443V,H468G,Q491 E;A159F.T411 A,A443V,H468S,Q491 K;A159F.T411 A,A443V,H4 68S.Q491 R;A159F.T41 1 A,A443V,H468S,Q491 E;A159F.T411 Q,A443I,H468R,Q491 K;A159F ,T411 Q,A443I,H468R,Q491 R;A159F.T411 Q,A443I,H468R,Q491 E;A159F.T41 1 Q,A443I,H46 8A.Q491 K;A159F.T411 Q,A443I,H468A,Q491 R;A159F.T41 1 Q,A443I,H468A,Q491 E;A159F,T 411 Q,A443I,H468K,Q491 K;A159F.T411 Q,A443I,H468K,Q491 R;A159F.T411 Q,A443I,H468K ,Q491 E;A159F.T41 1 Q,A443I,H468G,Q491 K;A159F.T41 1 Q,A443I,H468G,Q491 R;A159F.T4 11 Q,A443I,H468G,Q491 E;A159F.T411 Q,A443I,H468S,Q491 K;A159F.T411 Q,A443I,H468S, Q491 R;A159F.T411 Q,A443I,H468S,Q491 E;A159F.T41 1 Q,A443L,H468R,Q491 K;A159F.T41

[0064] I Q,A443L,H468R,Q491 R;A159F.T411 Q,A443L,H468R,Q491 E;A159F.T41 1 Q,A443L,H468A, Q491 K;A159F.T411 Q,A443L,H468A,Q491 R;A159F.T411 Q,A443L,H468A,Q491 E;A159F.T4

[0065] I I Q,A443L,H468K,Q491 K;A159F.T411 Q,A443L,H468K,Q491 R;A159F.T411 Q,A443L,H468 K.Q491 E;A159F.T41 1 Q,A443L,H468G,Q491 K;A159F.T41 1 Q,A443L,H468G,Q491 R;A159F, T41 1 Q,A443L,H468G,Q491 E;A159F.T411 Q,A443L,H468S,Q491 K;A159F.T411 Q,A443L,H4 68S.Q491 R;A159F.T41 1 Q,A443L,H468S,Q491 E;A159F.T411 Q,A443F,H468R,Q491 K;A159 F.T411 Q,A443F,H468R,Q491 R;A159F.T41 1 Q,A443F,H468R,Q491 E;A159F.T411 Q.A443F, H468A.Q491 K;A159F.T41 1 Q,A443F,H468A,Q491 R;A159F.T411 Q,A443F,H468A,Q491 E;A1 59F.T41 1 Q,A443F,H468K,Q491 K;A159F.T41 1 Q,A443F,H468K,Q491 R;A159F.T411 Q.A443

[0066] F,H468K,Q491 E;A159F.T411 Q,A443F,H468G,Q491 K;A159F.T411 Q,A443F,H468G,Q491 R; A159F.T41 1 Q,A443F,H468G,Q491 E;A159F.T41 1 Q,A443F,H468S,Q491 K;A159F.T411 Q,A4 43F,H468S,Q491 R;A159F.T411 Q,A443F,H468S,Q491 E;A159F.T411 Q,A443M,H468R,Q491 K;A159F.T41 1 Q,A443M,H468R,Q491 R;A159F.T411 Q,A443M,H468R,Q491 E;A159F.T411 Q, A443M,H468A,Q491 K;A159F.T411 Q,A443M,H468A,Q491 R;A159F.T411 Q,A443M,H468A,Q 491 E;A159F.T411 Q,A443M,H468K,Q491 K;A159F.T411 Q,A443M,H468K,Q491 R;A159F.T41 1 Q,A443M,H468K,Q491 E;A159F.T41 1 Q,A443M,H468G,Q491 K;A159F.T41 1 Q,A443M,H468

[0067] G.Q491 R;A159F.T411 Q,A443M,H468G,Q491 E;A159F.T411 Q,A443M,H468S,Q491 K;A159F ,T411 Q,A443M,H468S,Q491 R;A159F.T411 Q,A443M,H468S,Q491 E;A159F.T41 1 Q,A443Y,H 468R.Q491 K;A159F.T411 Q,A443Y,H468R,Q491 R;A159F.T411 Q,A443Y,H468R,Q491 E;A15 9F.T411 Q,A443Y,H468A,Q491 K;A159F.T41 1 Q,A443Y,H468A,Q491 R;A159F.T411 Q.A443Y ,H468A,Q491 E;A159F.T411 Q,A443Y,H468K,Q491 K;A159F.T411 Q,A443Y,H468K,Q491 R;A 159F.T411 Q,A443Y,H468K,Q491 E;A159F.T411 Q,A443Y,H468G,Q491 K;A159F.T41 1 Q,A44 3Y,H468G,Q491 R;A159F.T411 Q,A443Y,H468G,Q491 E;A159F.T411 Q,A443Y,H468S,Q491 K;A159F.T411 Q,A443Y,H468S,Q491 R;A159F.T41 1 Q,A443Y,H468S,Q491 E;A159F.T411 Q, A443V,H468R,Q491 K;A159F.T411 Q,A443V,H468R,Q491 R;A159F.T41 1 Q,A443V,H468R,Q 491 E;A159F.T411 Q,A443V,H468A,Q491 K;A159F.T411 Q,A443V,H468A,Q491 R;A159F.T41

[0068] I Q,A443V,H468A,Q491 E;A159F.T411 Q,A443V,H468K,Q491 K;A159F.T411 Q,A443V,H468K ,Q491 R;A159F.T411 Q,A443V,H468K,Q491 E;A159F.T411 Q,A443V,H468G,Q491 K;A159F,T 411 Q,A443V,H468G,Q491 R;A159F.T411 Q,A443V,H468G,Q491 E;A159F.T411 Q,A443V,H4 68S.Q491 K;A159F.T411 Q,A443V,H468S,Q491 R;A159F.T411 Q,A443V,H468S,Q491 E;A159 F.T411 E,A443I,H468R,Q491 K;A159F.T41 1 E,A443I,H468R,Q491 R;A159F.T411 E.A443I.H46 8R.Q491 E;A159F.T411 E,A443I,H468A,Q491 K;A159F.T41 1 E,A443I,H468A,Q491 R;A159F,T 411 E,A443I,H468A,Q491 E;A159F.T411 E,A443I,H468K,Q491 K;A159F.T41 1 E.A443I.H468K, Q491 R;A159F.T411 E,A443I,H468K,Q491 E;A159F.T411 E,A443I,H468G,Q491 K;A159F.T411 E,A443I,H468G,Q491 R;A159F,T411 E,A443I,H468G,Q491 E;A159F,T41 1 E,A443I,H468S,Q4 91 K;A159F.T411 E,A443I,H468S,Q491 R;A159F.T41 1 E,A443I,H468S,Q491 E;A159F.T411 E, A443L,H468R,Q491 K;A159F.T411 E,A443L,H468R,Q491 R;A159F.T41 1 E,A443L,H468R,Q4 91 E;A159F.T411 E,A443L,H468A,Q491 K;A159F.T411 E,A443L,H468A,Q491 R;A159F.T411 E ,A443L,H468A,Q491 E;A159F.T411 E,A443L,H468K,Q491 K;A159F.T411 E,A443L,H468K,Q4 91 R;A159F.T411 E,A443L,H468K,Q491 E;A159F.T41 1 E,A443L,H468G,Q491 K;A159F.T411 E ,A443L,H468G,Q491 R;A159F.T411 E,A443L,H468G,Q491 E;A159F.T41 1 E,A443L,H468S,Q4 91 K;A159F.T411 E,A443L,H468S,Q491 R;A159F.T411 E,A443L,H468S,Q491 E;A159F.T411 E ,A443F,H468R,Q491 K;A159F.T411 E,A443F,H468R,Q491 R;A159F.T411 E,A443F,H468R,Q4 91 E;A159F.T411 E,A443F,H468A,Q491 K;A159F.T41 1 E,A443F,H468A,Q491 R;A159F.T411 E ,A443F,H468A,Q491 E;A159F.T411 E,A443F,H468K,Q491 K;A159F.T411 E,A443F,H468K,Q4 91 R;A159F.T411 E,A443F,H468K,Q491 E;A159F.T411 E,A443F,H468G,Q491 K;A159F.T41 1 E ,A443F,H468G,Q491 R;A159F.T41 1 E,A443F,H468G,Q491 E;A159F.T41 1 E,A443F,H468S,Q 491 K;A159F.T411 E,A443F,H468S,Q491 R;A159F.T411 E,A443F,H468S,Q491 E;A159F.T411 E,A443M,H468R,Q491 K;A159F.T411 E,A443M,H468R,Q491 R;A159F.T411 E,A443M,H468R, Q491 E;A159F.T411 E,A443M,H468A,Q491 K;A159F.T411 E,A443M,H468A,Q491 R;A159F.T4

[0069] I I E,A443M,H468A,Q491 E;A159F.T411 E,A443M,H468K,Q491 K;A159F.T411 E,A443M,H468 K.Q491 R;A159F.T41 1 E,A443M,H468K,Q491 E;A159F.T41 1 E,A443M,H468G,Q491 K;A159F, T41 1 E,A443M,H468G,Q491 R;A159F.T411 E,A443M,H468G,Q491 E;A159F.T41 1 E,A443M,H 468S.Q491 K;A159F.T41 1 E,A443M,H468S,Q491 R;A159F.T41 1 E,A443M,H468S,Q491 E;A15 9F.T411 E,A443Y,H468R,Q491 K;A159F.T411 E,A443Y,H468R,Q491 R;A159F.T411 E.A443Y, H468R.Q491 E;A159F.T411 E,A443Y,H468A,Q491 K;A159F.T41 1 E,A443Y,H468A,Q491 R;A1 59F.T41 1 E,A443Y,H468A,Q491 E;A159F.T41 1 E,A443Y,H468K,Q491 K;A159F.T411 E.A443Y ,H468K,Q491 R;A159F.T41 1 E,A443Y,H468K,Q491 E;A159F.T411 E,A443Y,H468G,Q491 K;A

[0070] 159F.T411 E,A443Y,H468G,Q491 R;A159F.T41 1 E,A443Y,H468G,Q491 E;A159F.T411 E,A44 3Y,H468S,Q491 K;A159F.T411 E,A443Y,H468S,Q491 R;A159F.T41 1 E,A443Y,H468S,Q491 E; A159F.T411 E,A443V,H468R,Q491 K;A159F.T411 E,A443V,H468R,Q491 R;A159F.T41 1 E,A4 43V,H468R,Q491 E;A159F.T41 1 E,A443V,H468A,Q491 K;A159F.T411 E,A443V,H468A,Q491 R;A159F.T411 E,A443V,H468A,Q491 E;A159F.T411 E,A443V,H468K,Q491 K;A159F.T41 1 E,A 443V,H468K,Q491 R;A159F.T41 1 E,A443V,H468K,Q491 E;A159F.T411 E,A443V,H468G,Q49 1 K;A159F.T41 1 E,A443V,H468G,Q491 R;A159F.T411 E,A443V,H468G,Q491 E;A159F.T411 E, A443V,H468S,Q491 K;A159F.T411 E,A443V,H468S,Q491 R;A159F.T411 E,A443V,H468S,Q4 91 E;A159F.T411 K,A443I,H468R,Q491 K;A159F.T411 K,A443I,H468R,Q491 R;A159F.T41 1 K, A443I.H468R.Q491 E;A159F.T411 K,A443I,H468A,Q491 K;A159F.T41 1 K,A443I,H468A,Q491 R;A159F.T411 K,A443I,H468A,Q491 E;A159F.T411 K,A443I,H468K,Q491 K;A159F.T411 K,A4 43I.H468K.Q491 R;A159F.T411 K,A443I,H468K,Q491 E;A159F.T411 K,A443I,H468G,Q491 K; A159F.T411 K,A443I,H468G,Q491 R;A159F.T411 K,A443I,H468G,Q491 E;A159F.T411 K.A443 l,H468S,Q491 K;A159F.T411 K,A443I,H468S,Q491 R;A159F.T41 1 K,A443I,H468S,Q491 E;A1 59F.T41 1 K,A443L,H468R,Q491 K;A159F.T411 K,A443L,H468R,Q491 R;A159F.T41 1 K.A443L ,H468R,Q491 E;A159F.T41 1 K,A443L,H468A,Q491 K;A159F.T411 K,A443L,H468A,Q491 R;A1 59F.T41 1 K,A443L,H468A,Q491 E;A159F.T411 K,A443L,H468K,Q491 K;A159F.T411 K.A443L, H468K.Q491 R;A159F.T411 K,A443L,H468K,Q491 E;A159F.T411 K,A443L,H468G,Q491 K;A1 59F.T41 1 K,A443L,H468G,Q491 R;A159F.T411 K,A443L,H468G,Q491 E;A159F.T411 K.A443L ,H468S,Q491 K;A159F.T411 K,A443L,H468S,Q491 R;A159F.T41 1 K,A443L,H468S,Q491 E;A1 59F.T41 1 K,A443F,H468R,Q491 K;A159F.T411 K,A443F,H468R,Q491 R;A159F.T41 1 K.A443F ,H468R,Q491 E;A159F.T411 K,A443F,H468A,Q491 K;A159F.T411 K,A443F,H468A,Q491 R;A1 59F.T41 1 K,A443F,H468A,Q491 E;A159F.T41 1 K,A443F,H468K,Q491 K;A159F.T41 1 K.A443F ,H468K,Q491 R;A159F.T41 1 K,A443F,H468K,Q491 E;A159F.T41 1 K,A443F,H468G,Q491 K;A1 59F.T41 1 K,A443F,H468G,Q491 R;A159F.T41 1 K,A443F,H468G,Q491 E;A159F.T41 1 K.A443 F,H468S,Q491 K;A159F.T411 K,A443F,H468S,Q491 R;A159F.T411 K,A443F,H468S,Q491 E;A 159F.T411 K,A443M,H468R,Q491 K;A159F.T411 K,A443M,H468R,Q491 R;A159F.T411 K,A44 3M,H468R,Q491 E;A159F.T411 K,A443M,H468A,Q491 K;A159F.T411 K,A443M,H468A,Q491 R;A159F.T41 1 K,A443M,H468A,Q491 E;A159F.T411 K,A443M,H468K,Q491 K;A159F.T411 K, A443M,H468K,Q491 R;A159F.T41 1 K,A443M,H468K,Q491 E;A159F.T411 K,A443M,H468G,Q 491 K;A159F.T411 K,A443M,H468G,Q491 R;A159F.T41 1 K,A443M,H468G,Q491 E;A159F.T41 1 K,A443M,H468S,Q491 K;A159F.T411 K,A443M,H468S,Q491 R;A159F.T411 K,A443M,H468

[0071] S.Q491 E;A159F.T41 1 K,A443Y,H468R,Q491 K;A159F.T41 1 K,A443Y,H468R,Q491 R;A159F, T41 1 K,A443Y,H468R,Q491 E;A159F.T41 1 K,A443Y,H468A,Q491 K;A159F.T41 1 K,A443Y,H4 68A.Q491 R;A159F.T41 1 K,A443Y,H468A,Q491 E;A159F.T411 K,A443Y,H468K,Q491 K;A159 F.T411 K,A443Y,H468K,Q491 R;A159F.T411 K,A443Y,H468K,Q491 E;A159F.T41 1 K,A443Y,H 468G.Q491 K;A159F.T411 K,A443Y,H468G,Q491 R;A159F.T411 K,A443Y,H468G,Q491 E;A15 9F.T411 K,A443Y,H468S,Q491 K;A159F.T411 K,A443Y,H468S,Q491 R;A159F.T411 K.A443Y, H468S.Q491 E;A159F.T41 1 K,A443V,H468R,Q491 K;A159F.T41 1 K,A443V,H468R,Q491 R;A1 59F.T41 1 K,A443V,H468R,Q491 E;A159F.T411 K,A443V,H468A,Q491 K;A159F.T411 K.A443V ,H468A,Q491 R;A159F.T41 1 K,A443V,H468A,Q491 E;A159F.T411 K,A443V,H468K,Q491 K;A1 59F.T41 1 K,A443V,H468K,Q491 R;A159F.T411 K,A443V,H468K,Q491 E;A159F.T411 K.A443V ,H468G,Q491 K;A159F.T411 K,A443V,H468G,Q491 R;A159F.T41 1 K,A443V,H468G,Q491 E;A 159F.T411 K,A443V,H468S,Q491 K;A159F.T41 1 K,A443V,H468S,Q491 R;A159F.T41 1 K.A443 V,H468S,Q491 E;A159L.T411 V,A443I,H468R,Q491 K;A159L.T411 V,A443I,H468R,Q491 R;A1 59L.T411 V,A443I,H468R,Q491 E;A159L,T411 V,A443I,H468A,Q491 K;A159L.T41 1 V,A443I,H 468A.Q491 R;A159L.T411 V.A443I.H468A.Q491 E;A159L.T41 1 V,A443I,H468K,Q491 K;A159L ,T411 V,A443I,H468K,Q491 R;A159L.T411 V,A443I,H468K,Q491 E;A159L.T411 V.A443I.H468 G.Q491 K;A159L.T411 V,A443I,H468G,Q491 R;A159L.T411 V,A443I,H468G,Q491 E;A159L.T4 11 V,A443I,H468S,Q491 K;A159L.T41 1 V,A443I,H468S,Q491 R;A159L,T411 V,A443I,H468S,Q 491 E;A159L.T411 V,A443L,H468R,Q491 K;A159L.T411 V,A443L,H468R,Q491 R;A159L.T411 V,A443L,H468R,Q491 E;A159L.T411 V,A443L,H468A,Q491 K;A159L.T411 V,A443L,H468A,Q 491 R;A159L.T41 1 V,A443L,H468A,Q491 E;A159L.T411 V,A443L,H468K,Q491 K;A159L.T41 1 V,A443L,H468K,Q491 R;A159L.T411 V,A443L,H468K,Q491 E;A159L.T411 V,A443L,H468G,Q 491 K;A159L.T411 V,A443L,H468G,Q491 R;A159L.T41 1 V,A443L,H468G,Q491 E;A159L.T411 V,A443L,H468S,Q491 K;A159L.T411 V,A443L,H468S,Q491 R;A159L.T411 V,A443L,H468S,Q 491 E;A159L.T411 V,A443F,H468R,Q491 K;A159L.T411 V,A443F,H468R,Q491 R;A159L.T41 1 V,A443F,H468R,Q491 E;A159L,T41 1 V,A443F,H468A,Q491 K;A159L,T411 V,A443F,H468A,Q 491 R;A159L.T41 1 V,A443F,H468A,Q491 E;A159L.T41 1 V,A443F,H468K,Q491 K;A159L.T411 V,A443F,H468K,Q491 R;A159L,T41 1 V,A443F,H468K,Q491 E;A159L,T411 V,A443F,H468G,Q 491 K;A159L.T411 V,A443F,H468G,Q491 R;A159L.T411 V,A443F,H468G,Q491 E;A159L.T41 1 V,A443F,H468S,Q491 K;A159L.T411 V,A443F,H468S,Q491 R;A159L.T411 V,A443F,H468S,Q 491 E;A159L.T411 V,A443M,H468R,Q491 K;A159L.T411 V,A443M,H468R,Q491 R;A159L.T41

[0072] I V,A443M,H468R,Q491 E;A159L,T411 V,A443M,H468A,Q491 K;A159L.T41 1 V,A443M,H468A ,Q491 R;A159L,T41 1 V,A443M,H468A,Q491 E;A159L,T411 V,A443M,H468K,Q491 K;A159L,T4

[0073] I I V,A443M,H468K,Q491 R;A159L.T411 V,A443M,H468K,Q491 E;A159L.T41 1 V,A443M,H468 G.Q491 K;A159L.T41 1 V,A443M,H468G,Q491 R;A159L.T411 V,A443M,H468G,Q491 E;A159L, T41 1 V,A443M,H468S,Q491 K;A159L.T411 V,A443M,H468S,Q491 R;A159L.T41 1 V,A443M,H4 68S.Q491 E;A159L.T411 V,A443Y,H468R,Q491 K;A159L.T411 V,A443Y,H468R,Q491 R;A159 L.T411 V,A443Y,H468R,Q491 E;A159L.T41 1 V,A443Y,H468A,Q491 K;A159L.T41 1 V,A443Y,H 468A.Q491 R;A159L.T41 1 V,A443Y,H468A,Q491 E;A159L.T41 1 V,A443Y,H468K,Q491 K;A159 L.T411 V,A443Y,H468K,Q491 R;A159L.T41 1 V,A443Y,H468K,Q491 E;A159L.T41 1 V,A443Y,H 468G.Q491 K;A159L,T41 1 V,A443Y,H468G,Q491 R;A159L,T41 1 V,A443Y,H468G,Q491 E;A15 9L.T411 V,A443Y,H468S,Q491 K;A159L,T411 V,A443Y,H468S,Q491 R;A159L,T411 V.A443Y, H468S.Q491 E;A159L.T41 1 V,A443V,H468R,Q491 K;A159L.T411 V,A443V,H468R,Q491 R;A1 59L.T411 V,A443V,H468R,Q491 E;A159L.T411 V,A443V,H468A,Q491 K;A159L.T411 V.A443V ,H468A,Q491 R;A159L.T411 V,A443V,H468A,Q491 E;A159L.T411 V,A443V,H468K,Q491 K;A1 59L.T411 V,A443V,H468K,Q491 R;A159L.T411 V,A443V,H468K,Q491 E;A159L.T41 1 V.A443V ,H468G,Q491 K;A159L,T41 1 V,A443V,H468G,Q491 R;A159L,T411 V,A443V,H468G,Q491 E;A 159L.T41 1 V,A443V,H468S,Q491 K;A159L.T411 V,A443V,H468S,Q491 R;A159L.T41 1 V.A443 V,H468S,Q491 E;A159L.T411 S,A443I,H468R,Q491 K;A159L.T411 S,A443I,H468R,Q491 R;A1 59L.T411 S,A443I,H468R,Q491 E;A159L,T411 S,A443I,H468A,Q491 K;A159L.T41 1 S,A443I,H 468A.Q491 R;A159L.T41 1 S,A443I,H468A,Q491 E;A159L.T41 1 S,A443I,H468K,Q491 K;A159L ,T411 S,A443I,H468K,Q491 R;A159L.T411 S,A443I,H468K,Q491 E;A159L.T411 S.A443I.H468 G.Q491 K;A159L.T411 S,A443I,H468G,Q491 R;A159L.T411 S,A443I,H468G,Q491 E;A159L.T4 11 S,A443I,H468S,Q491 K;A159L.T41 1 S,A443I,H468S,Q491 R;A159L,T411 S,A443I,H468S,Q 491 E;A159L.T411 S,A443L,H468R,Q491 K;A159L.T411 S,A443L,H468R,Q491 R;A159L.T41 1 S,A443L,H468R,Q491 E;A159L.T411 S,A443L,H468A,Q491 K;A159L.T411 S,A443L,H468A,Q 491 R;A159L.T41 1 S,A443L,H468A,Q491 E;A159L.T411 S,A443L,H468K,Q491 K;A159L.T41 1 S,A443L,H468K,Q491 R;A159L.T411 S,A443L,H468K,Q491 E;A159L.T411 S,A443L,H468G,Q 491 K;A159L.T411 S,A443L,H468G,Q491 R;A159L.T41 1 S,A443L,H468G,Q491 E;A159L.T411 S,A443L,H468S,Q491 K;A159L.T411 S,A443L,H468S,Q491 R;A159L.T411 S,A443L,H468S,Q 491 E;A159L.T411 S,A443F,H468R,Q491 K;A159L.T411 S,A443F,H468R,Q491 R;A159L.T41 1 S,A443F,H468R,Q491 E;A159L.T41 1 S,A443F,H468A,Q491 K;A159L.T411 S,A443F,H468A,Q 491 R;A159L.T41 1 S,A443F,H468A,Q491 E;A159L.T41 1 S,A443F,H468K,Q491 K;A159L.T411 S,A443F,H468K,Q491 R;A159L.T41 1 S,A443F,H468K,Q491 E;A159L.T411 S,A443F,H468G,Q 491 K;A159L.T411 S,A443F,H468G,Q491 R;A159L.T411 S,A443F,H468G,Q491 E;A159L.T411 S,A443F,H468S,Q491 K;A159L.T411 S,A443F,H468S,Q491 R;A159L.T411 S,A443F,H468S,Q 491 E;A159L.T411 S,A443M,H468R,Q491 K;A159L.T411 S,A443M,H468R,Q491 R;A159L.T41

[0074] I S,A443M,H468R,Q491 E;A159L.T411 S,A443M,H468A,Q491 K;A159L.T41 1 S,A443M,H468A ,Q491 R;A159L.T41 1 S,A443M,H468A,Q491 E;A159L.T411 S,A443M,H468K,Q491 K;A159L.T4

[0075] I I S,A443M,H468K,Q491 R;A159L.T411 S,A443M,H468K,Q491 E;A159L.T41 1 S,A443M,H468 G.Q491 K;A159L.T41 1 S,A443M,H468G,Q491 R;A159L.T411 S,A443M,H468G,Q491 E;A159L, T41 1 S,A443M,H468S,Q491 K;A159L.T411 S,A443M,H468S,Q491 R;A159L.T41 1 S,A443M,H4 68S.Q491 E;A159L.T411 S,A443Y,H468R,Q491 K;A159L.T411 S,A443Y,H468R,Q491 R;A159 L.T411 S,A443Y,H468R,Q491 E;A159L.T41 1 S,A443Y,H468A,Q491 K;A159L.T41 1 S,A443Y,H 468A.Q491 R;A159L.T41 1 S,A443Y,H468A,Q491 E;A159L.T41 1 S,A443Y,H468K,Q491 K;A159 L.T411 S,A443Y,H468K,Q491 R;A159L.T41 1 S,A443Y,H468K,Q491 E;A159L.T41 1 S,A443Y,H 468G.Q491 K;A159L.T41 1 S,A443Y,H468G,Q491 R;A159L.T41 1 S,A443Y,H468G,Q491 E;A15 9L.T411 S,A443Y,H468S,Q491 K;A159L.T411 S,A443Y,H468S,Q491 R;A159L.T411 S.A443Y, H468S.Q491 E;A159L.T411 S,A443V,H468R,Q491 K;A159L.T411 S,A443V,H468R,Q491 R;A1 59L.T411 S,A443V,H468R,Q491 E;A159L.T411 S,A443V,H468A,Q491 K;A159L.T41 1 S.A443V ,H468A,Q491 R;A159L.T411 S,A443V,H468A,Q491 E;A159L.T411 S,A443V,H468K,Q491 K;A1 59L.T411 S,A443V,H468K,Q491 R;A159L.T411 S,A443V,H468K,Q491 E;A159L.T411 S.A443V ,H468G,Q491 K;A159L.T41 1 S,A443V,H468G,Q491 R;A159L.T411 S,A443V,H468G,Q491 E;A 159L.T41 1 S,A443V,H468S,Q491 K;A159L.T41 1 S,A443V,H468S,Q491 R;A159L.T41 1 S.A443 V,H468S,Q491 E;A159L.T411 A,A443I,H468R,Q491 K;A159L.T411 A,A443I,H468R,Q491 R;A1 59L.T411 A,A443I,H468R,Q491 E;A159L.T411 A,A443I,H468A,Q491 K;A159L.T41 1 A.A443I.H 468A.Q491 R;A159L.T41 1 A,A443I,H468A,Q491 E;A159L.T41 1 A,A443I,H468K,Q491 K;A159L ,T411A,A443I,H468K,Q491 R;A159L,T411A,A443I,H468K,Q491 E;A159L,T411A,A443I,H468 G,Q491 K;A159L,T411A,A443I,H468G,Q491 R;A159L,T411A,A443I,H468G,Q491 E;A159L,T4 11 A,A443I,H468S,Q491 K;A159L.T41 1 A,A443I,H468S,Q491 R;A159L.T411 A,A443I,H468S,Q 491 E;A159L.T411 A,A443L,H468R,Q491 K;A159L.T411 A,A443L,H468R,Q491 R;A159L.T411 A,A443L,H468R,Q491 E;A159L,T411A,A443L,H468A,Q491 K;A159L,T411A,A443L,H468A,Q 491 R;A159L.T41 1 A,A443L,H468A,Q491 E;A159L.T411 A,A443L,H468K,Q491 K;A159L.T41 1 A,A443L,H468K,Q491 R;A159L,T411A,A443L,H468K,Q491 E;A159L,T411A,A443L,H468G,Q 491 K;A159L.T411 A,A443L,H468G,Q491 R;A159L.T41 1 A,A443L,H468G,Q491 E;A159L.T411 A,A443L,H468S,Q491 K;A159L.T411 A,A443L,H468S,Q491 R;A159L.T411 A,A443L,H468S,Q 491 E;A159L.T411 A,A443F,H468R,Q491 K;A159L.T411 A,A443F,H468R,Q491 R;A159L.T41 1 A,A443F,H468R,Q491 E;A159L,T41 1 A,A443F,H468A,Q491 K;A159L,T411 A,A443F,H468A,Q 491 R;A159L.T41 1 A,A443F,H468A,Q491 E;A159L.T41 1 A,A443F,H468K,Q491 K;A159L.T411 A,A443F,H468K,Q491 R;A159L,T41 1 A,A443F,H468K,Q491 E;A159L,T411 A,A443F,H468G,Q 491 K;A159L.T411 A,A443F,H468G,Q491 R;A159L.T411 A,A443F,H468G,Q491 E;A159L.T411 A,A443F,H468S,Q491 K;A159L.T411 A,A443F,H468S,Q491 R;A159L.T411 A,A443F,H468S,Q 491 E;A159L.T411 A,A443M,H468R,Q491 K;A159L.T411 A,A443M,H468R,Q491 R;A159L.T41

[0076] I A,A443M,H468R,Q491 E;A159L,T411 A,A443M,H468A,Q491 K;A159L.T41 1 A,A443M,H468A ,Q491 R;A159L,T41 1 A,A443M,H468A,Q491 E;A159L,T411 A,A443M,H468K,Q491 K;A159L,T4

[0077] I I A,A443M,H468K,Q491 R;A159L,T411 A,A443M,H468K,Q491 E;A159L,T41 1 A,A443M,H468 G.Q491 K;A159L,T41 1 A,A443M,H468G,Q491 R;A159L,T411 A,A443M,H468G,Q491 E;A159L, T41 1 A,A443M,H468S,Q491 K;A159L,T411 A,A443M,H468S,Q491 R;A159L.T41 1 A,A443M,H4 68S.Q491 E;A159L.T411 A,A443Y,H468R,Q491 K;A159L.T411 A,A443Y,H468R,Q491 R;A159 L.T411 A,A443Y,H468R,Q491 E;A159L.T41 1 A,A443Y,H468A,Q491 K;A159L.T41 1 A,A443Y,H 468A.Q491 R;A159L,T41 1 A,A443Y,H468A,Q491 E;A159L,T41 1 A,A443Y,H468K,Q491 K;A159 L.T411 A,A443Y,H468K,Q491 R;A159L.T41 1 A,A443Y,H468K,Q491 E;A159L.T41 1 A,A443Y,H 468G.Q491 K;A159L.T41 1 A,A443Y,H468G,Q491 R;A159L.T411 A,A443Y,H468G,Q491 E;A15 9L.T411 A,A443Y,H468S,Q491 K;A159L,T411 A,A443Y,H468S,Q491 R;A159L,T411 A.A443Y, H468S.Q491 E;A159L.T41 1 A,A443V,H468R,Q491 K;A159L.T411 A,A443V,H468R,Q491 R;A1 59L.T411 A,A443V,H468R,Q491 E;A159L.T411 A,A443V,H468A,Q491 K;A159L.T411 A.A443V ,H468A,Q491 R;A159L.T411 A,A443V,H468A,Q491 E;A159L,T411 A,A443V,H468K,Q491 K;A1 59L.T411 A,A443V,H468K,Q491 R;A159L.T411 A,A443V,H468K,Q491 E;A159L.T41 1 A.A443V ,H468G,Q491 K;A159L,T41 1 A,A443V,H468G,Q491 R;A159L,T411 A,A443V,H468G,Q491 E;A 159L.T41 1 A,A443V,H468S,Q491 K;A159L,T411 A,A443V,H468S,Q491 R;A159L,T41 1 A.A443 V,H468S,Q491 E;A159L.T411 Q,A443I,H468R,Q491 K;A159L.T411 Q,A443I,H468R,Q491 R;A 159L.T41 1 Q,A443I,H468R,Q491 E;A159L.T41 1 Q,A443I,H468A,Q491 K;A159L.T411 Q.A443I, H468A.Q491 R;A159L.T41 1 Q,A443I,H468A,Q491 E;A159L.T411 Q,A443I,H468K,Q491 K;A15 9L.T411 Q,A443I,H468K,Q491 R;A159L.T411 Q,A443I,H468K,Q491 E;A159L.T411 Q,A443I,H4 68G.Q491 K;A159L.T41 1 Q,A443I,H468G,Q491 R;A159L.T411 Q,A443I,H468G,Q491 E;A159L ,T411 Q,A443I,H468S,Q491 K;A159L.T411 Q,A443I,H468S,Q491 R;A159L.T411 Q,A443I,H468 S.Q491 E;A159L.T411 Q,A443L,H468R,Q491 K;A159L.T411 Q,A443L,H468R,Q491 R;A159L,T 411 Q,A443L,H468R,Q491 E;A159L.T411 Q,A443L,H468A,Q491 K;A159L.T411 Q,A443L,H468 A.Q491 R;A159L.T411 Q,A443L,H468A,Q491 E;A159L.T411 Q,A443L,H468K,Q491 K;A159L,T 411 Q,A443L,H468K,Q491 R;A159L.T411 Q,A443L,H468K,Q491 E;A159L.T411 Q,A443L,H468 G.Q491 K;A159L.T41 1 Q,A443L,H468G,Q491 R;A159L.T411 Q,A443L,H468G,Q491 E;A159L, T41 1 Q,A443L,H468S,Q491 K;A159L.T411 Q,A443L,H468S,Q491 R;A159L.T41 1 Q,A443L,H46 8S.Q491 E;A159L.T41 1 Q,A443F,H468R,Q491 K;A159L.T41 1 Q,A443F,H468R,Q491 R;A159L, T41 1 Q,A443F,H468R,Q491 E;A159L.T41 1 Q,A443F,H468A,Q491 K;A159L.T41 1 Q,A443F,H4 68A.Q491 R;A159L.T411 Q,A443F,H468A,Q491 E;A159L.T411 Q,A443F,H468K,Q491 K;A159 L.T411 Q,A443F,H468K,Q491 R;A159L.T411 Q,A443F,H468K,Q491 E;A159L.T41 1 Q,A443F,H 468G.Q491 K;A159L.T41 1 Q,A443F,H468G,Q491 R;A159L.T411 Q,A443F,H468G,Q491 E;A15 9L.T411 Q,A443F,H468S,Q491 K;A159L.T411 Q,A443F,H468S,Q491 R;A159L.T41 1 Q.A443F, H468S.Q491 E;A159L.T411 Q,A443M,H468R,Q491 K;A159L.T411 Q,A443M,H468R,Q491 R;A 159L.T41 1 Q,A443M,H468R,Q491 E;A159L.T41 1 Q,A443M,H468A,Q491 K;A159L.T411 Q,A44 3M,H468A,Q491 R;A159L.T41 1 Q,A443M,H468A,Q491 E;A159L.T41 1 Q,A443M,H468K,Q491 K;A159L.T411 Q,A443M,H468K,Q491 R;A159L.T411 Q,A443M,H468K,Q491 E;A159L.T411 Q, A443M,H468G,Q491 K;A159L.T41 1 Q,A443M,H468G,Q491 R;A159L.T41 1 Q,A443M,H468G, Q491 E;A159L.T41 1 Q,A443M,H468S,Q491 K;A159L.T41 1 Q,A443M,H468S,Q491 R;A159L.T4 11 Q,A443M,H468S,Q491 E;A159L.T41 1 Q,A443Y,H468R,Q491 K;A159L.T411 Q,A443Y,H468 R.Q491 R;A159L.T411 Q,A443Y,H468R,Q491 E;A159L.T411 Q,A443Y,H468A,Q491 K;A159L, T41 1 Q,A443Y,H468A,Q491 R;A159L.T411 Q,A443Y,H468A,Q491 E;A159L.T411 Q,A443Y,H4 68K.Q491 K;A159L.T411 Q,A443Y,H468K,Q491 R;A159L.T411 Q,A443Y,H468K,Q491 E;A159 L.T411 Q,A443Y,H468G,Q491 K;A159L.T41 1 Q,A443Y,H468G,Q491 R;A159L.T411 Q.A443Y, H468G.Q491 E;A159L.T411 Q,A443Y,H468S,Q491 K;A159L.T411 Q,A443Y,H468S,Q491 R;A1 59L.T411 Q,A443Y,H468S,Q491 E;A159L.T411 Q,A443V,H468R,Q491 K;A159L.T41 1 Q.A443 V,H468R,Q491 R;A159L.T41 1 Q,A443V,H468R,Q491 E;A159L.T411 Q,A443V,H468A,Q491 K; A159L.T41 1 Q,A443V,H468A,Q491 R;A159L.T41 1 Q,A443V,H468A,Q491 E;A159L.T41 1 Q,A4 43V,H468K,Q491 K;A159L.T41 1 Q,A443V,H468K,Q491 R;A159L.T411 Q,A443V,H468K,Q491 E;A159L.T411 Q,A443V,H468G,Q491 K;A159L.T411 Q,A443V,H468G,Q491 R;A159L.T411 Q, A443V,H468G,Q491 E;A159L.T41 1 Q,A443V,H468S,Q491 K;A159L.T41 1 Q,A443V,H468S,Q4 91 R;A159L.T411 Q,A443V,H468S,Q491 E;A159L.T41 1 E,A443I,H468R,Q491 K;A159L.T41 1 E, A443I.H468R.Q491 R;A159L.T411 E,A443I,H468R,Q491 E;A159L.T41 1 E,A443I,H468A,Q491 K;A159L.T411 E,A443I,H468A,Q491 R;A159L.T411 E,A443I,H468A,Q491 E;A159L.T411 E,A44 3I.H468K.Q491 K;A159L.T411 E,A443I,H468K,Q491 R;A159L.T411 E,A443I,H468K,Q491 E;A1 59L.T411 E,A443I,H468G,Q491 K;A159L.T41 1 E,A443I,H468G,Q491 R;A159L.T411 E.A443I.H 468G.Q491 E;A159L.T41 1 E,A443I,H468S,Q491 K;A159L.T411 E,A443I,H468S,Q491 R;A159L ,T411 E,A443I,H468S,Q491 E;A159L.T41 1 E,A443L,H468R,Q491 K;A159L.T411 E,A443L,H46 8R.Q491 R;A159L.T411 E,A443L,H468R,Q491 E;A159L.T411 E,A443L,H468A,Q491 K;A159L, T41 1 E,A443L,H468A,Q491 R;A159L.T411 E,A443L,H468A,Q491 E;A159L.T411 E,A443L,H46 8K.Q491 K;A159L.T41 1 E,A443L,H468K,Q491 R;A159L.T41 1 E,A443L,H468K,Q491 E;A159L, T41 1 E,A443L,H468G,Q491 K;A159L.T411 E,A443L,H468G,Q491 R;A159L.T41 1 E,A443L,H46 8G.Q491 E;A159L.T411 E,A443L,H468S,Q491 K;A159L.T411 E,A443L,H468S,Q491 R;A159L, T41 1 E,A443L,H468S,Q491 E;A159L.T411 E,A443F,H468R,Q491 K;A159L.T41 1 E,A443F,H46 8R.Q491 R;A159L.T411 E,A443F,H468R,Q491 E;A159L.T41 1 E,A443F,H468A,Q491 K;A159L, T41 1 E,A443F,H468A,Q491 R;A159L.T411 E,A443F,H468A,Q491 E;A159L.T411 E,A443F,H46 8K.Q491 K;A159L.T41 1 E,A443F,H468K,Q491 R;A159L.T411 E,A443F,H468K,Q491 E;A159L, T41 1 E,A443F,H468G,Q491 K;A159L.T41 1 E,A443F,H468G,Q491 R;A159L.T411 E,A443F,H4 68G.Q491 E;A159L.T41 1 E,A443F,H468S,Q491 K;A159L.T411 E,A443F,H468S,Q491 R;A159L ,T411 E,A443F,H468S,Q491 E;A159L.T411 E,A443M,H468R,Q491 K;A159L.T411 E,A443M,H4 68R.Q491 R;A159L.T41 1 E,A443M,H468R,Q491 E;A159L.T411 E,A443M,H468A,Q491 K;A159

[0078] L.T411 E,A443M,H468A,Q491 R;A159L.T411 E,A443M,H468A,Q491 E;A159L.T411 E.A443M, H468K.Q491 K;A159L.T411 E,A443M,H468K,Q491 R;A159L.T411 E,A443M,H468K,Q491 E;A1 59L.T411 E,A443M,H468G,Q491 K;A159L.T411 E,A443M,H468G,Q491 R;A159L.T41 1 E.A443

[0079] M,H468G,Q491 E;A159L.T41 1 E,A443M,H468S,Q491 K;A159L.T411 E,A443M,H468S,Q491 R; A159L.T41 1 E,A443M,H468S,Q491 E;A159L.T411 E,A443Y,H468R,Q491 K;A159L.T41 1 E,A44 3Y,H468R,Q491 R;A159L.T411 E,A443Y,H468R,Q491 E;A159L.T411 E,A443Y,H468A,Q491 K; A159L.T41 1 E,A443Y,H468A,Q491 R;A159L.T411 E,A443Y,H468A,Q491 E;A159L.T411 E,A44 3Y,H468K,Q491 K;A159L.T41 1 E,A443Y,H468K,Q491 R;A159L.T411 E,A443Y,H468K,Q491 E; A159L.T41 1 E,A443Y,H468G,Q491 K;A159L.T41 1 E,A443Y,H468G,Q491 R;A159L.T411 E,A4 43Y,H468G,Q491 E;A159L.T411 E,A443Y,H468S,Q491 K;A159L.T41 1 E,A443Y,H468S,Q491 R;A159L.T411 E,A443Y,H468S,Q491 E;A159L.T411 E,A443V,H468R,Q491 K;A159L.T411 E,A 443V,H468R,Q491 R;A159L.T41 1 E,A443V,H468R,Q491 E;A159L.T411 E,A443V,H468A,Q49 1 K;A159L.T411 E,A443V,H468A,Q491 R;A159L.T411 E,A443V,H468A,Q491 E;A159L.T411 E, A443V,H468K,Q491 K;A159L.T411 E,A443V,H468K,Q491 R;A159L.T411 E,A443V,H468K,Q4 91 E;A159L.T41 1 E,A443V,H468G,Q491 K;A159L.T41 1 E,A443V,H468G,Q491 R;A159L.T411 E,A443V,H468G,Q491 E;A159L.T411 E,A443V,H468S,Q491 K;A159L.T41 1 E,A443V,H468S, Q491 R;A159L.T411 E,A443V,H468S,Q491 E;A159L.T411 K,A443I,H468R,Q491 K;A159L.T41 1 K,A443I,H468R,Q491 R;A159L.T411 K,A443I,H468R,Q491 E;A159L.T41 1 K,A443I,H468A,Q 491 K;A159L.T411 K,A443I,H468A,Q491 R;A159L.T411 K,A443I,H468A,Q491 E;A159L.T41 1 K, A443I.H468K.Q491 K;A159L.T411 K,A443I,H468K,Q491 R;A159L.T411 K,A443I,H468K,Q491 E;A159L.T411 K,A443I,H468G,Q491 K;A159L.T411 K,A443I,H468G,Q491 R;A159L.T41 1 K,A4 43I.H468G.Q491 E;A159L.T411 K,A443I,H468S,Q491 K;A159L.T411 K,A443I,H468S,Q491 R;

[0080] A159L.T41 1 K.A443I.H468S.Q491 E;A159L.T411 K,A443L,H468R,Q491 K;A159L.T41 1 K.A443 L,H468R,Q491 R;A159L.T411 K,A443L,H468R,Q491 E;A159L.T411 K,A443L,H468A,Q491 K;A 159L.T41 1 K,A443L,H468A,Q491 R;A159L.T41 1 K,A443L,H468A,Q491 E;A159L.T411 K.A443 L,H468K,Q491 K;A159L.T41 1 K,A443L,H468K,Q491 R;A159L.T411 K,A443L,H468K,Q491 E;A 159L.T41 1 K,A443L,H468G,Q491 K;A159L.T411 K,A443L,H468G,Q491 R;A159L.T41 1 K.A443

[0081] L,H468G,Q491 E;A159L.T411 K,A443L,H468S,Q491 K;A159L.T41 1 K,A443L,H468S,Q491 R;A 159L.T41 1 K,A443L,H468S,Q491 E;A159L.T41 1 K,A443F,H468R,Q491 K;A159L.T411 K.A443 F,H468R,Q491 R;A159L.T411 K,A443F,H468R,Q491 E;A159L.T41 1 K,A443F,H468A,Q491 K;A 159L.T41 1 K,A443F,H468A,Q491 R;A159L.T41 1 K,A443F,H468A,Q491 E;A159L.T411 K.A443 F,H468K,Q491 K;A159L.T41 1 K,A443F,H468K,Q491 R;A159L.T411 K,A443F,H468K,Q491 E;A 159L.T41 1 K,A443F,H468G,Q491 K;A159L.T411 K,A443F,H468G,Q491 R;A159L.T411 K.A443 F,H468G,Q491 E;A159L.T411 K,A443F,H468S,Q491 K;A159L.T411 K,A443F,H468S,Q491 R;A 159L.T41 1 K,A443F,H468S,Q491 E;A159L.T411 K,A443M,H468R,Q491 K;A159L.T411 K.A443

[0082] M,H468R,Q491 R;A159L.T411 K,A443M,H468R,Q491 E;A159L.T411 K,A443M,H468A,Q491 K; A159L.T41 1 K,A443M,H468A,Q491 R;A159L.T411 K,A443M,H468A,Q491 E;A159L.T41 1 K,A4 43M,H468K,Q491 K;A159L.T411 K,A443M,H468K,Q491 R;A159L.T41 1 K,A443M,H468K,Q491 E;A159L.T411 K,A443M,H468G,Q491 K;A159L.T411 K,A443M,H468G,Q491 R;A159L.T411 K, A443M,H468G,Q491 E;A159L.T41 1 K,A443M,H468S,Q491 K;A159L.T41 1 K,A443M,H468S,Q 491 R;A159L.T411 K,A443M,H468S,Q491 E;A159L.T411 K,A443Y,H468R,Q491 K;A159L.T411 K,A443Y,H468R,Q491 R;A159L.T411 K,A443Y,H468R,Q491 E;A159L.T411 K,A443Y,H468A, Q491 K;A159L.T411 K,A443Y,H468A,Q491 R;A159L.T411 K,A443Y,H468A,Q491 E;A159L.T41

[0083] I K,A443Y,H468K,Q491 K;A159L.T411 K,A443Y,H468K,Q491 R;A159L.T411 K,A443Y,H468K, Q491 E;A159L.T411 K,A443Y,H468G,Q491 K;A159L.T411 K,A443Y,H468G,Q491 R;A159L.T4

[0084] I I K,A443Y,H468G,Q491 E;A159L.T411 K,A443Y,H468S,Q491 K;A159L.T411 K,A443Y,H468 S.Q491 R;A159L.T411 K,A443Y,H468S,Q491 E;A159L.T411 K,A443V,H468R,Q491 K;A159L,T 411 K,A443V,H468R,Q491 R;A159L.T411 K,A443V,H468R,Q491 E;A159L.T411 K,A443V,H46 8A.Q491 K;A159L.T41 1 K,A443V,H468A,Q491 R;A159L.T411 K,A443V,H468A,Q491 E;A159L, T41 1 K,A443V,H468K,Q491 K;A159L.T41 1 K,A443V,H468K,Q491 R;A159L.T41 1 K,A443V,H46 8K.Q491 E;A159L.T41 1 K,A443V,H468G,Q491 K;A159L.T41 1 K,A443V,H468G,Q491 R;A159L, T41 1 K,A443V,H468G,Q491 E;A159L.T411 K,A443V,H468S,Q491 K;A159L.T411 K,A443V,H4 68S.Q491 R;A159L.T411 K,A443V,H468S,Q491 E;A159K.T411 V,A443I,H468R,Q491 K;A159K ,T411 V,A443I,H468R,Q491 R;A159K.T411 V,A443I,H468R,Q491 E;A159K.T411 V.A443I.H468 A.Q491 K;A159K.T411 V,A443I,H468A,Q491 R;A159K.T411 V,A443I,H468A,Q491 E;A159K.T4 11 V,A443I,H468K,Q491 K;A159K,T411 V,A443I,H468K,Q491 R;A159K,T41 1 V,A443I,H468K, Q491 E;A159K.T411 V,A443I,H468G,Q491 K;A159K.T411 V,A443I,H468G,Q491 R;A159K.T41

[0085] I V,A443I,H468G,Q491 E;A159K.T411 V,A443I,H468S,Q491 K;A159K.T41 1 V,A443I,H468S,Q 491 R;A159K.T411 V,A443I,H468S,Q491 E;A159K.T411 V,A443L,H468R,Q491 K;A159K.T41 1 V,A443L,H468R,Q491 R;A159K.T411 V,A443L,H468R,Q491 E;A159K.T41 1 V,A443L,H468A,Q 491 K;A159K.T411 V,A443L,H468A,Q491 R;A159K.T41 1 V,A443L,H468A,Q491 E;A159K.T411 V,A443L,H468K,Q491 K;A159K.T411 V,A443L,H468K,Q491 R;A159K.T411 V,A443L,H468K,Q 491 E;A159K.T411 V,A443L,H468G,Q491 K;A159K.T411 V,A443L,H468G,Q491 R;A159K.T41 1V,A443L,H468G,Q491 E;A159K,T411V,A443L,H468S,Q491 K;A159K,T411 V,A443L,H468S, Q491 R;A159K.T41 1 V,A443L,H468S,Q491 E;A159K.T411 V,A443F,H468R,Q491 K;A159K.T4

[0086] I I V,A443F,H468R,Q491 R;A159K.T411 V,A443F,H468R,Q491 E;A159K.T411 V,A443F,H468 A.Q491 K;A159K.T411 V,A443F,H468A,Q491 R;A159K.T41 1 V,A443F,H468A,Q491 E;A159K,T 411 V,A443F,H468K,Q491 K;A159K,T411 V,A443F,H468K,Q491 R;A159K,T41 1 V,A443F,H468 K.Q491 E;A159K.T411 V,A443F,H468G,Q491 K;A159K.T411 V,A443F,H468G,Q491 R;A159K, T41 1 V,A443F,H468G,Q491 E;A159K.T411 V,A443F,H468S,Q491 K;A159K.T411 V,A443F,H4 68S.Q491 R;A159K.T411 V,A443F,H468S,Q491 E;A159K.T411 V,A443M,H468R,Q491 K;A159 K.T411 V,A443M,H468R,Q491 R;A159K.T411 V,A443M,H468R,Q491 E;A159K.T411 V.A443M, H468A.Q491 K;A159K.T411 V,A443M,H468A,Q491 R;A159K.T411 V,A443M,H468A,Q491 E;A 159K.T411 V,A443M,H468K,Q491 K;A159K.T411 V,A443M,H468K,Q491 R;A159K.T41 1 V,A44 3M,H468K,Q491 E;A159K.T411 V,A443M,H468G,Q491 K;A159K.T41 1 V,A443M,H468G,Q491 R;A159K.T411 V,A443M,H468G,Q491 E;A159K.T411 V,A443M,H468S,Q491 K;A159K.T411 V, A443M,H468S,Q491 R;A159K,T411V,A443M,H468S,Q491 E;A159K,T411V,A443Y,H468R,Q 491 K;A159K.T411 V,A443Y,H468R,Q491 R;A159K.T41 1 V,A443Y,H468R,Q491 E;A159K.T41

[0087] IV,A443Y,H468A,Q491 K;A159K,T411V,A443Y,H468A,Q491 R;A159K,T411V,A443Y,H468A, Q491 E;A159K.T411 V,A443Y,H468K,Q491 K;A159K.T411 V,A443Y,H468K,Q491 R;A159K.T4 11 V,A443Y,H468K,Q491 E;A159K.T411 V,A443Y,H468G,Q491 K;A159K.T411 V,A443Y,H468 G.Q491 R;A159K.T411 V,A443Y,H468G,Q491 E;A159K.T41 1 V,A443Y,H468S,Q491 K;A159K, T41 1 V,A443Y,H468S,Q491 R;A159K.T41 1 V,A443Y,H468S,Q491 E;A159K.T411 V,A443V,H4 68R.Q491 K;A159K.T411 V,A443V,H468R,Q491 R;A159K.T41 1 V,A443V,H468R,Q491 E;A159 K.T411 V,A443V,H468A,Q491 K;A159K,T41 1 V,A443V,H468A,Q491 R;A159K,T411 V.A443V, H468A.Q491 E;A159K.T411 V,A443V,H468K,Q491 K;A159K.T411 V,A443V,H468K,Q491 R;A1 59K.T411 V,A443V,H468K,Q491 E;A159K.T411 V,A443V,H468G,Q491 K;A159K.T41 1 V.A443

[0088] V,H468G,Q491 R;A159K.T41 1 V,A443V,H468G,Q491 E;A159K.T411 V,A443V,H468S,Q491 K; A159K.T411 V,A443V,H468S,Q491 R;A159K.T411 V,A443V,H468S,Q491 E;A159K.T411 S,A4 43I.H468R.Q491 K;A159K.T411 S,A443I,H468R,Q491 R;A159K.T411 S,A443I,H468R,Q491 E;

[0089] A159K.T411 S,A443I,H468A,Q491 K;A159K.T411 S,A443I,H468A,Q491 R;A159K.T41 1 S.A443 I,H468A,Q491 E;A159K.T411 S,A443I,H468K,Q491 K;A159K.T411 S,A443I,H468K,Q491 R;A1 59K.T411 S,A443I,H468K,Q491 E;A159K.T411 S,A443I,H468G,Q491 K;A159K.T411 S.A443I, H468G.Q491 R;A159K.T411 S,A443I,H468G,Q491 E;A159K.T41 1 S,A443I,H468S,Q491 K;A15 9K.T41 1 S,A443I,H468S,Q491 R;A159K.T411 S,A443I,H468S,Q491 E;A159K.T41 1 S,A443L,H 468R.Q491 K;A159K.T41 1 S,A443L,H468R,Q491 R;A159K.T41 1 S,A443L,H468R,Q491 E;A15 9K.T41 1 S,A443L,H468A,Q491 K;A159K.T411 S,A443L,H468A,Q491 R;A159K.T411 S.A443L, H468A.Q491 E;A159K.T411 S,A443L,H468K,Q491 K;A159K.T411 S,A443L,H468K,Q491 R;A1 59K.T411 S,A443L,H468K,Q491 E;A159K.T411 S,A443L,H468G,Q491 K;A159K.T411 S.A443L ,H468G,Q491 R;A159K.T411 S,A443L,H468G,Q491 E;A159K.T411 S,A443L,H468S,Q491 K;A 159K.T411 S,A443L,H468S,Q491 R;A159K.T41 1 S,A443L,H468S,Q491 E;A159K.T411 S.A443 F,H468R,Q491 K;A159K.T41 1 S,A443F,H468R,Q491 R;A159K.T411 S,A443F,H468R,Q491 E; A159K.T411 S,A443F,H468A,Q491 K;A159K.T41 1 S,A443F,H468A,Q491 R;A159K.T41 1 S,A4 43F,H468A,Q491 E;A159K.T411 S,A443F,H468K,Q491 K;A159K.T411 S,A443F,H468K,Q491 R;A159K.T411 S,A443F,H468K,Q491 E;A159K.T41 1 S,A443F,H468G,Q491 K;A159K.T411 S,A 443F,H468G,Q491 R;A159K.T411 S,A443F,H468G,Q491 E;A159K.T411 S,A443F,H468S,Q49 1 K;A159K.T411 S,A443F,H468S,Q491 R;A159K.T411 S,A443F,H468S,Q491 E;A159K.T411 S, A443M,H468R,Q491 K;A159K.T411 S,A443M,H468R,Q491 R;A159K.T41 1 S,A443M,H468R,Q 491 E;A159K.T411 S,A443M,H468A,Q491 K;A159K.T41 1 S,A443M,H468A,Q491 R;A159K.T41

[0090] I S,A443M,H468A,Q491 E;A159K.T411 S,A443M,H468K,Q491 K;A159K.T411 S,A443M,H468 K.Q491 R;A159K.T411 S,A443M,H468K,Q491 E;A159K.T411 S,A443M,H468G,Q491 K;A159K, T41 1 S,A443M,H468G,Q491 R;A159K.T41 1 S,A443M,H468G,Q491 E;A159K.T411 S,A443M,H 468S.Q491 K;A159K.T411 S,A443M,H468S,Q491 R;A159K.T411 S,A443M,H468S,Q491 E;A15 9K.T41 1 S,A443Y,H468R,Q491 K;A159K.T41 1 S,A443Y,H468R,Q491 R;A159K.T41 1 S.A443Y, H468R.Q491 E;A159K.T41 1 S,A443Y,H468A,Q491 K;A159K.T411 S,A443Y,H468A,Q491 R;A1 59K.T411 S,A443Y,H468A,Q491 E;A159K.T411 S,A443Y,H468K,Q491 K;A159K.T411 S.A443 Y,H468K,Q491 R;A159K.T411 S,A443Y,H468K,Q491 E;A159K.T411 S,A443Y,H468G,Q491 K; A159K.T411 S,A443Y,H468G,Q491 R;A159K.T411 S,A443Y,H468G,Q491 E;A159K.T411 S,A4 43Y,H468S,Q491 K;A159K.T411 S,A443Y,H468S,Q491 R;A159K.T411 S,A443Y,H468S,Q491 E;A159K.T411 S,A443V,H468R,Q491 K;A159K.T411 S,A443V,H468R,Q491 R;A159K.T41 1 S, A443V,H468R,Q491 E;A159K.T411 S,A443V,H468A,Q491 K;A159K.T411 S,A443V,H468A,Q4 91 R;A159K.T411 S,A443V,H468A,Q491 E;A159K.T411 S,A443V,H468K,Q491 K;A159K.T411 S,A443V,H468K,Q491 R;A159K.T411 S,A443V,H468K,Q491 E;A159K.T41 1 S,A443V,H468G, Q491 K;A159K.T411 S,A443V,H468G,Q491 R;A159K.T41 1 S,A443V,H468G,Q491 E;A159K.T4

[0091] I I S,A443V,H468S,Q491 K;A159K.T411 S,A443V,H468S,Q491 R;A159K.T411 S,A443V,H468 S.Q491 E;A159K.T411 A,A443I,H468R,Q491 K;A159K.T41 1 A,A443I,H468R,Q491 R;A159K.T4 11 A,A443I,H468R,Q491 E;A159K,T411 A,A443I,H468A,Q491 K;A159K,T41 1 A,A443I,H468A, Q491 R;A159K,T41 1 A,A443I,H468A,Q491 E;A159K,T411 A,A443I,H468K,Q491 K;A159K.T41 I A,A443I,H468K,Q491 R;A159K,T411 A,A443I,H468K,Q491 E;A159K,T41 1 A,A443I,H468G,Q 491 K;A159K.T411 A,A443I,H468G,Q491 R;A159K.T41 1 A,A443I,H468G,Q491 E;A159K.T411 A,A443I,H468S,Q491 K;A159K,T411A,A443I,H468S,Q491 R;A159K,T411A,A443I,H468S,Q4 91 E;A159K.T411 A,A443L,H468R,Q491 K;A159K.T411 A,A443L,H468R,Q491 R;A159K.T411 A,A443L,H468R,Q491 E;A159K.T411 A,A443L,H468A,Q491 K;A159K.T411 A,A443L,H468A,Q 491 R;A159K.T411 A,A443L,H468A,Q491 E;A159K.T411 A,A443L,H468K,Q491 K;A159K.T411 A,A443L,H468K,Q491 R;A159K.T41 1 A,A443L,H468K,Q491 E;A159K.T41 1 A,A443L,H468G,Q 491 K;A159K.T411 A,A443L,H468G,Q491 R;A159K.T411 A,A443L,H468G,Q491 E;A159K.T41 1A,A443L,H468S,Q491 K;A159K,T411A,A443L,H468S,Q491 R;A159K,T411A,A443L,H468S, Q491 E;A159K.T411 A,A443F,H468R,Q491 K;A159K.T41 1 A,A443F,H468R,Q491 R;A159K.T4

[0092] I I A,A443F,H468R,Q491 E;A159K,T41 1 A,A443F,H468A,Q491 K;A159K,T411 A,A443F,H468 A.Q491 R;A159K.T411 A,A443F,H468A,Q491 E;A159K.T41 1 A,A443F,H468K,Q491 K;A159K,T 411 A,A443F,H468K,Q491 R;A159K.T411 A,A443F,H468K,Q491 E;A159K.T41 1 A,A443F,H468 G.Q491 K;A159K.T411 A,A443F,H468G,Q491 R;A159K.T41 1 A,A443F,H468G,Q491 E;A159K, T41 1 A,A443F,H468S,Q491 K;A159K,T41 1 A,A443F,H468S,Q491 R;A159K,T41 1 A,A443F,H4 68S.Q491 E;A159K.T411 A,A443M,H468R,Q491 K;A159K.T41 1 A,A443M,H468R,Q491 R;A15 9K.T41 1 A,A443M,H468R,Q491 E;A159K.T411 A,A443M,H468A,Q491 K;A159K.T411 A.A443 M,H468A,Q491 R;A159K.T411 A,A443M,H468A,Q491 E;A159K.T411 A,A443M,H468K,Q491 K ;A159K.T411 A,A443M,H468K,Q491 R;A159K.T411 A,A443M,H468K,Q491 E;A159K.T41 1 A, A 443M,H468G,Q491 K;A159K.T411 A,A443M,H468G,Q491 R;A159K.T411 A,A443M,H468G,Q4 91 E;A159K.T411 A,A443M,H468S,Q491 K;A159K.T411 A,A443M,H468S,Q491 R;A159K.T411 A,A443M,H468S,Q491 E;A159K.T411 A,A443Y,H468R,Q491 K;A159K.T411 A,A443Y,H468R, Q491 R;A159K.T41 1 A,A443Y,H468R,Q491 E;A159K.T411 A,A443Y,H468A,Q491 K;A159K.T4 11 A,A443Y,H468A,Q491 R;A159K.T411 A,A443Y,H468A,Q491 E;A159K,T411 A,A443Y,H468 K.Q491 K;A159K.T411 A,A443Y,H468K,Q491 R;A159K.T411 A,A443Y,H468K,Q491 E;A159K, T41 1 A,A443Y,H468G,Q491 K;A159K,T411 A,A443Y,H468G,Q491 R;A159K.T411 A,A443Y,H4 68G.Q491 E;A159K.T411 A,A443Y,H468S,Q491 K;A159K.T411 A,A443Y,H468S,Q491 R;A159 K.T411 A,A443Y,H468S,Q491 E;A159K.T41 1 A,A443V,H468R,Q491 K;A159K.T411 A.A443V, H468R.Q491 R;A159K.T411 A,A443V,H468R,Q491 E;A159K.T411 A,A443V,H468A,Q491 K;A1 59K.T411 A,A443V,H468A,Q491 R;A159K.T411 A,A443V,H468A,Q491 E;A159K.T411 A.A443 V,H468K,Q491 K;A159K,T41 1 A,A443V,H468K,Q491 R;A159K,T411 A,A443V,H468K,Q491 E; A159K.T411 A,A443V,H468G,Q491 K;A159K.T411 A,A443V,H468G,Q491 R;A159K.T41 1 A,A4 43V,H468G,Q491 E;A159K,T411 A,A443V,H468S,Q491 K;A159K.T411 A,A443V,H468S,Q491 R;A159K.T411 A,A443V,H468S,Q491 E;A159K.T411 Q,A443I,H468R,Q491 K;A159K.T411 Q,A 443I.H468R.Q491 R;A159K.T411 Q,A443I,H468R,Q491 E;A159K.T411 Q,A443I,H468A,Q491 K;A159K.T411 Q,A443I,H468A,Q491 R;A159K.T41 1 Q,A443I,H468A,Q491 E;A159K.T411 Q,A 443I.H468K.Q491 K;A159K.T411 Q,A443I,H468K,Q491 R;A159K.T411 Q,A443I,H468K,Q491 E ;A159K.T411 Q,A443I,H468G,Q491 K;A159K.T411 Q,A443I,H468G,Q491 R;A159K.T411 Q,A4 43I.H468G.Q491 E;A159K.T411 Q,A443I,H468S,Q491 K;A159K.T411 Q,A443I,H468S,Q491 R; A159K.T411 Q,A443I,H468S,Q491 E;A159K.T411 Q,A443L,H468R,Q491 K;A159K.T411 Q,A44 3L,H468R,Q491 R;A159K.T411 Q,A443L,H468R,Q491 E;A159K.T41 1 Q,A443L,H468A,Q491 K ;A159K.T411 Q,A443L,H468A,Q491 R;A159K.T411 Q,A443L,H468A,Q491 E;A159K.T411 Q,A4 43L,H468K,Q491 K;A159K.T41 1 Q,A443L,H468K,Q491 R;A159K.T411 Q,A443L,H468K,Q491 E;A159K.T411 Q,A443L,H468G,Q491 K;A159K.T41 1 Q,A443L,H468G,Q491 R;A159K.T411 Q, A443L,H468G,Q491 E;A159K.T41 1 Q,A443L,H468S,Q491 K;A159K.T41 1 Q,A443L,H468S,Q4 91 R;A159K.T411 Q,A443L,H468S,Q491 E;A159K.T411 Q,A443F,H468R,Q491 K;A159K.T411 Q,A443F,H468R,Q491 R;A159K.T411 Q,A443F,H468R,Q491 E;A159K.T411 Q,A443F,H468A, Q491 K;A159K.T411 Q,A443F,H468A,Q491 R;A159K.T411 Q,A443F,H468A,Q491 E;A159K.T4 11 Q,A443F,H468K,Q491 K;A159K.T411 Q,A443F,H468K,Q491 R;A159K.T411 Q,A443F,H468 K.Q491 E;A159K.T411 Q,A443F,H468G,Q491 K;A159K.T411 Q,A443F,H468G,Q491 R;A159K, T41 1 Q,A443F,H468G,Q491 E;A159K.T411 Q,A443F,H468S,Q491 K;A159K.T411 Q,A443F,H4 68S.Q491 R;A159K.T411 Q,A443F,H468S,Q491 E;A159K.T411 Q,A443M,H468R,Q491 K;A15 9K.T41 1 Q,A443M,H468R,Q491 R;A159K.T411 Q,A443M,H468R,Q491 E;A159K.T411 Q.A443 M,H468A,Q491 K;A159K.T41 1 Q,A443M,H468A,Q491 R;A159K.T411 Q,A443M,H468A,Q491 E ;A159K.T411 Q,A443M,H468K,Q491 K;A159K.T41 1 Q,A443M,H468K,Q491 R;A159K.T41 1 Q,A 443M,H468K,Q491 E;A159K.T41 1 Q,A443M,H468G,Q491 K;A159K.T411 Q,A443M,H468G,Q 491 R;A159K.T411 Q,A443M,H468G,Q491 E;A159K.T411 Q,A443M,H468S,Q491 K;A159K.T4 11 Q,A443M,H468S,Q491 R;A159K.T411 Q,A443M,H468S,Q491 E;A159K.T411 Q,A443Y,H46 8R.Q491 K;A159K.T41 1 Q,A443Y,H468R,Q491 R;A159K.T411 Q,A443Y,H468R,Q491 E;A159 K.T411 Q,A443Y,H468A,Q491 K;A159K.T411 Q,A443Y,H468A,Q491 R;A159K.T411 Q.A443Y, H468A.Q491 E;A159K.T411 Q,A443Y,H468K,Q491 K;A159K.T411 Q,A443Y,H468K,Q491 R;A 159K.T411 Q,A443Y,H468K,Q491 E;A159K.T411 Q,A443Y,H468G,Q491 K;A159K.T411 Q,A44 3Y,H468G,Q491 R;A159K.T411 Q,A443Y,H468G,Q491 E;A159K.T411 Q,A443Y,H468S,Q491 K;A159K.T411 Q,A443Y,H468S,Q491 R;A159K.T411 Q,A443Y,H468S,Q491 E;A159K.T411 Q, A443V,H468R,Q491 K;A159K.T411 Q,A443V,H468R,Q491 R;A159K.T411 Q,A443V,H468R,Q 491 E;A159K.T41 1 Q,A443V,H468A,Q491 K;A159K.T411 Q,A443V,H468A,Q491 R;A159K.T41

[0093] 1 Q,A443V,H468A,Q491 E;A159K.T411 Q,A443V,H468K,Q491 K;A159K.T41 1 Q,A443V,H468K ,Q491 R;A159K.T411 Q,A443V,H468K,Q491 E;A159K.T41 1 Q,A443V,H468G,Q491 K;A159K,T 411 Q,A443V,H468G,Q491 R;A159K.T411 Q,A443V,H468G,Q491 E;A159K.T411 Q,A443V,H4 68S.Q491 K;A159K.T411 Q,A443V,H468S,Q491 R;A159K.T41 1 Q,A443V,H468S,Q491 E;A159 K.T411 E,A443I,H468R,Q491 K;A159K.T411 E,A443I,H468R,Q491 R;A159K.T411 E.A443I.H4 68R.Q491 E;A159K.T411 E,A443I,H468A,Q491 K;A159K.T411 E,A443I,H468A,Q491 R;A159K, T41 1 E,A443I,H468A,Q491 E;A159K.T411 E,A443I,H468K,Q491 K;A159K.T411 E.A443I.H468 K.Q491 R;A159K.T411 E,A443I,H468K,Q491 E;A159K.T41 1 E,A443I,H468G,Q491 K;A159K.T4 11 E,A443I,H468G,Q491 R;A159K.T411 E,A443I,H468G,Q491 E;A159K.T41 1 E.A443I.H468S, Q491 K;A159K.T411 E,A443I,H468S,Q491 R;A159K.T41 1 E,A443I,H468S,Q491 E;A159K.T41

[0094] I E,A443L,H468R,Q491 K;A159K.T411 E,A443L,H468R,Q491 R;A159K.T411 E,A443L,H468R, Q491 E;A159K.T41 1 E,A443L,H468A,Q491 K;A159K.T411 E,A443L,H468A,Q491 R;A159K.T4

[0095] I I E,A443L,H468A,Q491 E;A159K.T411 E,A443L,H468K,Q491 K;A159K.T411 E,A443L,H468K ,Q491 R;A159K.T411 E,A443L,H468K,Q491 E;A159K.T41 1 E,A443L,H468G,Q491 K;A159K.T4 11 E,A443L,H468G,Q491 R;A159K.T41 1 E,A443L,H468G,Q491 E;A159K.T411 E,A443L,H468 S.Q491 K;A159K.T411 E,A443L,H468S,Q491 R;A159K.T411 E,A443L,H468S,Q491 E;A159K,T 411 E,A443F,H468R,Q491 K;A159K.T411 E,A443F,H468R,Q491 R;A159K.T411 E,A443F,H46 8R.Q491 E;A159K.T41 1 E,A443F,H468A,Q491 K;A159K.T411 E,A443F,H468A,Q491 R;A159K, T41 1 E,A443F,H468A,Q491 E;A159K.T411 E,A443F,H468K,Q491 K;A159K.T41 1 E,A443F,H46 8K.Q491 R;A159K.T411 E,A443F,H468K,Q491 E;A159K.T411 E,A443F,H468G,Q491 K;A159K ,T411 E,A443F,H468G,Q491 R;A159K.T411 E,A443F,H468G,Q491 E;A159K.T411 E,A443F,H4 68S.Q491 K;A159K.T41 1 E,A443F,H468S,Q491 R;A159K.T411 E,A443F,H468S,Q491 E;A159 K.T411 E,A443M,H468R,Q491 K;A159K.T41 1 E,A443M,H468R,Q491 R;A159K.T411 E.A443M, H468R.Q491 E;A159K.T411 E,A443M,H468A,Q491 K;A159K.T411 E,A443M,H468A,Q491 R;A 159K.T411 E,A443M,H468A,Q491 E;A159K.T411 E,A443M,H468K,Q491 K;A159K.T411 E,A44 3M,H468K,Q491 R;A159K.T411 E,A443M,H468K,Q491 E;A159K.T41 1 E,A443M,H468G,Q491 K;A159K.T411 E,A443M,H468G,Q491 R;A159K.T411 E,A443M,H468G,Q491 E;A159K.T411 E, A443M,H468S,Q491 K;A159K.T411 E,A443M,H468S,Q491 R;A159K.T411 E,A443M,H468S,Q 491 E;A159K.T41 1 E,A443Y,H468R,Q491 K;A159K.T411 E,A443Y,H468R,Q491 R;A159K.T41

[0096] I E,A443Y,H468R,Q491 E;A159K.T411 E,A443Y,H468A,Q491 K;A159K.T411 E,A443Y,H468A, Q491 R;A159K.T411 E,A443Y,H468A,Q491 E;A159K.T411 E,A443Y,H468K,Q491 K;A159K.T4

[0097] I I E,A443Y,H468K,Q491 R;A159K.T411 E,A443Y,H468K,Q491 E;A159K.T411 E,A443Y,H468 G.Q491 K;A159K.T411 E,A443Y,H468G,Q491 R;A159K.T411 E,A443Y,H468G,Q491 E;A159K, T41 1 E,A443Y,H468S,Q491 K;A159K.T41 1 E,A443Y,H468S,Q491 R;A159K.T411 E,A443Y,H4 68S.Q491 E;A159K.T411 E,A443V,H468R,Q491 K;A159K.T41 1 E,A443V,H468R,Q491 R;A159 K.T411 E,A443V,H468R,Q491 E;A159K.T411 E,A443V,H468A,Q491 K;A159K.T411 E.A443V, H468A.Q491 R;A159K.T411 E,A443V,H468A,Q491 E;A159K.T411 E,A443V,H468K,Q491 K;A1 59K.T411 E,A443V,H468K,Q491 R;A159K.T411 E,A443V,H468K,Q491 E;A159K.T411 E.A443 V,H468G,Q491 K;A159K.T411 E,A443V,H468G,Q491 R;A159K.T41 1 E,A443V,H468G,Q491 E; A159K.T411 E,A443V,H468S,Q491 K;A159K.T411 E,A443V,H468S,Q491 R;A159K.T41 1 E,A4 43V,H468S,Q491 E;A159K.T411 K,A443I,H468R,Q491 K;A159K.T41 1 K,A443I,H468R,Q491 R; A159K.T411 K,A443I,H468R,Q491 E;A159K.T411 K,A443I,H468A,Q491 K;A159K.T411 K.A443 l,H468A,Q491 R;A159K.T41 1 K,A443I,H468A,Q491 E;A159K.T411 K,A443I,H468K,Q491 K;A1 59K.T411 K,A443I,H468K,Q491 R;A159K.T41 1 K,A443I,H468K,Q491 E;A159K.T411 K.A443I.H 468G.Q491 K;A159K.T411 K,A443I,H468G,Q491 R;A159K.T411 K,A443I,H468G,Q491 E;A159 K.T411 K,A443I,H468S,Q491 K;A159K.T411 K,A443I,H468S,Q491 R;A159K.T411 K.A443I.H46 8S.Q491 E;A159K.T411 K,A443L,H468R,Q491 K;A159K.T41 1 K,A443L,H468R,Q491 R;A159K, T41 1 K,A443L,H468R,Q491 E;A159K.T41 1 K,A443L,H468A,Q491 K;A159K.T411 K,A443L,H46 8A.Q491 R;A159K.T411 K,A443L,H468A,Q491 E;A159K.T411 K,A443L,H468K,Q491 K;A159K, T41 1 K,A443L,H468K,Q491 R;A159K.T41 1 K,A443L,H468K,Q491 E;A159K.T411 K,A443L,H46 8G.Q491 K;A159K.T41 1 K,A443L,H468G,Q491 R;A159K.T411 K,A443L,H468G,Q491 E;A159K ,T411 K,A443L,H468S,Q491 K;A159K.T41 1 K,A443L,H468S,Q491 R;A159K.T41 1 K,A443L,H4 68S.Q491 E;A159K.T41 1 K,A443F,H468R,Q491 K;A159K.T411 K,A443F,H468R,Q491 R;A159 K.T411 K,A443F,H468R,Q491 E;A159K.T41 1 K,A443F,H468A,Q491 K;A159K.T411 K,A443F,H 468A.Q491 R;A159K.T411 K,A443F,H468A,Q491 E;A159K.T411 K,A443F,H468K,Q491 K;A15 9K.T41 1 K,A443F,H468K,Q491 R;A159K.T411 K,A443F,H468K,Q491 E;A159K.T411 K.A443F, H468G.Q491 K;A159K.T411 K,A443F,H468G,Q491 R;A159K.T411 K,A443F,H468G,Q491 E;A 159K.T411 K,A443F,H468S,Q491 K;A159K.T411 K,A443F,H468S,Q491 R;A159K.T41 1 K.A443 F,H468S,Q491 E;A159K.T411 K,A443M,H468R,Q491 K;A159K.T411 K,A443M,H468R,Q491 R; A159K.T411 K,A443M,H468R,Q491 E;A159K.T411 K,A443M,H468A,Q491 K;A159K.T411 K,A4 43M,H468A,Q491 R;A159K.T41 1 K,A443M,H468A,Q491 E;A159K.T411 K,A443M,H468K,Q49 1 K;A159K.T411 K,A443M,H468K,Q491 R;A159K.T41 1 K,A443M,H468K,Q491 E;A159K.T41 1 K ,A443M,H468G,Q491 K;A159K.T411 K,A443M,H468G,Q491 R;A159K.T41 1 K,A443M,H468G, Q491 E;A159K.T411 K,A443M,H468S,Q491 K;A159K.T411 K,A443M,H468S,Q491 R;A159K,T 411 K,A443M,H468S,Q491 E;A159K.T411 K,A443Y,H468R,Q491 K;A159K.T411 K,A443Y,H46 8R.Q491 R;A159K.T411 K,A443Y,H468R,Q491 E;A159K.T411 K,A443Y,H468A,Q491 K;A159K ,T411 K,A443Y,H468A,Q491 R;A159K.T41 1 K,A443Y,H468A,Q491 E;A159K.T411 K,A443Y,H4 68K.Q491 K;A159K.T411 K,A443Y,H468K,Q491 R;A159K.T41 1 K,A443Y,H468K,Q491 E;A159 K.T411 K,A443Y,H468G,Q491 K;A159K.T411 K,A443Y,H468G,Q491 R;A159K.T411 K.A443Y, H468G.Q491 E;A159K.T411 K,A443Y,H468S,Q491 K;A159K.T411 K,A443Y,H468S,Q491 R;A1 59K.T411 K,A443Y,H468S,Q491 E;A159K.T411 K,A443V,H468R,Q491 K;A159K.T411 K.A443 V,H468R,Q491 R;A159K.T411 K,A443V,H468R,Q491 E;A159K.T411 K,A443V,H468A,Q491 K; A159K.T411 K,A443V,H468A,Q491 R;A159K.T41 1 K,A443V,H468A,Q491 E;A159K.T41 1 K,A4 43V,H468K,Q491 K;A159K.T411 K,A443V,H468K,Q491 R;A159K.T411 K,A443V,H468K,Q491 E;A159K.T411 K,A443V,H468G,Q491 K;A159K.T411 K,A443V,H468G,Q491 R;A159K.T411 K, A443V,H468G,Q491 E;A159K.T411 K,A443V,H468S,Q491 K;A159K.T411 K,A443V,H468S,Q4 91 R;A159K.T411 K,A443V,H468S,Q491 E;A159R.T411 V,A443I,H468R,Q491 K;A159R.T41 1 V ,A443I,H468R,Q491 R;A159R,T41 1 V,A443I,H468R,Q491 E;A159R.T411 V,A443I,H468A,Q49 1 K;A159R.T411 V,A443I,H468A,Q491 R;A159R.T41 1 V,A443I,H468A,Q491 E;A159R.T41 1 V,A 443I,H468K,Q491 K;A159R.T41 1 V,A443I,H468K,Q491 R;A159R,T411 V,A443I,H468K,Q491 E ;A159R.T411 V,A443I,H468G,Q491 K;A159R.T411 V,A443I,H468G,Q491 R;A159R.T411 V,A4 43I,H468G,Q491 E;A159R,T411V,A443I,H468S,Q491 K;A159R,T411V,A443I,H468S,Q491 R; A159R.T41 1 V,A443I,H468S,Q491 E;A159R.T411 V,A443L,H468R,Q491 K;A159R.T411 V,A44 3L,H468R,Q491 R;A159R.T411 V,A443L,H468R,Q491 E;A159R.T411 V,A443L,H468A,Q491 K; A159R.T41 1 V,A443L,H468A,Q491 R;A159R.T41 1 V,A443L,H468A,Q491 E;A159R.T411 V,A4 43L,H468K,Q491 K;A159R.T411 V,A443L,H468K,Q491 R;A159R.T411 V,A443L,H468K,Q491 E;A159R.T411 V,A443L,H468G,Q491 K;A159R.T41 1 V,A443L,H468G,Q491 R;A159R.T411 V, A443L,H468G,Q491 E;A159R.T41 1 V,A443L,H468S,Q491 K;A159R.T41 1 V,A443L,H468S,Q4 91 R;A159R.T411 V,A443L,H468S,Q491 E;A159R.T411 V,A443F,H468R,Q491 K;A159R.T411 V,A443F,H468R,Q491 R;A159R,T411 V,A443F,H468R,Q491 E;A159R.T41 1 V,A443F,H468A, Q491 K;A159R.T41 1 V,A443F,H468A,Q491 R;A159R.T411 V,A443F,H468A,Q491 E;A159R.T4 11 V,A443F,H468K,Q491 K;A159R,T41 1 V,A443F,H468K,Q491 R;A159R,T411 V,A443F,H468 K.Q491 E;A159R.T411 V,A443F,H468G,Q491 K;A159R.T411 V,A443F,H468G,Q491 R;A159R, T41 1 V,A443F,H468G,Q491 E;A159R.T411 V,A443F,H468S,Q491 K;A159R.T41 1 V,A443F,H4 68S.Q491 R;A159R.T411 V,A443F,H468S,Q491 E;A159R.T411 V,A443M,H468R,Q491 K;A159 R,T41 1 V,A443M,H468R,Q491 R;A159R.T41 1 V,A443M,H468R,Q491 E;A159R,T41 1 V.A443M ,H468A,Q491 K;A159R.T411 V,A443M,H468A,Q491 R;A159R.T411 V,A443M,H468A,Q491 E;A 159R.T411 V,A443M,H468K,Q491 K;A159R.T411 V,A443M,H468K,Q491 R;A159R.T411 V,A44 3M,H468K,Q491 E;A159R.T411 V,A443M,H468G,Q491 K;A159R.T411 V,A443M,H468G,Q491 R;A159R,T41 1 V,A443M,H468G,Q491 E;A159R.T41 1V,A443M,H468S,Q491 K;A159R,T41 1V, A443M,H468S,Q491 R;A159R.T411 V,A443M,H468S,Q491 E;A159R.T411 V,A443Y,H468R,Q 491 K;A159R.T41 1 V,A443Y,H468R,Q491 R;A159R.T411 V,A443Y,H468R,Q491 E;A159R.T41 1 V,A443Y,H468A,Q491 K;A159R,T411 V,A443Y,H468A,Q491 R;A159R.T41 1 V,A443Y,H468A ,Q491 E;A159R.T411 V,A443Y,H468K,Q491 K;A159R.T411 V,A443Y,H468K,Q491 R;A159R,T 411 V,A443Y,H468K,Q491 E;A159R,T411 V,A443Y,H468G,Q491 K;A159R,T411 V,A443Y,H46 8G.Q491 R;A159R.T411 V,A443Y,H468G,Q491 E;A159R.T411 V,A443Y,H468S,Q491 K;A159

[0098] R,T41 1 V,A443Y,H468S,Q491 R;A159R.T41 1 V,A443Y,H468S,Q491 E;A159R.T41 1 V,A443V, H468R.Q491 K;A159R.T411 V,A443V,H468R,Q491 R;A159R.T41 1 V,A443V,H468R,Q491 E;A 159R.T411 V,A443V,H468A,Q491 K;A159R.T411 V,A443V,H468A,Q491 R;A159R.T41 1 V,A44 3V,H468A,Q491 E;A159R.T411 V,A443V,H468K,Q491 K;A159R.T411 V,A443V,H468K,Q491 R ;A159R.T411 V,A443V,H468K,Q491 E;A159R.T411 V,A443V,H468G,Q491 K;A159R.T41 1 V,A 443V,H468G,Q491 R;A159R,T411V,A443V,H468G,Q491 E;A159R,T411V,A443V,H468S,Q4 91 K;A159R.T41 1 V,A443V,H468S,Q491 R;A159R.T411 V,A443V,H468S,Q491 E;A159R.T41 1

[0099] S,A443I,H468R,Q491 K;A159R,T41 1 S,A443I,H468R,Q491 R;A159R,T411 S,A443I,H468R,Q4 91 E;A159R.T41 1 S,A443I,H468A,Q491 K;A159R.T41 1 S,A443I,H468A,Q491 R;A159R.T411 S, A443I.H468A.Q491 E;A159R.T411 S,A443I,H468K,Q491 K;A159R.T411 S,A443I,H468K,Q491 R;A159R.T41 1 S,A443I,H468K,Q491 E;A159R.T411 S,A443I,H468G,Q491 K;A159R.T411 S,A 443I.H468G.Q491 R;A159R.T41 1 S,A443I,H468G,Q491 E;A159R.T41 1 S,A443I,H468S,Q491 K;A159R.T411 S,A443I,H468S,Q491 R;A159R.T41 1 S,A443I,H468S,Q491 E;A159R.T41 1 S,A4 43L,H468R,Q491 K;A159R.T411 S,A443L,H468R,Q491 R;A159R.T41 1 S,A443L,H468R,Q491 E;A159R.T411 S,A443L,H468A,Q491 K;A159R.T411 S,A443L,H468A,Q491 R;A159R.T411 S,A 443L,H468A,Q491 E;A159R.T411 S,A443L,H468K,Q491 K;A159R.T41 1 S,A443L,H468K,Q491 R;A159R.T41 1 S,A443L,H468K,Q491 E;A159R.T411 S,A443L,H468G,Q491 K;A159R.T411 S, A443L,H468G,Q491 R;A159R.T411 S,A443L,H468G,Q491 E;A159R.T41 1 S,A443L,H468S,Q4 91 K;A159R.T41 1 S,A443L,H468S,Q491 R;A159R.T41 1 S,A443L,H468S,Q491 E;A159R.T41 1 S,A443F,H468R,Q491 K;A159R.T41 1 S,A443F,H468R,Q491 R;A159R.T411 S,A443F,H468R, Q491 E;A159R.T411 S,A443F,H468A,Q491 K;A159R.T411 S,A443F,H468A,Q491 R;A159R.T4 11 S,A443F,H468A,Q491 E;A159R.T411 S,A443F,H468K,Q491 K;A159R.T41 1 S,A443F,H468 K.Q491 R;A159R.T41 1 S,A443F,H468K,Q491 E;A159R.T41 1 S,A443F,H468G,Q491 K;A159R, T41 1 S,A443F,H468G,Q491 R;A159R.T41 1 S,A443F,H468G,Q491 E;A159R.T411 S,A443F,H4 68S.Q491 K;A159R.T411 S,A443F,H468S,Q491 R;A159R.T411 S,A443F,H468S,Q491 E;A159

[0100] R,T41 1 S,A443M,H468R,Q491 K;A159R.T411 S,A443M,H468R,Q491 R;A159R.T41 1 S.A443M ,H468R,Q491 E;A159R.T41 1 S,A443M,H468A,Q491 K;A159R.T411 S,A443M,H468A,Q491 R; A159R.T41 1 S,A443M,H468A,Q491 E;A159R.T411 S,A443M,H468K,Q491 K;A159R.T411 S,A 443M,H468K,Q491 R;A159R.T411 S,A443M,H468K,Q491 E;A159R.T411 S,A443M,H468G,Q4 91 K;A159R.T41 1 S,A443M,H468G,Q491 R;A159R.T411 S,A443M,H468G,Q491 E;A159R.T41 1 S,A443M,H468S,Q491 K;A159R.T411 S,A443M,H468S,Q491 R;A159R.T41 1 S,A443M,H468

[0101] S.Q491 E;A159R.T411 S,A443Y,H468R,Q491 K;A159R.T41 1 S,A443Y,H468R,Q491 R;A159R, T41 1 S,A443Y,H468R,Q491 E;A159R.T411 S,A443Y,H468A,Q491 K;A159R.T41 1 S,A443Y,H4 68A.Q491 R;A159R.T411 S,A443Y,H468A,Q491 E;A159R.T41 1 S,A443Y,H468K,Q491 K;A159

[0102] R,T41 1 S,A443Y,H468K,Q491 R;A159R.T41 1 S,A443Y,H468K,Q491 E;A159R.T411 S.A443Y, H468G.Q491 K;A159R.T411 S,A443Y,H468G,Q491 R;A159R.T41 1 S,A443Y,H468G,Q491 E;A 159R.T411 S,A443Y,H468S,Q491 K;A159R.T411 S,A443Y,H468S,Q491 R;A159R.T41 1 S,A44 3Y,H468S,Q491 E;A159R.T411 S,A443V,H468R,Q491 K;A159R.T411 S,A443V,H468R,Q491 R;A159R.T41 1 S,A443V,H468R,Q491 E;A159R.T411 S,A443V,H468A,Q491 K;A159R.T411 S, A443V,H468A,Q491 R;A159R.T411 S,A443V,H468A,Q491 E;A159R.T411 S,A443V,H468K,Q4 91 K;A159R.T41 1 S,A443V,H468K,Q491 R;A159R.T411 S,A443V,H468K,Q491 E;A159R.T41 1

[0103] S,A443V,H468G,Q491 K;A159R.T411 S,A443V,H468G,Q491 R;A159R.T411 S,A443V,H468G, Q491 E;A159R.T411 S,A443V,H468S,Q491 K;A159R.T411 S,A443V,H468S,Q491 R;A159R.T4 11 S,A443V,H468S,Q491 E;A159R,T411 A,A443I,H468R,Q491 K;A159R,T41 1 A,A443I,H468R, Q491 R;A159R.T411 A,A443I,H468R,Q491 E;A159R.T411 A,A443I,H468A,Q491 K;A159R.T41 1A,A443I,H468A,Q491 R;A159R,T411A,A443I,H468A,Q491 E;A159R,T411A,A443I,H468K,Q 491 K;A159R,T411A,A443I,H468K,Q491 R;A159R,T411A,A443I,H468K,Q491 E;A159R,T411 A,A443I,H468G,Q491 K;A159R,T41 1 A,A443I,H468G,Q491 R;A159R.T41 1 A,A443I,H468G,Q 491 E;A159R.T411 A,A443I,H468S,Q491 K;A159R.T411 A,A443I,H468S,Q491 R;A159R.T41 1 A,A443I,H468S,Q491 E;A159R.T411 A,A443L,H468R,Q491 K;A159R.T411 A,A443L,H468R,Q 491 R;A159R.T411 A,A443L,H468R,Q491 E;A159R,T41 1 A,A443L,H468A,Q491 K;A159R,T41

[0104] I A,A443L,H468A,Q491 R;A159R,T411 A,A443L,H468A,Q491 E;A159R.T41 1 A,A443L,H468K, Q491 K;A159R.T411 A,A443L,H468K,Q491 R;A159R.T411 A,A443L,H468K,Q491 E;A159R.T4

[0105] I I A,A443L,H468G,Q491 K;A159R,T411 A,A443L,H468G,Q491 R;A159R,T411 A,A443L,H468 G.Q491 E;A159R.T411 A,A443L,H468S,Q491 K;A159R.T41 1 A,A443L,H468S,Q491 R;A159R, T41 1A,A443L,H468S,Q491 E;A159R,T41 1A,A443F,H468R,Q491 K;A159R,T41 1A,A443F,H4 68R.Q491 R;A159R.T41 1 A,A443F,H468R,Q491 E;A159R.T411 A,A443F,H468A,Q491 K;A159 R,T41 1 A,A443F,H468A,Q491 R;A159R,T411 A,A443F,H468A,Q491 E;A159R,T411 A.A443F, H468K.Q491 K;A159R.T411 A,A443F,H468K,Q491 R;A159R.T411 A,A443F,H468K,Q491 E;A1 59R.T411 A,A443F,H468G,Q491 K;A159R,T41 1 A,A443F,H468G,Q491 R;A159R,T411 A.A443

[0106] F,H468G,Q491 E;A159R.T411 A,A443F,H468S,Q491 K;A159R.T411 A,A443F,H468S,Q491 R; A159R.T411 A,A443F,H468S,Q491 E;A159R.T411 A,A443M,H468R,Q491 K;A159R.T41 1 A,A4 43M,H468R,Q491 R;A159R,T411A,A443M,H468R,Q491 E;A159R,T411A,A443M,H468A,Q49

[0107] I K;A159R.T411 A,A443M,H468A,Q491 R;A159R.T41 1 A,A443M,H468A,Q491 E;A159R.T411 A,A443M,H468K,Q491 K;A159R.T41 1 A,A443M,H468K,Q491 R;A159R,T411 A,A443M,H468K ,Q491 E;A159R.T411 A,A443M,H468G,Q491 K;A159R.T411 A,A443M,H468G,Q491 R;A159R, T41 1 A,A443M,H468G,Q491 E;A159R.T411 A,A443M,H468S,Q491 K;A159R.T411 A,A443M,H 468S.Q491 R;A159R.T41 1 A,A443M,H468S,Q491 E;A159R.T411 A,A443Y,H468R,Q491 K;A15 9R.T411 A,A443Y,H468R,Q491 R;A159R,T411 A,A443Y,H468R,Q491 E;A159R,T41 1 A.A443Y ,H468A,Q491 K;A159R.T411 A,A443Y,H468A,Q491 R;A159R.T41 1 A,A443Y,H468A,Q491 E;A 159R.T411 A,A443Y,H468K,Q491 K;A159R,T411 A,A443Y,H468K,Q491 R;A159R.T41 1 A,A44 3Y,H468K,Q491 E;A159R.T411 A,A443Y,H468G,Q491 K;A159R.T411 A,A443Y,H468G,Q491 R;A159R.T41 1 A,A443Y,H468G,Q491 E;A159R.T411 A,A443Y,H468S,Q491 K;A159R.T41 1 A, A443Y,H468S,Q491 R;A159R,T411A,A443Y,H468S,Q491 E;A159R,T411A,A443V,H468R,Q4 91 K;A159R,T41 1 A,A443V,H468R,Q491 R;A159R,T411 A,A443V,H468R,Q491 E;A159R.T41 1 A,A443V,H468A,Q491 K;A159R,T411A,A443V,H468A,Q491 R;A159R,T411A,A443V,H468A, Q491 E;A159R.T411 A,A443V,H468K,Q491 K;A159R.T411 A,A443V,H468K,Q491 R;A159R.T4

[0108] I I A,A443V,H468K,Q491 E;A159R,T411 A,A443V,H468G,Q491 K;A159R,T411 A,A443V,H468

[0109] G.Q491 R;A159R.T411 A,A443V,H468G,Q491 E;A159R.T411 A,A443V,H468S,Q491 K;A159R, T41 1 A,A443V,H468S,Q491 R;A159R,T411 A,A443V,H468S,Q491 E;A159R,T41 1 Q,A443I,H4 68R.Q491 K;A159R.T411 Q,A443I,H468R,Q491 R;A159R.T411 Q,A443I,H468R,Q491 E;A159 R,T41 1 Q,A443I,H468A,Q491 K;A159R.T411 Q,A443I,H468A,Q491 R;A159R.T411 Q.A443I.H4 68A.Q491 E;A159R.T411 Q,A443I,H468K,Q491 K;A159R.T411 Q,A443I,H468K,Q491 R;A159R ,T411 Q,A443I,H468K,Q491 E;A159R.T411 Q,A443I,H468G,Q491 K;A159R.T411 Q,A443I,H46 8G.Q491 R;A159R.T41 1 Q,A443I,H468G,Q491 E;A159R.T41 1 Q,A443I,H468S,Q491 K;A159R, T41 1 Q,A443I,H468S,Q491 R;A159R.T41 1 Q,A443I,H468S,Q491 E;A159R.T411 Q,A443L,H46 8R.Q491 K;A159R.T411 Q,A443L,H468R,Q491 R;A159R.T411 Q,A443L,H468R,Q491 E;A159 R,T411 Q,A443L,H468A,Q491 K;A159R.T411 Q,A443L,H468A,Q491 R;A159R.T41 1 Q.A443L, H468A.Q491 E;A159R.T41 1 Q,A443L,H468K,Q491 K;A159R.T411 Q,A443L,H468K,Q491 R;A1 59R.T411 Q,A443L,H468K,Q491 E;A159R.T411 Q,A443L,H468G,Q491 K;A159R.T411 Q.A443 L,H468G,Q491 R;A159R.T411 Q,A443L,H468G,Q491 E;A159R.T41 1 Q,A443L,H468S,Q491 K; A159R.T41 1 Q,A443L,H468S,Q491 R;A159R.T41 1 Q,A443L,H468S,Q491 E;A159R.T41 1 Q,A4 43F,H468R,Q491 K;A159R.T41 1 Q,A443F,H468R,Q491 R;A159R.T411 Q,A443F,H468R,Q49

[0110] 1 E;A159R.T411 Q,A443F,H468A,Q491 K;A159R.T411 Q,A443F,H468A,Q491 R;A159R.T411 Q ,A443F,H468A,Q491 E;A159R.T411 Q,A443F,H468K,Q491 K;A159R.T411 Q,A443F,H468K,Q 491 R;A159R.T411 Q,A443F,H468K,Q491 E;A159R.T411 Q,A443F,H468G,Q491 K;A159R.T41 1 Q,A443F,H468G,Q491 R;A159R.T411 Q,A443F,H468G,Q491 E;A159R.T411 Q,A443F,H468

[0111] S.Q491 K;A159R.T411 Q,A443F,H468S,Q491 R;A159R.T411 Q,A443F,H468S,Q491 E;A159R, T41 1 Q,A443M,H468R,Q491 K;A159R.T411 Q,A443M,H468R,Q491 R;A159R.T411 Q.A443M, H468R.Q491 E;A159R.T411 Q,A443M,H468A,Q491 K;A159R.T411 Q,A443M,H468A,Q491 R;A 159R.T411 Q,A443M,H468A,Q491 E;A159R.T411 Q,A443M,H468K,Q491 K;A159R.T411 Q,A4 43M,H468K,Q491 R;A159R.T411 Q,A443M,H468K,Q491 E;A159R.T411 Q,A443M,H468G,Q4 91 K;A159R.T41 1 Q,A443M,H468G,Q491 R;A159R.T411 Q,A443M,H468G,Q491 E;A159R.T41 1 Q,A443M,H468S,Q491 K;A159R.T411 Q,A443M,H468S,Q491 R;A159R.T411 Q,A443M,H468 S.Q491 E;A159R.T411 Q,A443Y,H468R,Q491 K;A159R.T41 1 Q,A443Y,H468R,Q491 R;A159R, T41 1 Q,A443Y,H468R,Q491 E;A159R.T41 1 Q,A443Y,H468A,Q491 K;A159R.T41 1 Q,A443Y,H 468A.Q491 R;A159R.T41 1 Q,A443Y,H468A,Q491 E;A159R.T411 Q,A443Y,H468K,Q491 K;A15 9R.T411 Q,A443Y,H468K,Q491 R;A159R.T411 Q,A443Y,H468K,Q491 E;A159R.T411 Q.A443 Y,H468G,Q491 K;A159R.T41 1 Q,A443Y,H468G,Q491 R;A159R.T411 Q,A443Y,H468G,Q491 E ;A159R.T411 Q,A443Y,H468S,Q491 K;A159R.T411 Q,A443Y,H468S,Q491 R;A159R.T41 1 Q,A 443Y,H468S,Q491 E;A159R.T411 Q,A443V,H468R,Q491 K;A159R.T411 Q,A443V,H468R,Q4 91 R;A159R.T411 Q,A443V,H468R,Q491 E;A159R.T41 1 Q,A443V,H468A,Q491 K;A159R.T41 1

[0112] Q,A443V,H468A,Q491 R;A159R.T411 Q,A443V,H468A,Q491 E;A159R.T41 1 Q,A443V,H468K, Q491 K;A159R.T41 1 Q,A443V,H468K,Q491 R;A159R.T41 1 Q,A443V,H468K,Q491 E;A159R,T 411 Q,A443V,H468G,Q491 K;A159R.T411 Q,A443V,H468G,Q491 R;A159R.T411 Q,A443V,H4 68G.Q491 E;A159R.T411 Q,A443V,H468S,Q491 K;A159R.T411 Q,A443V,H468S,Q491 R;A15 9R.T411 Q,A443V,H468S,Q491 E;A159R.T41 1 E,A443I,H468R,Q491 K;A159R.T411 E.A443I, H468R.Q491 R;A159R.T411 E,A443I,H468R,Q491 E;A159R.T41 1 E,A443I,H468A,Q491 K;A15 9R.T411 E,A443I,H468A,Q491 R;A159R.T411 E.A443I.H468A.Q491 E;A159R.T41 1 E.A443I.H 468K.Q491 K;A159R.T41 1 E,A443I,H468K,Q491 R;A159R.T411 E,A443I,H468K,Q491 E;A159

[0113] R,T41 1 E,A443I,H468G,Q491 K;A159R.T41 1 E.A443I.H468G.Q491 R;A159R.T411 E.A443I.H4 68G.Q491 E;A159R.T411 E,A443I,H468S,Q491 K;A159R.T411 E,A443I,H468S,Q491 R;A159R ,T411 E,A443I,H468S,Q491 E;A159R.T411 E,A443L,H468R,Q491 K;A159R.T411 E,A443L,H46 8R.Q491 R;A159R.T411 E,A443L,H468R,Q491 E;A159R.T411 E,A443L,H468A,Q491 K;A159R ,T411 E,A443L,H468A,Q491 R;A159R.T411 E,A443L,H468A,Q491 E;A159R.T411 E,A443L,H4 68K.Q491 K;A159R.T411 E,A443L,H468K,Q491 R;A159R.T411 E,A443L,H468K,Q491 E;A159 R,T41 1 E,A443L,H468G,Q491 K;A159R.T411 E,A443L,H468G,Q491 R;A159R.T411 E.A443L, H468G.Q491 E;A159R.T411 E,A443L,H468S,Q491 K;A159R.T411 E,A443L,H468S,Q491 R;A1 59R.T411 E,A443L,H468S,Q491 E;A159R.T411 E,A443F,H468R,Q491 K;A159R.T411 E.A443 F,H468R,Q491 R;A159R.T411 E,A443F,H468R,Q491 E;A159R.T41 1 E,A443F,H468A,Q491 K; A159R.T41 1 E,A443F,H468A,Q491 R;A159R.T411 E,A443F,H468A,Q491 E;A159R.T411 E,A4 43F,H468K,Q491 K;A159R.T411 E,A443F,H468K,Q491 R;A159R.T41 1 E,A443F,H468K,Q491 E;A159R.T411 E,A443F,H468G,Q491 K;A159R.T411 E,A443F,H468G,Q491 R;A159R.T411 E, A443F,H468G,Q491 E;A159R.T411 E,A443F,H468S,Q491 K;A159R.T41 1 E,A443F,H468S,Q4 91 R;A159R.T411 E,A443F,H468S,Q491 E;A159R.T411 E,A443M,H468R,Q491 K;A159R.T41 1 E,A443M,H468R,Q491 R;A159R.T411 E,A443M,H468R,Q491 E;A159R.T411 E,A443M,H468A ,Q491 K;A159R.T411 E,A443M,H468A,Q491 R;A159R.T411 E,A443M,H468A,Q491 E;A159R,T 411 E,A443M,H468K,Q491 K;A159R.T411 E,A443M,H468K,Q491 R;A159R.T411 E,A443M,H4 68K.Q491 E;A159R.T411 E,A443M,H468G,Q491 K;A159R.T411 E,A443M,H468G,Q491 R;A15 9R.T411 E,A443M,H468G,Q491 E;A159R.T411 E,A443M,H468S,Q491 K;A159R.T41 1 E.A443 M,H468S,Q491 R;A159R.T411 E,A443M,H468S,Q491 E;A159R.T411 E,A443Y,H468R,Q491 K ;A159R.T411 E,A443Y,H468R,Q491 R;A159R.T411 E,A443Y,H468R,Q491 E;A159R.T411 E,A 443Y,H468A,Q491 K;A159R.T411 E,A443Y,H468A,Q491 R;A159R.T41 1 E,A443Y,H468A,Q49 1 E;A159R.T411 E,A443Y,H468K,Q491 K;A159R.T411 E,A443Y,H468K,Q491 R;A159R.T411 E ,A443Y,H468K,Q491 E;A159R.T41 1 E,A443Y,H468G,Q491 K;A159R.T41 1 E,A443Y,H468G,Q 491 R;A159R.T411 E,A443Y,H468G,Q491 E;A159R.T411 E,A443Y,H468S,Q491 K;A159R.T41 1 E,A443Y,H468S,Q491 R;A159R.T411 E,A443Y,H468S,Q491 E;A159R.T411 E,A443V,H468R ,Q491 K;A159R.T411 E,A443V,H468R,Q491 R;A159R.T411 E,A443V,H468R,Q491 E;A159R,T 411 E,A443V,H468A,Q491 K;A159R.T411 E,A443V,H468A,Q491 R;A159R.T411 E,A443V,H46 8A.Q491 E;A159R.T41 1 E,A443V,H468K,Q491 K;A159R.T411 E,A443V,H468K,Q491 R;A159R ,T411 E,A443V,H468K,Q491 E;A159R.T411 E,A443V,H468G,Q491 K;A159R.T41 1 E,A443V,H 468G.Q491 R;A159R.T41 1 E,A443V,H468G,Q491 E;A159R.T411 E,A443V,H468S,Q491 K;A15 9R.T411 E,A443V,H468S,Q491 R;A159R.T41 1 E,A443V,H468S,Q491 E;A159R.T411 K.A443I, H468R.Q491 K;A159R.T411 K,A443I,H468R,Q491 R;A159R.T411 K,A443I,H468R,Q491 E;A15 9R.T411 K,A443I,H468A,Q491 K;A159R.T411 K,A443I,H468A,Q491 R;A159R.T411 K.A443I.H 468A.Q491 E;A159R.T411 K,A443I,H468K,Q491 K;A159R.T411 K,A443I,H468K,Q491 R;A159 R,T41 1 K,A443I,H468K,Q491 E;A159R.T41 1 K,A443I,H468G,Q491 K;A159R.T411 K.A443I.H4 68G.Q491 R;A159R.T41 1 K,A443I,H468G,Q491 E;A159R.T41 1 K,A443I,H468S,Q491 K;A159R ,T411 K,A443I,H468S,Q491 R;A159R.T41 1 K,A443I,H468S,Q491 E;A159R.T41 1 K,A443L,H46 8R.Q491 K;A159R.T411 K,A443L,H468R,Q491 R;A159R.T411 K,A443L,H468R,Q491 E;A159R ,T411 K,A443L,H468A,Q491 K;A159R.T411 K,A443L,H468A,Q491 R;A159R.T411 K,A443L,H4 68A.Q491 E;A159R.T411 K,A443L,H468K,Q491 K;A159R.T411 K,A443L,H468K,Q491 R;A159

[0114] R,T41 1 K,A443L,H468K,Q491 E;A159R.T411 K,A443L,H468G,Q491 K;A159R.T41 1 K,A443L,H 468G.Q491 R;A159R.T411 K,A443L,H468G,Q491 E;A159R.T411 K,A443L,H468S,Q491 K;A15 9R.T411 K,A443L,H468S,Q491 R;A159R.T411 K,A443L,H468S,Q491 E;A159R.T411 K.A443F, H468R.Q491 K;A159R.T411 K,A443F,H468R,Q491 R;A159R.T41 1 K,A443F,H468R,Q491 E;A1 59R.T411 K,A443F,H468A,Q491 K;A159R.T411 K,A443F,H468A,Q491 R;A159R.T41 1 K.A443 F,H468A,Q491 E;A159R.T411 K,A443F,H468K,Q491 K;A159R.T41 1 K,A443F,H468K,Q491 R; A159R.T41 1 K,A443F,H468K,Q491 E;A159R.T411 K,A443F,H468G,Q491 K;A159R.T411 K,A4 43F,H468G,Q491 R;A159R.T411 K,A443F,H468G,Q491 E;A159R.T41 1 K,A443F,H468S,Q491 K;A159R.T411 K,A443F,H468S,Q491 R;A159R.T41 1 K,A443F,H468S,Q491 E;A159R.T41 1 K, A443M,H468R,Q491 K;A159R.T411 K,A443M,H468R,Q491 R;A159R.T411 K,A443M,H468R, Q491 E;A159R.T411 K,A443M,H468A,Q491 K;A159R.T411 K,A443M,H468A,Q491 R;A159R,T 411 K,A443M,H468A,Q491 E;A159R.T411 K,A443M,H468K,Q491 K;A159R.T411 K,A443M,H4 68K.Q491 R;A159R.T411 K,A443M,H468K,Q491 E;A159R.T41 1 K,A443M,H468G,Q491 K;A15 9R.T411 K,A443M,H468G,Q491 R;A159R.T41 1 K,A443M,H468G,Q491 E;A159R.T411 K.A443 M,H468S,Q491 K;A159R.T411 K,A443M,H468S,Q491 R;A159R.T411 K,A443M,H468S,Q491 E ;A159R.T411 K,A443Y,H468R,Q491 K;A159R.T41 1 K,A443Y,H468R,Q491 R;A159R.T41 1 K,A 443Y,H468R,Q491 E;A159R.T411 K,A443Y,H468A,Q491 K;A159R.T41 1 K,A443Y,H468A,Q49 1 R;A159R.T411 K,A443Y,H468A,Q491 E;A159R.T411 K,A443Y,H468K,Q491 K;A159R.T41 1 K ,A443Y,H468K,Q491 R;A159R.T411 K,A443Y,H468K,Q491 E;A159R.T41 1 K,A443Y,H468G,Q 491 K;A159R.T411 K,A443Y,H468G,Q491 R;A159R.T411 K,A443Y,H468G,Q491 E;A159R.T41 1 K,A443Y,H468S,Q491 K;A159R.T411 K,A443Y,H468S,Q491 R;A159R.T41 1 K,A443Y,H468S ,Q491 E;A159R.T411 K,A443V,H468R,Q491 K;A159R.T411 K,A443V,H468R,Q491 R;A159R,T 411 K,A443V,H468R,Q491 E;A159R.T411 K,A443V,H468A,Q491 K;A159R.T411 K,A443V,H46 8A.Q491 R;A159R.T41 1 K,A443V,H468A,Q491 E;A159R.T411 K,A443V,H468K,Q491 K;A159R ,T411 K,A443V,H468K,Q491 R;A159R.T411 K,A443V,H468K,Q491 E;A159R.T41 1 K,A443V,H 468G.Q491 K;A159R.T411 K,A443V,H468G,Q491 R;A159R.T411 K,A443V,H468G,Q491 E;A1 59R.T411 K,A443V,H468S,Q491 K;A159R.T41 1 K,A443V,H468S,Q491 R;A159R.T411 K.A443 V,H468S,Q491 E;A159Y,T41 1V,A443I,H468R,Q491 K;A159Y,T41 1V,A443I,H468R,Q491 R;A 159Y.T411 V,A443I,H468R,Q491 E;A159Y.T411 V,A443I,H468A,Q491 K;A159Y.T41 1 V.A443I, H468A.Q491 R;A159Y.T411 V,A443I,H468A,Q491 E;A159Y.T411 V,A443I,H468K,Q491 K;A15 9Y,T41 1 V,A443I,H468K,Q491 R;A159Y,T41 1 V,A443I,H468K,Q491 E;A159Y,T411 V,A443I,H4 68G.Q491 K;A159Y.T411 V,A443I,H468G,Q491 R;A159Y.T41 1 V,A443I,H468G,Q491 E;A159Y ,T411 V,A443I,H468S,Q491 K;A159Y,T411V,A443I,H468S,Q491 R;A159Y,T411 V,A443I,H468

[0115] S.Q491 E;A159Y.T411 V,A443L,H468R,Q491 K;A159Y,T41 1 V,A443L,H468R,Q491 R;A159Y,T 411 V,A443L,H468R,Q491 E;A159Y.T41 1 V,A443L,H468A,Q491 K;A159Y.T411 V,A443L,H468 A.Q491 R;A159Y.T411 V,A443L,H468A,Q491 E;A159Y.T411 V,A443L,H468K,Q491 K;A159Y,T 411 V,A443L,H468K,Q491 R;A159Y.T411 V,A443L,H468K,Q491 E;A159Y.T411 V,A443L,H468 G.Q491 K;A159Y.T411 V,A443L,H468G,Q491 R;A159Y.T41 1 V,A443L,H468G,Q491 E;A159Y, T41 1 V,A443L,H468S,Q491 K;A159Y.T411 V,A443L,H468S,Q491 R;A159Y,T41 1 V,A443L,H46 8S.Q491 E;A159Y.T411 V,A443F,H468R,Q491 K;A159Y.T411 V,A443F,H468R,Q491 R;A159Y ,T411 V,A443F,H468R,Q491 E;A159Y.T411 V,A443F,H468A,Q491 K;A159Y.T411 V,A443F,H4 68A.Q491 R;A159Y.T411 V,A443F,H468A,Q491 E;A159Y.T41 1 V,A443F,H468K,Q491 K;A159 Y.T411 V,A443F,H468K,Q491 R;A159Y.T41 1 V,A443F,H468K,Q491 E;A159Y.T411 V,A443F,H 468G.Q491 K;A159Y.T411 V,A443F,H468G,Q491 R;A159Y.T411 V,A443F,H468G,Q491 E;A15 9Y.T41 1 V,A443F,H468S,Q491 K;A159Y,T411 V,A443F,H468S,Q491 R;A159Y.T411 V.A443F, H468S.Q491 E;A159Y.T411 V,A443M,H468R,Q491 K;A159Y,T41 1 V,A443M,H468R,Q491 R;A 159Y.T411 V,A443M,H468R,Q491 E;A159Y.T41 1 V,A443M,H468A,Q491 K;A159Y.T41 1 V,A44 3M,H468A,Q491 R;A159Y.T411 V,A443M,H468A,Q491 E;A159Y.T41 1 V,A443M,H468K,Q491 K;A159Y.T411 V,A443M,H468K,Q491 R;A159Y.T411 V,A443M,H468K,Q491 E;A159Y.T411 V, A443M,H468G,Q491 K;A159Y.T411 V,A443M,H468G,Q491 R;A159Y.T411 V,A443M,H468G, Q491 E;A159Y.T411 V,A443M,H468S,Q491 K;A159Y.T411 V,A443M,H468S,Q491 R;A159Y,T 411 V,A443M,H468S,Q491 E;A159Y.T411 V,A443Y,H468R,Q491 K;A159Y.T411 V.A443Y.H46 8R.Q491 R;A159Y.T411 V,A443Y,H468R,Q491 E;A159Y.T411 V,A443Y,H468A,Q491 K;A159Y ,T411 V,A443Y,H468A,Q491 R;A159Y,T411 V,A443Y,H468A,Q491 E;A159Y,T41 1 V,A443Y,H4 68K.Q491 K;A159Y.T411 V,A443Y,H468K,Q491 R;A159Y.T41 1 V,A443Y,H468K,Q491 E;A159 Y.T411 V,A443Y,H468G,Q491 K;A159Y.T411 V,A443Y,H468G,Q491 R;A159Y.T41 1 V.A443Y, H468G.Q491 E;A159Y.T411 V,A443Y,H468S,Q491 K;A159Y.T41 1 V,A443Y,H468S,Q491 R;A1 59Y.T411 V,A443Y,H468S,Q491 E;A159Y.T411 V,A443V,H468R,Q491 K;A159Y.T41 1 V.A443 V,H468R,Q491 R;A159Y,T411V,A443V,H468R,Q491 E;A159Y,T411V,A443V,H468A,Q491 K; A159Y.T411 V,A443V,H468A,Q491 R;A159Y.T41 1 V,A443V,H468A,Q491 E;A159Y.T41 1 V,A4 43V,H468K,Q491 K;A159Y.T411 V,A443V,H468K,Q491 R;A159Y.T411 V,A443V,H468K,Q491 E;A159Y.T411 V,A443V,H468G,Q491 K;A159Y.T411 V,A443V,H468G,Q491 R;A159Y.T411 V, A443V,H468G,Q491 E;A159Y.T411 V,A443V,H468S,Q491 K;A159Y.T411 V,A443V,H468S,Q4 91 R;A159Y.T411 V,A443V,H468S,Q491 E;A159Y.T41 1 S,A443I,H468R,Q491 K;A159Y.T41 1 S ,A443I,H468R,Q491 R;A159Y,T411 S,A443I,H468R,Q491 E;A159Y,T41 1 S,A443I,H468A,Q49

[0116] 1 K;A159Y.T411 S,A443I,H468A,Q491 R;A159Y.T411 S,A443I,H468A,Q491 E;A159Y.T411 S,A 443I.H468K.Q491 K;A159Y.T411 S,A443I,H468K,Q491 R;A159Y.T411 S,A443I,H468K,Q491 E ;A159Y.T411 S,A443I,H468G,Q491 K;A159Y.T411 S,A443I,H468G,Q491 R;A159Y.T411 S,A44 3I.H468G.Q491 E;A159Y.T411 S,A443I,H468S,Q491 K;A159Y.T411 S,A443I,H468S,Q491 R;A 159Y.T411 S,A443I,H468S,Q491 E;A159Y.T411 S,A443L,H468R,Q491 K;A159Y.T411 S.A443 L,H468R,Q491 R;A159Y.T411 S,A443L,H468R,Q491 E;A159Y.T41 1 S,A443L,H468A,Q491 K;A 159Y.T411 S,A443L,H468A,Q491 R;A159Y.T41 1 S,A443L,H468A,Q491 E;A159Y.T411 S.A443 L,H468K,Q491 K;A159Y.T411 S,A443L,H468K,Q491 R;A159Y.T41 1 S,A443L,H468K,Q491 E;A 159Y.T411 S,A443L,H468G,Q491 K;A159Y.T411 S,A443L,H468G,Q491 R;A159Y.T411 S,A44 3L,H468G,Q491 E;A159Y.T411 S,A443L,H468S,Q491 K;A159Y.T41 1 S,A443L,H468S,Q491 R; A159Y.T411 S,A443L,H468S,Q491 E;A159Y.T41 1 S,A443F,H468R,Q491 K;A159Y.T41 1 S,A44 3F,H468R,Q491 R;A159Y.T411 S,A443F,H468R,Q491 E;A159Y.T41 1 S,A443F,H468A,Q491 K ;A159Y.T411 S,A443F,H468A,Q491 R;A159Y.T411 S,A443F,H468A,Q491 E;A159Y.T41 1 S,A4 43F,H468K,Q491 K;A159Y.T411 S,A443F,H468K,Q491 R;A159Y.T411 S,A443F,H468K,Q491 E;A159Y.T411 S,A443F,H468G,Q491 K;A159Y.T411 S,A443F,H468G,Q491 R;A159Y.T411 S, A443F,H468G,Q491 E;A159Y.T41 1 S,A443F,H468S,Q491 K;A159Y.T411 S,A443F,H468S,Q4 91 R;A159Y.T411 S,A443F,H468S,Q491 E;A159Y.T411 S,A443M,H468R,Q491 K;A159Y.T411 S,A443M,H468R,Q491 R;A159Y.T411 S,A443M,H468R,Q491 E;A159Y.T411 S,A443M,H468A ,Q491 K;A159Y.T411 S,A443M,H468A,Q491 R;A159Y.T41 1 S,A443M,H468A,Q491 E;A159Y,T 411 S,A443M,H468K,Q491 K;A159Y.T411 S,A443M,H468K,Q491 R;A159Y.T411 S,A443M,H4 68K.Q491 E;A159Y.T411 S,A443M,H468G,Q491 K;A159Y.T411 S,A443M,H468G,Q491 R;A15 9Y.T41 1 S,A443M,H468G,Q491 E;A159Y.T411 S,A443M,H468S,Q491 K;A159Y.T411 S.A443 M,H468S,Q491 R;A159Y.T411 S,A443M,H468S,Q491 E;A159Y.T41 1 S,A443Y,H468R,Q491 K; A159Y.T411 S,A443Y,H468R,Q491 R;A159Y.T41 1 S,A443Y,H468R,Q491 E;A159Y.T411 S,A4 43Y,H468A,Q491 K;A159Y.T411 S,A443Y,H468A,Q491 R;A159Y.T411 S,A443Y,H468A,Q491 E;A159Y.T411 S,A443Y,H468K,Q491 K;A159Y.T411 S,A443Y,H468K,Q491 R;A159Y.T411 S,A 443Y,H468K,Q491 E;A159Y.T41 1 S,A443Y,H468G,Q491 K;A159Y.T411 S,A443Y,H468G,Q49

[0117] I R;A159Y.T41 1 S,A443Y,H468G,Q491 E;A159Y.T411 S,A443Y,H468S,Q491 K;A159Y.T411 S, A443Y,H468S,Q491 R;A159Y.T411 S,A443Y,H468S,Q491 E;A159Y.T411 S,A443V,H468R,Q4 91 K;A159Y.T411 S,A443V,H468R,Q491 R;A159Y.T41 1 S,A443V,H468R,Q491 E;A159Y.T411 S,A443V,H468A,Q491 K;A159Y.T411 S,A443V,H468A,Q491 R;A159Y.T41 1 S,A443V,H468A, Q491 E;A159Y.T411 S,A443V,H468K,Q491 K;A159Y.T41 1 S,A443V,H468K,Q491 R;A159Y.T4

[0118] I I S,A443V,H468K,Q491 E;A159Y.T411 S,A443V,H468G,Q491 K;A159Y.T411 S,A443V,H468 G.Q491 R;A159Y.T411 S,A443V,H468G,Q491 E;A159Y.T41 1 S,A443V,H468S,Q491 K;A159Y, T41 1 S,A443V,H468S,Q491 R;A159Y.T41 1 S,A443V,H468S,Q491 E;A159Y.T411 A,A443I,H46 8R.Q491 K;A159Y.T41 1 A,A443I,H468R,Q491 R;A159Y.T411 A,A443I,H468R,Q491 E;A159Y, T41 1 A,A443I,H468A,Q491 K;A159Y.T411 A,A443I,H468A,Q491 R;A159Y.T411 A.A443I.H468 A,Q491 E;A159Y.T411 A,A443I,H468K,Q491 K;A159Y,T41 1 A,A443I,H468K,Q491 R;A159Y,T4 11 A,A443I,H468K,Q491 E;A159Y,T411 A,A443I,H468G,Q491 K;A159Y,T411 A.A443I.H468G, Q491 R;A159Y,T411A,A443I,H468G,Q491 E;A159Y,T411A,A443I,H468S,Q491 K;A159Y,T41

[0119] 1 A,A443I,H468S,Q491 R;A159Y,T41 1 A,A443I,H468S,Q491 E;A159Y.T411 A,A443L,H468R,Q 491 K;A159Y.T411 A,A443L,H468R,Q491 R;A159Y.T411 A,A443L,H468R,Q491 E;A159Y.T41 1 A,A443L,H468A,Q491 K;A159Y,T411A,A443L,H468A,Q491 R;A159Y,T411A,A443L,H468A,Q 491 E;A159Y.T411 A,A443L,H468K,Q491 K;A159Y.T411 A,A443L,H468K,Q491 R;A159Y.T411 A,A443L,H468K,Q491 E;A159Y.T411 A,A443L,H468G,Q491 K;A159Y.T41 1 A,A443L,H468G, Q491 R;A159Y.T411 A,A443L,H468G,Q491 E;A159Y.T41 1 A,A443L,H468S,Q491 K;A159Y.T4 11 A,A443L,H468S,Q491 R;A159Y.T41 1 A,A443L,H468S,Q491 E;A159Y.T411 A,A443F,H468 R.Q491 K;A159Y.T411 A,A443F,H468R,Q491 R;A159Y.T41 1 A,A443F,H468R,Q491 E;A159Y, T41 1 A,A443F,H468A,Q491 K;A159Y,T41 1 A,A443F,H468A,Q491 R;A159Y,T41 1 A,A443F,H4 68A.Q491 E;A159Y.T411 A,A443F,H468K,Q491 K;A159Y.T411 A,A443F,H468K,Q491 R;A159 Y.T411 A,A443F,H468K,Q491 E;A159Y.T411 A,A443F,H468G,Q491 K;A159Y,T41 1 A,A443F,H 468G.Q491 R;A159Y.T411 A,A443F,H468G,Q491 E;A159Y.T411 A,A443F,H468S,Q491 K;A15 9Y.T41 1 A,A443F,H468S,Q491 R;A159Y,T41 1 A,A443F,H468S,Q491 E;A159Y,T411 A.A443M, H468R.Q491 K;A159Y.T411 A,A443M,H468R,Q491 R;A159Y.T411 A,A443M,H468R,Q491 E;A 159Y.T411 A,A443M,H468A,Q491 K;A159Y.T411 A,A443M,H468A,Q491 R;A159Y,T41 1 A,A44 3M,H468A,Q491 E;A159Y.T411 A,A443M,H468K,Q491 K;A159Y.T411 A,A443M,H468K,Q491 R;A159Y.T411 A,A443M,H468K,Q491 E;A159Y,T411 A,A443M,H468G,Q491 K;A159Y,T41 1 A, A443M,H468G,Q491 R;A159Y.T41 1 A,A443M,H468G,Q491 E;A159Y.T411 A,A443M,H468S,Q 491 K;A159Y.T411 A,A443M,H468S,Q491 R;A159Y.T411 A,A443M,H468S,Q491 E;A159Y.T41

[0120] I A,A443Y,H468R,Q491 K;A159Y,T411 A,A443Y,H468R,Q491 R;A159Y,T41 1 A,A443Y,H468R ,Q491 E;A159Y.T411 A,A443Y,H468A,Q491 K;A159Y.T411 A,A443Y,H468A,Q491 R;A159Y.T4

[0121] I I A,A443Y,H468A,Q491 E;A159Y,T411 A,A443Y,H468K,Q491 K;A159Y,T41 1 A,A443Y,H468 K.Q491 R;A159Y.T411 A,A443Y,H468K,Q491 E;A159Y.T411 A,A443Y,H468G,Q491 K;A159Y, T41 1 A,A443Y,H468G,Q491 R;A159Y.T41 1 A,A443Y,H468G,Q491 E;A159Y.T411 A,A443Y,H4 68S.Q491 K;A159Y.T411 A,A443Y,H468S,Q491 R;A159Y.T41 1 A,A443Y,H468S,Q491 E;A159 Y.T411 A,A443V,H468R,Q491 K;A159Y,T41 1 A,A443V,H468R,Q491 R;A159Y,T41 1 A.A443V, H468R.Q491 E;A159Y.T41 1 A,A443V,H468A,Q491 K;A159Y.T411 A,A443V,H468A,Q491 R;A1 59Y.T411 A,A443V,H468A,Q491 E;A159Y.T411 A,A443V,H468K,Q491 K;A159Y.T411 A.A443 V,H468K,Q491 R;A159Y.T411 A,A443V,H468K,Q491 E;A159Y.T411 A,A443V,H468G,Q491 K; A159Y.T411 A,A443V,H468G,Q491 R;A159Y.T411 A,A443V,H468G,Q491 E;A159Y.T411 A,A4 43V,H468S,Q491 K;A159Y.T411 A,A443V,H468S,Q491 R;A159Y.T411 A,A443V,H468S,Q491 E;A159Y.T411 Q,A443I,H468R,Q491 K;A159Y.T411 Q,A443I,H468R,Q491 R;A159Y.T41 1 Q,A 443I.H468R.Q491 E;A159Y.T411 Q,A443I,H468A,Q491 K;A159Y.T411 Q,A443I,H468A,Q491 R;A159Y.T411 Q,A443I,H468A,Q491 E;A159Y.T41 1 Q,A443I,H468K,Q491 K;A159Y.T411 Q,A 443I.H468K.Q491 R;A159Y.T41 1 Q,A443I,H468K,Q491 E;A159Y.T411 Q,A443I,H468G,Q491 K;A159Y.T411 Q,A443I,H468G,Q491 R;A159Y.T411 Q,A443I,H468G,Q491 E;A159Y.T41 1 Q,A 443I.H468S.Q491 K;A159Y.T411 Q,A443I,H468S,Q491 R;A159Y.T411 Q,A443I,H468S,Q491 E ;A159Y.T411 Q,A443L,H468R,Q491 K;A159Y.T411 Q,A443L,H468R,Q491 R;A159Y.T411 Q,A 443L,H468R,Q491 E;A159Y.T411 Q,A443L,H468A,Q491 K;A159Y.T411 Q,A443L,H468A,Q49

[0122] 1 R;A159Y.T41 1 Q,A443L,H468A,Q491 E;A159Y.T41 1 Q,A443L,H468K,Q491 K;A159Y.T41 1 Q, A443L,H468K,Q491 R;A159Y.T411 Q,A443L,H468K,Q491 E;A159Y.T411 Q,A443L,H468G,Q4 91 K;A159Y.T411 Q,A443L,H468G,Q491 R;A159Y.T411 Q,A443L,H468G,Q491 E;A159Y.T411 Q,A443L,H468S,Q491 K;A159Y.T411 Q,A443L,H468S,Q491 R;A159Y.T411 Q,A443L,H468S, Q491 E;A159Y.T411 Q,A443F,H468R,Q491 K;A159Y.T411 Q,A443F,H468R,Q491 R;A159Y.T4 11 Q,A443F,H468R,Q491 E;A159Y.T41 1 Q,A443F,H468A,Q491 K;A159Y.T411 Q,A443F,H468 A.Q491 R;A159Y.T411 Q,A443F,H468A,Q491 E;A159Y.T411 Q,A443F,H468K,Q491 K;A159Y, T41 1 Q,A443F,H468K,Q491 R;A159Y.T411 Q,A443F,H468K,Q491 E;A159Y.T41 1 Q,A443F,H4 68G.Q491 K;A159Y.T411 Q,A443F,H468G,Q491 R;A159Y.T41 1 Q,A443F,H468G,Q491 E;A15 9Y.T41 1 Q,A443F,H468S,Q491 K;A159Y.T41 1 Q,A443F,H468S,Q491 R;A159Y.T41 1 Q.A443F ,H468S,Q491 E;A159Y.T411 Q,A443M,H468R,Q491 K;A159Y.T411 Q,A443M,H468R,Q491 R; A159Y.T411 Q,A443M,H468R,Q491 E;A159Y.T41 1 Q,A443M,H468A,Q491 K;A159Y.T411 Q,A 443M,H468A,Q491 R;A159Y.T411 Q,A443M,H468A,Q491 E;A159Y.T411 Q,A443M,H468K,Q4 91 K;A159Y.T411 Q,A443M,H468K,Q491 R;A159Y.T411 Q,A443M,H468K,Q491 E;A159Y.T41 1 Q,A443M,H468G,Q491 K;A159Y.T41 1 Q,A443M,H468G,Q491 R;A159Y.T411 Q,A443M,H46 8G.Q491 E;A159Y.T41 1 Q,A443M,H468S,Q491 K;A159Y.T411 Q,A443M,H468S,Q491 R;A159 Y.T411 Q,A443M,H468S,Q491 E;A159Y.T411 Q,A443Y,H468R,Q491 K;A159Y.T411 Q.A443Y, H468R.Q491 R;A159Y.T411 Q,A443Y,H468R,Q491 E;A159Y.T411 Q,A443Y,H468A,Q491 K;A 159Y.T411 Q,A443Y,H468A,Q491 R;A159Y.T41 1 Q,A443Y,H468A,Q491 E;A159Y.T411 Q,A44 3Y,H468K,Q491 K;A159Y.T411 Q,A443Y,H468K,Q491 R;A159Y.T41 1 Q,A443Y,H468K,Q491 E;A159Y.T411 Q,A443Y,H468G,Q491 K;A159Y.T411 Q,A443Y,H468G,Q491 R;A159Y.T411 Q, A443Y,H468G,Q491 E;A159Y.T411 Q,A443Y,H468S,Q491 K;A159Y.T411 Q,A443Y,H468S,Q 491 R;A159Y.T411 Q,A443Y,H468S,Q491 E;A159Y.T411 Q,A443V,H468R,Q491 K;A159Y.T41 1 Q,A443V,H468R,Q491 R;A159Y.T411 Q,A443V,H468R,Q491 E;A159Y.T41 1 Q,A443V,H468 A.Q491 K;A159Y.T411 Q,A443V,H468A,Q491 R;A159Y.T411 Q,A443V,H468A,Q491 E;A159Y, T41 1 Q,A443V,H468K,Q491 K;A159Y.T41 1 Q,A443V,H468K,Q491 R;A159Y.T41 1 Q,A443V,H4 68K.Q491 E;A159Y.T411 Q,A443V,H468G,Q491 K;A159Y.T41 1 Q,A443V,H468G,Q491 R;A15 9Y.T41 1 Q,A443V,H468G,Q491 E;A159Y.T411 Q,A443V,H468S,Q491 K;A159Y.T41 1 Q.A443V ,H468S,Q491 R;A159Y.T411 Q,A443V,H468S,Q491 E;A159Y.T41 1 E,A443I,H468R,Q491 K;A1 59Y.T411 E,A443I,H468R,Q491 R;A159Y.T411 E,A443I,H468R,Q491 E;A159Y.T411 E.A443I, H468A.Q491 K;A159Y.T411 E,A443I,H468A,Q491 R;A159Y.T411 E,A443I,H468A,Q491 E;A15 9Y.T41 1 E,A443I,H468K,Q491 K;A159Y.T411 E,A443I,H468K,Q491 R;A159Y.T411 E.A443I.H4 68K.Q491 E;A159Y.T411 E,A443I,H468G,Q491 K;A159Y.T411 E,A443I,H468G,Q491 R;A159Y ,T411 E,A443I,H468G,Q491 E;A159Y.T411 E,A443I,H468S,Q491 K;A159Y.T411 E.A443I.H468 S.Q491 R;A159Y.T411 E,A443I,H468S,Q491 E;A159Y.T41 1 E,A443L,H468R,Q491 K;A159Y,T 411 E,A443L,H468R,Q491 R;A159Y.T411 E,A443L,H468R,Q491 E;A159Y.T411 E,A443L,H468 A.Q491 K;A159Y.T411 E,A443L,H468A,Q491 R;A159Y.T411 E,A443L,H468A,Q491 E;A159Y,T 411 E,A443L,H468K,Q491 K;A159Y.T411 E,A443L,H468K,Q491 R;A159Y.T411 E,A443L,H468 K.Q491 E;A159Y.T411 E,A443L,H468G,Q491 K;A159Y.T41 1 E,A443L,H468G,Q491 R;A159Y, T41 1 E,A443L,H468G,Q491 E;A159Y.T411 E,A443L,H468S,Q491 K;A159Y.T41 1 E,A443L,H46 8S.Q491 R;A159Y.T411 E,A443L,H468S,Q491 E;A159Y.T41 1 E,A443F,H468R,Q491 K;A159Y, T41 1 E,A443F,H468R,Q491 R;A159Y.T41 1 E,A443F,H468R,Q491 E;A159Y.T411 E,A443F,H4 68A.Q491 K;A159Y.T411 E,A443F,H468A,Q491 R;A159Y.T411 E,A443F,H468A,Q491 E;A159 Y.T411 E,A443F,H468K,Q491 K;A159Y.T411 E,A443F,H468K,Q491 R;A159Y.T411 E,A443F,H 468K.Q491 E;A159Y.T411 E,A443F,H468G,Q491 K;A159Y.T411 E,A443F,H468G,Q491 R;A15 9Y.T41 1 E,A443F,H468G,Q491 E;A159Y.T41 1 E,A443F,H468S,Q491 K;A159Y.T41 1 E.A443F, H468S.Q491 R;A159Y.T411 E,A443F,H468S,Q491 E;A159Y.T411 E,A443M,H468R,Q491 K;A1 59Y.T411 E,A443M,H468R,Q491 R;A159Y.T41 1 E,A443M,H468R,Q491 E;A159Y.T411 E.A443 M,H468A,Q491 K;A159Y.T411 E,A443M,H468A,Q491 R;A159Y.T411 E,A443M,H468A,Q491 E ;A159Y.T411 E,A443M,H468K,Q491 K;A159Y.T41 1 E,A443M,H468K,Q491 R;A159Y.T411 E,A 443M,H468K,Q491 E;A159Y.T41 1 E,A443M,H468G,Q491 K;A159Y.T411 E,A443M,H468G,Q4 91 R;A159Y.T411 E,A443M,H468G,Q491 E;A159Y.T411 E,A443M,H468S,Q491 K;A159Y.T41 1 E,A443M,H468S,Q491 R;A159Y.T41 1 E,A443M,H468S,Q491 E;A159Y.T41 1 E,A443Y,H468R, Q491 K;A159Y.T411 E,A443Y,H468R,Q491 R;A159Y.T411 E,A443Y,H468R,Q491 E;A159Y.T4 11 E,A443Y,H468A,Q491 K;A159Y.T411 E,A443Y,H468A,Q491 R;A159Y.T411 E,A443Y,H468 A.Q491 E;A159Y.T411 E,A443Y,H468K,Q491 K;A159Y.T41 1 E,A443Y,H468K,Q491 R;A159Y, T41 1 E,A443Y,H468K,Q491 E;A159Y.T41 1 E,A443Y,H468G,Q491 K;A159Y.T411 E,A443Y,H4 68G.Q491 R;A159Y.T411 E,A443Y,H468G,Q491 E;A159Y.T411 E,A443Y,H468S,Q491 K;A159 Y.T411 E,A443Y,H468S,Q491 R;A159Y.T411 E,A443Y,H468S,Q491 E;A159Y.T411 E.A443V, H468R.Q491 K;A159Y.T41 1 E,A443V,H468R,Q491 R;A159Y.T411 E,A443V,H468R,Q491 E;A1 59Y.T411 E,A443V,H468A,Q491 K;A159Y.T411 E,A443V,H468A,Q491 R;A159Y.T411 E.A443 V,H468A,Q491 E;A159Y.T41 1 E,A443V,H468K,Q491 K;A159Y.T411 E,A443V,H468K,Q491 R; A159Y.T411 E,A443V,H468K,Q491 E;A159Y.T411 E,A443V,H468G,Q491 K;A159Y.T41 1 E,A4 43V,H468G,Q491 R;A159Y.T411 E,A443V,H468G,Q491 E;A159Y.T41 1 E,A443V,H468S,Q491 K;A159Y.T411 E,A443V,H468S,Q491 R;A159Y.T411 E,A443V,H468S,Q491 E;A159Y.T411 K,A 443I.H468R.Q491 K;A159Y.T41 1 K,A443I,H468R,Q491 R;A159Y.T411 K,A443I,H468R,Q491 E ;A159Y.T411 K,A443I,H468A,Q491 K;A159Y.T41 1 K,A443I,H468A,Q491 R;A159Y.T41 1 K,A44 3I.H468A.Q491 E;A159Y.T41 1 K,A443I,H468K,Q491 K;A159Y.T411 K,A443I,H468K,Q491 R;A 159Y.T411 K,A443I,H468K,Q491 E;A159Y.T41 1 K,A443I,H468G,Q491 K;A159Y.T411 K.A443I, H468G.Q491 R;A159Y.T411 K,A443I,H468G,Q491 E;A159Y.T41 1 K,A443I,H468S,Q491 K;A15 9Y.T41 1 K,A443I,H468S,Q491 R;A159Y.T41 1 K.A443I.H468S.Q491 E;A159Y.T411 K,A443L,H 468R.Q491 K;A159Y.T41 1 K,A443L,H468R,Q491 R;A159Y.T411 K,A443L,H468R,Q491 E;A15 9Y.T41 1 K,A443L,H468A,Q491 K;A159Y.T411 K,A443L,H468A,Q491 R;A159Y.T41 1 K.A443L, H468A.Q491 E;A159Y.T411 K,A443L,H468K,Q491 K;A159Y.T411 K,A443L,H468K,Q491 R;A1 59Y.T411 K,A443L,H468K,Q491 E;A159Y.T411 K,A443L,H468G,Q491 K;A159Y.T411 K.A443L ,H468G,Q491 R;A159Y.T411 K,A443L,H468G,Q491 E;A159Y.T411 K,A443L,H468S,Q491 K;A 159Y.T411 K,A443L,H468S,Q491 R;A159Y.T41 1 K,A443L,H468S,Q491 E;A159Y.T411 K.A443 F,H468R,Q491 K;A159Y.T41 1 K,A443F,H468R,Q491 R;A159Y.T411 K,A443F,H468R,Q491 E; A159Y.T411 K,A443F,H468A,Q491 K;A159Y.T41 1 K,A443F,H468A,Q491 R;A159Y.T41 1 K,A4 43F,H468A,Q491 E;A159Y.T411 K,A443F,H468K,Q491 K;A159Y.T411 K,A443F,H468K,Q491 R;A159Y.T411 K,A443F,H468K,Q491 E;A159Y.T41 1 K,A443F,H468G,Q491 K;A159Y.T411 K,A 443F,H468G,Q491 R;A159Y.T411 K,A443F,H468G,Q491 E;A159Y.T411 K,A443F,H468S,Q49 1 K;A159Y.T411 K,A443F,H468S,Q491 R;A159Y.T411 K,A443F,H468S,Q491 E;A159Y.T411 K, A443M,H468R,Q491 K;A159Y.T411 K,A443M,H468R,Q491 R;A159Y.T41 1 K,A443M,H468R,Q 491 E;A159Y.T411 K,A443M,H468A,Q491 K;A159Y.T41 1 K,A443M,H468A,Q491 R;A159Y.T41

[0123] I K,A443M,H468A,Q491 E;A159Y.T411 K,A443M,H468K,Q491 K;A159Y.T411 K,A443M,H468 K.Q491 R;A159Y.T411 K,A443M,H468K,Q491 E;A159Y.T411 K,A443M,H468G,Q491 K;A159Y, T41 1 K,A443M,H468G,Q491 R;A159Y.T41 1 K,A443M,H468G,Q491 E;A159Y.T411 K,A443M,H 468S.Q491 K;A159Y.T411 K,A443M,H468S,Q491 R;A159Y.T411 K,A443M,H468S,Q491 E;A15 9Y.T41 1 K,A443Y,H468R,Q491 K;A159Y.T41 1 K,A443Y,H468R,Q491 R;A159Y.T41 1 K.A443Y, H468R.Q491 E;A159Y.T41 1 K,A443Y,H468A,Q491 K;A159Y.T411 K,A443Y,H468A,Q491 R;A1 59Y.T411 K,A443Y,H468A,Q491 E;A159Y.T411 K,A443Y,H468K,Q491 K;A159Y.T411 K.A443 Y,H468K,Q491 R;A159Y.T411 K,A443Y,H468K,Q491 E;A159Y.T411 K,A443Y,H468G,Q491 K; A159Y.T411 K,A443Y,H468G,Q491 R;A159Y.T411 K,A443Y,H468G,Q491 E;A159Y.T411 K,A4 43Y,H468S,Q491 K;A159Y.T411 K,A443Y,H468S,Q491 R;A159Y.T411 K,A443Y,H468S,Q491 E;A159Y.T411 K,A443V,H468R,Q491 K;A159Y.T411 K,A443V,H468R,Q491 R;A159Y.T41 1 K, A443V,H468R,Q491 E;A159Y.T411 K,A443V,H468A,Q491 K;A159Y.T411 K,A443V,H468A,Q4 91 R;A159Y.T411 K,A443V,H468A,Q491 E;A159Y.T411 K,A443V,H468K,Q491 K;A159Y.T411 K,A443V,H468K,Q491 R;A159Y.T411 K,A443V,H468K,Q491 E;A159Y.T41 1 K,A443V,H468G, Q491 K;A159Y.T411 K,A443V,H468G,Q491 R;A159Y.T41 1 K,A443V,H468G,Q491 E;A159Y.T4

[0124] I I K,A443V,H468S,Q491 K;A159Y.T411 K,A443V,H468S,Q491 R;A159Y.T411 K,A443V,H468 S.Q491 E;A159T.T41 1 V,A443I,H468R,Q491 K;A159T.T411 V,A443I,H468R,Q491 R;A159T.T4 11 V,A443I,H468R,Q491 E;A159T,T41 1 V,A443I,H468A,Q491 K;A159T.T411 V,A443I,H468A, Q491 R;A159T.T411 V,A443I,H468A,Q491 E;A159T.T41 1 V,A443I,H468K,Q491 K;A159T.T411 V,A443I,H468K,Q491 R;A159T,T411V,A443I,H468K,Q491 E;A159T,T411 V,A443I,H468G,Q4 91 K;A159T.T411 V,A443I,H468G,Q491 R;A159T.T411 V,A443I,H468G,Q491 E;A159T.T411 V, A443I,H468S,Q491 K;A159T.T41 1 V,A443I,H468S,Q491 R;A159T,T411 V,A443I,H468S,Q491 E;A159T.T411 V,A443L,H468R,Q491 K;A159T.T411 V,A443L,H468R,Q491 R;A159T.T411 V,A 443L,H468R,Q491 E;A159T,T411 V,A443L,H468A,Q491 K;A159T,T41 1 V,A443L,H468A,Q491 R;A159T.T411 V,A443L,H468A,Q491 E;A159T.T41 1 V,A443L,H468K,Q491 K;A159T.T41 1 V,A 443L,H468K,Q491 R;A159T.T411 V,A443L,H468K,Q491 E;A159T.T411 V,A443L,H468G,Q491 K;A159T.T41 1 V,A443L,H468G,Q491 R;A159T.T411 V,A443L,H468G,Q491 E;A159T.T411 V,A 443L,H468S,Q491 K;A159T.T41 1 V,A443L,H468S,Q491 R;A159T.T41 1 V,A443L,H468S,Q491 E;A159T.T411 V,A443F,H468R,Q491 K;A159T.T411 V,A443F,H468R,Q491 R;A159T.T411 V,A 443F,H468R,Q491 E;A159T,T411 V,A443F,H468A,Q491 K;A159T.T41 1 V,A443F,H468A,Q491 R;A159T,T411V,A443F,H468A,Q491 E;A159T,T411V,A443F,H468K,Q491 K;A159T,T411V,A 443F,H468K,Q491 R;A159T,T411 V,A443F,H468K,Q491 E;A159T.T41 1 V,A443F,H468G,Q49

[0125] I K;A159T.T41 1 V,A443F,H468G,Q491 R;A159T.T411 V,A443F,H468G,Q491 E;A159T,T411 V, A443F,H468S,Q491 K;A159T,T411 V,A443F,H468S,Q491 R;A159T,T41 1 V,A443F,H468S,Q4 91 E;A159T.T411 V,A443M,H468R,Q491 K;A159T.T411 V,A443M,H468R,Q491 R;A159T.T411 V,A443M,H468R,Q491 E;A159T,T411V,A443M,H468A,Q491 K;A159T,T411V,A443M,H468A, Q491 R;A159T.T411 V,A443M,H468A,Q491 E;A159T.T411 V,A443M,H468K,Q491 K;A159T.T4

[0126] I I V,A443M,H468K,Q491 R;A159T.T41 1 V,A443M,H468K,Q491 E;A159T.T411 V,A443M,H468 G.Q491 K;A159T.T411 V,A443M,H468G,Q491 R;A159T.T41 1 V,A443M,H468G,Q491 E;A159T, T41 1 V,A443M,H468S,Q491 K;A159T.T411 V,A443M,H468S,Q491 R;A159T.T411 V,A443M,H 468S.Q491 E;A159T.T41 1 V,A443Y,H468R,Q491 K;A159T.T411 V,A443Y,H468R,Q491 R;A15 9T.T411 V,A443Y,H468R,Q491 E;A159T,T411 V,A443Y,H468A,Q491 K;A159T.T41 1 V.A443Y, H468A.Q491 R;A159T.T411 V,A443Y,H468A,Q491 E;A159T.T411 V,A443Y,H468K,Q491 K;A1 59T.T41 1 V,A443Y,H468K,Q491 R;A159T.T411 V,A443Y,H468K,Q491 E;A159T,T411 V.A443Y ,H468G,Q491 K;A159T.T411 V,A443Y,H468G,Q491 R;A159T.T41 1 V,A443Y,H468G,Q491 E;A 159T.T411 V,A443Y,H468S,Q491 K;A159T.T41 1 V,A443Y,H468S,Q491 R;A159T.T41 1 V.A443 Y,H468S,Q491 E;A159T.T41 1 V,A443V,H468R,Q491 K;A159T.T411 V,A443V,H468R,Q491 R; A159T.T411 V,A443V,H468R,Q491 E;A159T.T411 V,A443V,H468A,Q491 K;A159T.T411 V,A44 3V,H468A,Q491 R;A159T.T411 V,A443V,H468A,Q491 E;A159T.T41 1 V,A443V,H468K,Q491 K; A159T.T411 V,A443V,H468K,Q491 R;A159T.T411 V,A443V,H468K,Q491 E;A159T.T41 1 V,A44 3V,H468G,Q491 K;A159T.T411 V,A443V,H468G,Q491 R;A159T.T411 V,A443V,H468G,Q491 E;A159T.T411 V,A443V,H468S,Q491 K;A159T.T41 1 V,A443V,H468S,Q491 R;A159T.T411 V,A 443V,H468S,Q491 E;A159T.T411 S,A443I,H468R,Q491 K;A159T.T411 S,A443I,H468R,Q491 R;A159T.T411 S,A443I,H468R,Q491 E;A159T.T411 S,A443I,H468A,Q491 K;A159T.T41 1 S,A4 43I.H468A.Q491 R;A159T.T411 S,A443I,H468A,Q491 E;A159T.T411 S,A443I,H468K,Q491 K; A159T.T411 S,A443I,H468K,Q491 R;A159T.T411 S,A443I,H468K,Q491 E;A159T.T411 S.A443 l,H468G,Q491 K;A159T.T41 1 S,A443I,H468G,Q491 R;A159T.T411 S,A443I,H468G,Q491 E;A1 59T.T41 1 S,A443I,H468S,Q491 K;A159T.T41 1 S,A443I,H468S,Q491 R;A159T.T41 1 S.A443I.H 468S.Q491 E;A159T.T41 1 S,A443L,H468R,Q491 K;A159T.T411 S,A443L,H468R,Q491 R;A159 T.T411 S,A443L,H468R,Q491 E;A159T.T411 S,A443L,H468A,Q491 K;A159T.T411 S,A443L,H 468A.Q491 R;A159T.T411 S,A443L,H468A,Q491 E;A159T.T41 1 S,A443L,H468K,Q491 K;A159 T.T411 S,A443L,H468K,Q491 R;A159T.T411 S,A443L,H468K,Q491 E;A159T.T411 S,A443L,H 468G.Q491 K;A159T.T411 S,A443L,H468G,Q491 R;A159T.T41 1 S,A443L,H468G,Q491 E;A15 9T.T411 S,A443L,H468S,Q491 K;A159T.T411 S,A443L,H468S,Q491 R;A159T.T41 1 S.A443L, H468S.Q491 E;A159T.T411 S,A443F,H468R,Q491 K;A159T.T411 S,A443F,H468R,Q491 R;A1 59T.T41 1 S,A443F,H468R,Q491 E;A159T.T411 S,A443F,H468A,Q491 K;A159T.T411 S.A443F ,H468A,Q491 R;A159T.T41 1 S,A443F,H468A,Q491 E;A159T.T41 1 S,A443F,H468K,Q491 K;A1 59T.T41 1 S,A443F,H468K,Q491 R;A159T.T411 S,A443F,H468K,Q491 E;A159T.T411 S.A443F ,H468G,Q491 K;A159T.T411 S,A443F,H468G,Q491 R;A159T.T411 S,A443F,H468G,Q491 E;A 159T.T411 S,A443F,H468S,Q491 K;A159T.T411 S,A443F,H468S,Q491 R;A159T.T41 1 S.A443 F,H468S,Q491 E;A159T.T411 S,A443M,H468R,Q491 K;A159T.T411 S,A443M,H468R,Q491 R; A159T.T411 S,A443M,H468R,Q491 E;A159T.T41 1 S,A443M,H468A,Q491 K;A159T.T41 1 S,A4 43M,H468A,Q491 R;A159T.T411 S,A443M,H468A,Q491 E;A159T.T411 S,A443M,H468K,Q49

[0127] I K;A159T.T41 1 S,A443M,H468K,Q491 R;A159T.T411 S,A443M,H468K,Q491 E;A159T.T41 1 S ,A443M,H468G,Q491 K;A159T.T41 1 S,A443M,H468G,Q491 R;A159T.T411 S,A443M,H468G, Q491 E;A159T.T411 S,A443M,H468S,Q491 K;A159T.T411 S,A443M,H468S,Q491 R;A159T.T4

[0128] I I S,A443M,H468S,Q491 E;A159T.T411 S,A443Y,H468R,Q491 K;A159T.T411 S,A443Y,H468 R.Q491 R;A159T.T41 1 S,A443Y,H468R,Q491 E;A159T.T411 S,A443Y,H468A,Q491 K;A159T, T41 1 S,A443Y,H468A,Q491 R;A159T.T41 1 S,A443Y,H468A,Q491 E;A159T.T41 1 S,A443Y,H4 68K.Q491 K;A159T.T411 S,A443Y,H468K,Q491 R;A159T.T411 S,A443Y,H468K,Q491 E;A159 T.T411 S,A443Y,H468G,Q491 K;A159T.T411 S,A443Y,H468G,Q491 R;A159T.T411 S.A443Y, H468G.Q491 E;A159T.T41 1 S,A443Y,H468S,Q491 K;A159T.T41 1 S,A443Y,H468S,Q491 R;A1 59T.T41 1 S,A443Y,H468S,Q491 E;A159T.T41 1 S,A443V,H468R,Q491 K;A159T.T411 S.A443V ,H468R,Q491 R;A159T.T411 S,A443V,H468R,Q491 E;A159T.T411 S,A443V,H468A,Q491 K;A

[0129] 159T.T411 S,A443V,H468A,Q491 R;A159T.T411 S,A443V,H468A,Q491 E;A159T.T41 1 S.A443 V,H468K,Q491 K;A159T.T41 1 S,A443V,H468K,Q491 R;A159T.T41 1 S,A443V,H468K,Q491 E; A159T.T411 S,A443V,H468G,Q491 K;A159T.T411 S,A443V,H468G,Q491 R;A159T.T41 1 S,A4 43V,H468G,Q491 E;A159T.T41 1 S,A443V,H468S,Q491 K;A159T.T411 S,A443V,H468S,Q491 R;A159T,T411 S,A443V,H468S,Q491 E;A159T,T411A,A443I,H468R,Q491 K;A159T,T411A,A 443I,H468R,Q491 R;A159T,T41 1 A,A443I,H468R,Q491 E;A159T,T411 A,A443I,H468A,Q491 K ;A159T,T41 1 A,A443I,H468A,Q491 R;A159T,T411 A,A443I,H468A,Q491 E;A159T,T411 A,A44 3I,H468K,Q491 K;A159T,T411A,A443I,H468K,Q491 R;A159T,T411A,A443I,H468K,Q491 E;A 159T.T411 A,A443I,H468G,Q491 K;A159T.T41 1 A,A443I,H468G,Q491 R;A159T.T411 A.A443I, H468G.Q491 E;A159T,T411 A,A443I,H468S,Q491 K;A159T,T41 1 A,A443I,H468S,Q491 R;A15 9T,T411 A,A443I,H468S,Q491 E;A159T,T41 1 A,A443L,H468R,Q491 K;A159T,T411 A,A443L,H 468R.Q491 R;A159T.T411 A,A443L,H468R,Q491 E;A159T.T411 A,A443L,H468A,Q491 K;A159 T.T411 A,A443L,H468A,Q491 R;A159T.T411 A,A443L,H468A,Q491 E;A159T.T411 A,A443L,H 468K.Q491 K;A159T.T41 1 A,A443L,H468K,Q491 R;A159T.T411 A,A443L,H468K,Q491 E;A159 T.T411 A,A443L,H468G,Q491 K;A159T.T41 1 A,A443L,H468G,Q491 R;A159T.T41 1 A,A443L,H 468G.Q491 E;A159T.T411 A,A443L,H468S,Q491 K;A159T.T411 A,A443L,H468S,Q491 R;A159 T.T411 A,A443L,H468S,Q491 E;A159T.T411 A,A443F,H468R,Q491 K;A159T.T411 A,A443F,H 468R.Q491 R;A159T.T411 A,A443F,H468R,Q491 E;A159T.T411 A,A443F,H468A,Q491 K;A15 9T.T411 A,A443F,H468A,Q491 R;A159T.T411 A,A443F,H468A,Q491 E;A159T.T411 A.A443F, H468K.Q491 K;A159T.T41 1 A,A443F,H468K,Q491 R;A159T.T41 1 A,A443F,H468K,Q491 E;A1 59T.T41 1 A,A443F,H468G,Q491 K;A159T.T411 A,A443F,H468G,Q491 R;A159T.T411 A.A443 F,H468G,Q491 E;A159T.T41 1 A,A443F,H468S,Q491 K;A159T.T411 A,A443F,H468S,Q491 R; A159T.T411 A,A443F,H468S,Q491 E;A159T,T41 1 A,A443M,H468R,Q491 K;A159T,T411 A,A4 43M,H468R,Q491 R;A159T.T41 1 A,A443M,H468R,Q491 E;A159T.T41 1 A,A443M,H468A,Q49 1 K;A159T.T41 1 A,A443M,H468A,Q491 R;A159T.T411 A,A443M,H468A,Q491 E;A159T.T41 1 A ,A443M,H468K,Q491 K;A159T.T411 A,A443M,H468K,Q491 R;A159T.T411 A,A443M,H468K,Q 491 E;A159T.T411 A,A443M,H468G,Q491 K;A159T.T411 A,A443M,H468G,Q491 R;A159T.T41 1A,A443M,H468G,Q491 E;A159T,T41 1A,A443M,H468S,Q491 K;A159T,T411 A,A443M,H468

[0130] S.Q491 R;A159T.T41 1 A,A443M,H468S,Q491 E;A159T.T411 A,A443Y,H468R,Q491 K;A159T, T41 1 A,A443Y,H468R,Q491 R;A159T,T411 A,A443Y,H468R,Q491 E;A159T,T411 A,A443Y,H4 68A.Q491 K;A159T.T411 A,A443Y,H468A,Q491 R;A159T.T411 A,A443Y,H468A,Q491 E;A159

[0131] T.T411 A,A443Y,H468K,Q491 K;A159T,T41 1 A,A443Y,H468K,Q491 R;A159T,T411 A,A443Y,H 468K.Q491 E;A159T.T41 1 A,A443Y,H468G,Q491 K;A159T.T41 1 A,A443Y,H468G,Q491 R;A15 9T.T411 A,A443Y,H468G,Q491 E;A159T.T411 A,A443Y,H468S,Q491 K;A159T.T411 A.A443Y, H468S.Q491 R;A159T.T411 A,A443Y,H468S,Q491 E;A159T.T411 A,A443V,H468R,Q491 K;A1 59T.T41 1 A,A443V,H468R,Q491 R;A159T,T411 A,A443V,H468R,Q491 E;A159T,T411 A.A443 V,H468A,Q491 K;A159T,T41 1A,A443V,H468A,Q491 R;A159T,T41 1 A,A443V,H468A,Q491 E;

[0132] A159T.T411 A,A443V,H468K,Q491 K;A159T.T41 1 A,A443V,H468K,Q491 R;A159T.T41 1 A,A44 3V,H468K,Q491 E;A159T.T411 A,A443V,H468G,Q491 K;A159T.T411 A,A443V,H468G,Q491 R ;A159T.T41 1 A,A443V,H468G,Q491 E;A159T.T41 1 A,A443V,H468S,Q491 K;A159T.T411 A,A4 43V,H468S,Q491 R;A159T,T41 1 A,A443V,H468S,Q491 E;A159T,T411 Q,A443I,H468R,Q491 K;A159T.T41 1 Q,A443I,H468R,Q491 R;A159T.T411 Q,A443I,H468R,Q491 E;A159T.T411 Q,A 443I,H468A,Q491 K;A159T.T411 Q,A443I,H468A,Q491 R;A159T,T41 1 Q,A443I,H468A,Q491 E ;A159T.T41 1 Q,A443I,H468K,Q491 K;A159T.T41 1 Q,A443I,H468K,Q491 R;A159T.T41 1 Q,A44 3I.H468K.Q491 E;A159T.T411 Q,A443I,H468G,Q491 K;A159T.T411 Q,A443I,H468G,Q491 R;A 159T.T411 Q,A443I,H468G,Q491 E;A159T.T41 1 Q,A443I,H468S,Q491 K;A159T.T41 1 Q.A443I ,H468S,Q491 R;A159T.T41 1 Q,A443I,H468S,Q491 E;A159T.T411 Q,A443L,H468R,Q491 K;A1 59T.T41 1 Q,A443L,H468R,Q491 R;A159T.T41 1 Q,A443L,H468R,Q491 E;A159T.T411 Q.A443 L,H468A,Q491 K;A159T.T41 1 Q,A443L,H468A,Q491 R;A159T.T411 Q,A443L,H468A,Q491 E;A 159T.T411 Q,A443L,H468K,Q491 K;A159T.T41 1 Q,A443L,H468K,Q491 R;A159T.T41 1 Q.A443 L,H468K,Q491 E;A159T.T411 Q,A443L,H468G,Q491 K;A159T.T41 1 Q,A443L,H468G,Q491 R; A159T.T41 1 Q,A443L,H468G,Q491 E;A159T.T411 Q,A443L,H468S,Q491 K;A159T.T411 Q,A4 43L,H468S,Q491 R;A159T.T41 1 Q,A443L,H468S,Q491 E;A159T.T41 1 Q,A443F,H468R,Q491 K;A159T.T41 1 Q,A443F,H468R,Q491 R;A159T.T411 Q,A443F,H468R,Q491 E;A159T.T411 Q, A443F,H468A,Q491 K;A159T.T411 Q,A443F,H468A,Q491 R;A159T.T411 Q,A443F,H468A,Q4 91 E;A159T.T411 Q,A443F,H468K,Q491 K;A159T.T411 Q,A443F,H468K,Q491 R;A159T.T411 Q,A443F,H468K,Q491 E;A159T.T411 Q,A443F,H468G,Q491 K;A159T.T411 Q,A443F,H468G, Q491 R;A159T.T411 Q,A443F,H468G,Q491 E;A159T.T411 Q,A443F,H468S,Q491 K;A159T.T4 11 Q,A443F,H468S,Q491 R;A159T.T411 Q,A443F,H468S,Q491 E;A159T.T411 Q,A443M,H468

[0133] R.Q491 K;A159T.T411 Q,A443M,H468R,Q491 R;A159T.T411 Q,A443M,H468R,Q491 E;A159T ,T411 Q,A443M,H468A,Q491 K;A159T.T411 Q,A443M,H468A,Q491 R;A159T.T41 1 Q.A443M, H468A.Q491 E;A159T.T411 Q,A443M,H468K,Q491 K;A159T.T411 Q,A443M,H468K,Q491 R;A 159T.T411 Q,A443M,H468K,Q491 E;A159T.T411 Q,A443M,H468G,Q491 K;A159T.T411 Q,A4 43M,H468G,Q491 R;A159T.T411 Q,A443M,H468G,Q491 E;A159T.T411 Q,A443M,H468S,Q49

[0134] I K;A159T.T41 1 Q,A443M,H468S,Q491 R;A159T.T411 Q,A443M,H468S,Q491 E;A159T.T411 Q,A443Y,H468R,Q491 K;A159T.T41 1 Q,A443Y,H468R,Q491 R;A159T.T411 Q,A443Y,H468R, Q491 E;A159T.T411 Q,A443Y,H468A,Q491 K;A159T.T411 Q,A443Y,H468A,Q491 R;A159T.T4

[0135] I I Q,A443Y,H468A,Q491 E;A159T.T411 Q,A443Y,H468K,Q491 K;A159T.T41 1 Q,A443Y,H468 K.Q491 R;A159T.T41 1 Q,A443Y,H468K,Q491 E;A159T.T41 1 Q,A443Y,H468G,Q491 K;A159T, T41 1 Q,A443Y,H468G,Q491 R;A159T.T411 Q,A443Y,H468G,Q491 E;A159T.T411 Q,A443Y,H 468S.Q491 K;A159T.T41 1 Q,A443Y,H468S,Q491 R;A159T.T411 Q,A443Y,H468S,Q491 E;A15 9T.T411 Q,A443V,H468R,Q491 K;A159T.T411 Q,A443V,H468R,Q491 R;A159T.T411 Q.A443V ,H468R,Q491 E;A159T.T41 1 Q,A443V,H468A,Q491 K;A159T.T411 Q,A443V,H468A,Q491 R;A 159T.T411 Q,A443V,H468A,Q491 E;A159T.T411 Q,A443V,H468K,Q491 K;A159T.T411 Q,A44 3V,H468K,Q491 R;A159T.T411 Q,A443V,H468K,Q491 E;A159T.T411 Q,A443V,H468G,Q491 K;A159T.T41 1 Q,A443V,H468G,Q491 R;A159T.T41 1 Q,A443V,H468G,Q491 E;A159T.T41 1 Q, A443V,H468S,Q491 K;A159T.T411 Q,A443V,H468S,Q491 R;A159T.T411 Q,A443V,H468S,Q4 91 E;A159T.T411 E,A443I,H468R,Q491 K;A159T.T411 E,A443I,H468R,Q491 R;A159T.T41 1 E, A443I.H468R.Q491 E;A159T.T411 E,A443I,H468A,Q491 K;A159T.T41 1 E,A443I,H468A,Q491 R;A159T.T411 E,A443I,H468A,Q491 E;A159T.T411 E,A443I,H468K,Q491 K;A159T.T411 E,A4 43I.H468K.Q491 R;A159T.T411 E,A443I,H468K,Q491 E;A159T.T411 E,A443I,H468G,Q491 K; A159T.T411 E,A443I,H468G,Q491 R;A159T.T411 E,A443I,H468G,Q491 E;A159T.T411 E.A443 l,H468S,Q491 K;A159T.T411 E,A443I,H468S,Q491 R;A159T.T41 1 E,A443I,H468S,Q491 E;A1 59T.T41 1 E,A443L,H468R,Q491 K;A159T.T411 E,A443L,H468R,Q491 R;A159T.T41 1 E.A443L ,H468R,Q491 E;A159T.T41 1 E,A443L,H468A,Q491 K;A159T.T411 E,A443L,H468A,Q491 R;A1 59T.T41 1 E,A443L,H468A,Q491 E;A159T.T411 E,A443L,H468K,Q491 K;A159T.T411 E.A443L, H468K.Q491 R;A159T.T411 E,A443L,H468K,Q491 E;A159T.T411 E,A443L,H468G,Q491 K;A1 59T.T41 1 E,A443L,H468G,Q491 R;A159T.T411 E,A443L,H468G,Q491 E;A159T.T411 E.A443L ,H468S,Q491 K;A159T.T411 E,A443L,H468S,Q491 R;A159T.T41 1 E,A443L,H468S,Q491 E;A1 59T.T41 1 E,A443F,H468R,Q491 K;A159T.T411 E,A443F,H468R,Q491 R;A159T.T41 1 E.A443F ,H468R,Q491 E;A159T.T411 E,A443F,H468A,Q491 K;A159T.T411 E,A443F,H468A,Q491 R;A1 59T.T41 1 E,A443F,H468A,Q491 E;A159T.T411 E,A443F,H468K,Q491 K;A159T.T411 E.A443F ,H468K,Q491 R;A159T.T41 1 E,A443F,H468K,Q491 E;A159T.T411 E,A443F,H468G,Q491 K;A1 59T.T41 1 E,A443F,H468G,Q491 R;A159T.T41 1 E,A443F,H468G,Q491 E;A159T.T41 1 E.A443

[0136] F,H468S,Q491 K;A159T.T411 E,A443F,H468S,Q491 R;A159T.T411 E,A443F,H468S,Q491 E;A 159T.T411 E,A443M,H468R,Q491 K;A159T.T411 E,A443M,H468R,Q491 R;A159T.T411 E,A44 3M,H468R,Q491 E;A159T.T411 E,A443M,H468A,Q491 K;A159T.T411 E,A443M,H468A,Q491 R;A159T.T41 1 E,A443M,H468A,Q491 E;A159T.T411 E,A443M,H468K,Q491 K;A159T.T411 E, A443M,H468K,Q491 R;A159T.T41 1 E,A443M,H468K,Q491 E;A159T.T411 E,A443M,H468G,Q 491 K;A159T.T411 E,A443M,H468G,Q491 R;A159T.T41 1 E,A443M,H468G,Q491 E;A159T.T41 1 E,A443M,H468S,Q491 K;A159T.T411 E,A443M,H468S,Q491 R;A159T.T411 E,A443M,H468

[0137] S.Q491 E;A159T.T41 1 E,A443Y,H468R,Q491 K;A159T.T41 1 E,A443Y,H468R,Q491 R;A159T, T41 1 E,A443Y,H468R,Q491 E;A159T.T41 1 E,A443Y,H468A,Q491 K;A159T.T41 1 E,A443Y,H4 68A.Q491 R;A159T.T41 1 E,A443Y,H468A,Q491 E;A159T.T411 E,A443Y,H468K,Q491 K;A159

[0138] T.T411 E,A443Y,H468K,Q491 R;A159T.T411 E,A443Y,H468K,Q491 E;A159T.T41 1 E,A443Y,H 468G.Q491 K;A159T.T411 E,A443Y,H468G,Q491 R;A159T.T411 E,A443Y,H468G,Q491 E;A15 9T.T411 E,A443Y,H468S,Q491 K;A159T.T411 E,A443Y,H468S,Q491 R;A159T.T411 E.A443Y, H468S.Q491 E;A159T.T411 E,A443V,H468R,Q491 K;A159T.T41 1 E,A443V,H468R,Q491 R;A1 59T.T41 1 E,A443V,H468R,Q491 E;A159T.T411 E,A443V,H468A,Q491 K;A159T.T411 E.A443V ,H468A,Q491 R;A159T.T41 1 E,A443V,H468A,Q491 E;A159T.T411 E,A443V,H468K,Q491 K;A1 59T.T41 1 E,A443V,H468K,Q491 R;A159T.T411 E,A443V,H468K,Q491 E;A159T.T411 E.A443V ,H468G,Q491 K;A159T.T411 E,A443V,H468G,Q491 R;A159T.T41 1 E,A443V,H468G,Q491 E;A 159T.T411 E,A443V,H468S,Q491 K;A159T.T41 1 E,A443V,H468S,Q491 R;A159T.T411 E.A443 V,H468S,Q491 E;A159T.T411 K,A443I,H468R,Q491 K;A159T.T411 K,A443I,H468R,Q491 R;A1 59T.T41 1 K,A443I,H468R,Q491 E;A159T.T411 K,A443I,H468A,Q491 K;A159T.T411 K.A443I.H 468A.Q491 R;A159T.T411 K,A443I,H468A,Q491 E;A159T.T411 K,A443I,H468K,Q491 K;A159T ,T411 K,A443I,H468K,Q491 R;A159T,T411 K,A443I,H468K,Q491 E;A159T,T411 K.A443I.H468

[0139] G.Q491 K;A159T.T411 K,A443I,H468G,Q491 R;A159T.T41 1 K,A443I,H468G,Q491 E;A159T,T 411 K,A443I,H468S,Q491 K;A159T.T411 K,A443I,H468S,Q491 R;A159T.T411 K.A443I.H468S, Q491 E;A159T.T411 K,A443L,H468R,Q491 K;A159T.T411 K,A443L,H468R,Q491 R;A159T.T41 1 K,A443L,H468R,Q491 E;A159T.T411 K,A443L,H468A,Q491 K;A159T.T41 1 K,A443L,H468A, Q491 R;A159T.T411 K,A443L,H468A,Q491 E;A159T.T411 K,A443L,H468K,Q491 K;A159T.T41

[0140] I K,A443L,H468K,Q491 R;A159T.T411 K,A443L,H468K,Q491 E;A159T.T411 K,A443L,H468G, Q491 K;A159T.T411 K,A443L,H468G,Q491 R;A159T.T411 K,A443L,H468G,Q491 E;A159T.T4

[0141] I I K,A443L,H468S,Q491 K;A159T.T41 1 K,A443L,H468S,Q491 R;A159T.T41 1 K,A443L,H468S ,Q491 E;A159T.T411 K,A443F,H468R,Q491 K;A159T.T411 K,A443F,H468R,Q491 R;A159T.T4 11 K,A443F,H468R,Q491 E;A159T.T411 K,A443F,H468A,Q491 K;A159T.T41 1 K,A443F,H468A ,Q491 R;A159T.T411 K,A443F,H468A,Q491 E;A159T.T411 K,A443F,H468K,Q491 K;A159T.T4 11 K,A443F,H468K,Q491 R;A159T.T411 K,A443F,H468K,Q491 E;A159T.T41 1 K,A443F,H468 G.Q491 K;A159T.T411 K,A443F,H468G,Q491 R;A159T.T41 1 K,A443F,H468G,Q491 E;A159T, T41 1 K,A443F,H468S,Q491 K;A159T.T411 K,A443F,H468S,Q491 R;A159T.T41 1 K,A443F,H46 8S.Q491 E;A159T.T41 1 K,A443M,H468R,Q491 K;A159T.T411 K,A443M,H468R,Q491 R;A159 T.T411 K,A443M,H468R,Q491 E;A159T.T411 K,A443M,H468A,Q491 K;A159T.T411 K.A443M, H468A.Q491 R;A159T.T411 K,A443M,H468A,Q491 E;A159T.T41 1 K,A443M,H468K,Q491 K;A 159T.T411 K,A443M,H468K,Q491 R;A159T.T411 K,A443M,H468K,Q491 E;A159T.T41 1 K,A44 3M,H468G,Q491 K;A159T.T411 K,A443M,H468G,Q491 R;A159T.T411 K,A443M,H468G,Q491 E;A159T.T41 1 K,A443M,H468S,Q491 K;A159T.T411 K,A443M,H468S,Q491 R;A159T.T411 K, A443M,H468S,Q491 E;A159T.T411 K,A443Y,H468R,Q491 K;A159T.T411 K,A443Y,H468R,Q4 91 R;A159T.T411 K,A443Y,H468R,Q491 E;A159T.T411 K,A443Y,H468A,Q491 K;A159T.T411 K,A443Y,H468A,Q491 R;A159T.T411 K,A443Y,H468A,Q491 E;A159T.T411 K,A443Y,H468K, Q491 K;A159T.T411 K,A443Y,H468K,Q491 R;A159T.T411 K,A443Y,H468K,Q491 E;A159T.T4 11 K,A443Y,H468G,Q491 K;A159T.T411 K,A443Y,H468G,Q491 R;A159T.T41 1 K,A443Y,H468 G.Q491 E;A159T.T411 K,A443Y,H468S,Q491 K;A159T.T411 K,A443Y,H468S,Q491 R;A159T, T41 1 K,A443Y,H468S,Q491 E;A159T.T411 K,A443V,H468R,Q491 K;A159T.T41 1 K,A443V,H4 68R.Q491 R;A159T.T411 K,A443V,H468R,Q491 E;A159T.T41 1 K,A443V,H468A,Q491 K;A159 T.T411 K,A443V,H468A,Q491 R;A159T.T411 K,A443V,H468A,Q491 E;A159T.T41 1 K,A443V,H 468K.Q491 K;A159T.T41 1 K,A443V,H468K,Q491 R;A159T.T41 1 K,A443V,H468K,Q491 E;A15 9T.T411 K,A443V,H468G,Q491 K;A159T.T411 K,A443V,H468G,Q491 R;A159T.T411 K.A443V, H468G.Q491 E;A159T.T41 1 K,A443V,H468S,Q491 K;A159T.T41 1 K,A443V,H468S,Q491 R;A1 59T.T41 1 K,A443V,H468S,Q491 E;A159V, T41 1 V,A443I,H468R,Q491 K;A159V, T411 V.A443I, H468R.Q491 R;A159V, T411 V,A443I,H468R,Q491 E;A159V, T411 V,A443I,H468A,Q491 K;A15 9V,T41 1V,A443I,H468A,Q491 R;A159V,T41 1V,A443I,H468A,Q491 E;A159V,T411 V,A443I,H4 68K.Q491 K;A159V, T411 V,A443I,H468K,Q491 R;A159V, T411 V,A443I,H468K,Q491 E;A159V, T411V,A443I,H468G,Q491 K;A159V,T411V,A443I,H468G,Q491 R;A159V,T411V,A443I,H468 G,Q491 E;A159V, T411 V,A443I,H468S,Q491 K;A159V, T411 V,A443I,H468S,Q491 R;A159V, T4 11 V,A443I,H468S,Q491 E;A159V, T411 V,A443L,H468R,Q491 K;A159V.T411 V,A443L,H468R, Q491 R;A159V, T411 V,A443L,H468R,Q491 E;A159V, T41 1 V,A443L,H468A,Q491 K;A159V, T4 11 V,A443L,H468A,Q491 R;A159V,T41 1 V,A443L,H468A,Q491 E;A159V,T411 V,A443L,H468K ,Q491 K;A159V, T411 V,A443L,H468K,Q491 R;A159V, T411 V,A443L,H468K,Q491 E;A159V, T4 11 V,A443L,H468G,Q491 K;A159V,T41 1 V,A443L,H468G,Q491 R;A159V,T41 1 V,A443L,H468 G,Q491 E;A159V, T41 1 V,A443L,H468S,Q491 K;A159V, T41 1 V,A443L,H468S,Q491 R;A159V, T 411 V,A443L,H468S,Q491 E;A159V, T411 V,A443F,H468R,Q491 K;A159V, T41 1 V,A443F,H468 R,Q491 R;A159V, T41 1 V,A443F,H468R,Q491 E;A159V, T411 V,A443F,H468A,Q491 K;A159V, T41 1 V,A443F,H468A,Q491 R;A159V,T41 1 V,A443F,H468A,Q491 E;A159V,T411 V,A443F,H4 68K.Q491 K;A159V, T41 1 V,A443F,H468K,Q491 R;A159V, T411 V,A443F,H468K,Q491 E;A159 V,T411 V,A443F,H468G,Q491 K;A159V, T411 V,A443F,H468G,Q491 R;A159V, T411 V.A443F, H468G.Q491 E;A159V, T411 V,A443F,H468S,Q491 K;A159V, T411 V,A443F,H468S,Q491 R;A1 59V, T411 V,A443F,H468S,Q491 E;A159V,T411 V,A443M,H468R,Q491 K;A159V,T41 1 V.A443 M,H468R,Q491 R;A159V, T411 V,A443M,H468R,Q491 E;A159V, T411 V,A443M,H468A,Q491 K ;A159V,T411V,A443M,H468A,Q491 R;A159V,T411V,A443M,H468A,Q491 E;A159V,T411V,A 443M,H468K,Q491 K;A159V,T41 1 V,A443M,H468K,Q491 R;A159V,T411 V,A443M,H468K,Q4 91 E;A159V.T411 V,A443M,H468G,Q491 K;A159V.T411 V,A443M,H468G,Q491 R;A159V, T41 1 V,A443M,H468G,Q491 E;A159V,T411 V,A443M,H468S,Q491 K;A159V,T411 V,A443M,H468 S,Q491 R;A159V.T411 V,A443M,H468S,Q491 E;A159V.T411 V,A443Y,H468R,Q491 K;A159V, T41 1 V,A443Y,H468R,Q491 R;A159V, T411 V,A443Y,H468R,Q491 E;A159V, T411 V,A443Y,H4 68A.Q491 K;A159V, T411 V,A443Y,H468A,Q491 R;A159V, T41 1 V,A443Y,H468A,Q491 E;A159 V,T411 V,A443Y,H468K,Q491 K;A159V,T41 1 V,A443Y,H468K,Q491 R;A159V,T41 1 V.A443Y, H468K.Q491 E;A159V, T411 V,A443Y,H468G,Q491 K;A159V, T41 1 V,A443Y,H468G,Q491 R;A 159V, T411 V,A443Y,H468G,Q491 E;A159V, T411 V,A443Y,H468S,Q491 K;A159V, T411 V,A44 3Y,H468S,Q491 R;A159V, T41 1 V,A443Y,H468S,Q491 E;A159V, T411 V,A443V,H468R,Q491 K ;A159V, T411 V,A443V,H468R,Q491 R;A159V, T411 V,A443V,H468R,Q491 E;A159V, T411 V,A4 43V,H468A,Q491 K;A159V, T411 V,A443V,H468A,Q491 R;A159V, T411 V,A443V,H468A,Q491 E;A159V,T411 V,A443V,H468K,Q491 K;A159V,T411 V,A443V,H468K,Q491 R;A159V.T411 V,A 443V,H468K,Q491 E;A159V, T41 1 V,A443V,H468G,Q491 K;A159V, T411 V,A443V,H468G,Q49 1 R;A159V,T41 1 V,A443V,H468G,Q491 E;A159V,T411 V,A443V,H468S,Q491 K;A159V,T411 V, A443V,H468S,Q491 R;A159V.T411 V,A443V,H468S,Q491 E;A159V, T411 S,A443I,H468R,Q4 91 K;A159V, T411 S,A443I,H468R,Q491 R;A159V, T41 1 S,A443I,H468R,Q491 E;A159V, T411 S, A443I,H468A,Q491 K;A159V, T411 S,A443I,H468A,Q491 R;A159V, T411 S,A443I,H468A,Q491 E;A159V, T411 S,A443I,H468K,Q491 K;A159V, T41 1 S,A443I,H468K,Q491 R;A159V, T41 1 S,A4 43I,H468K,Q491 E;A159V, T411 S,A443I,H468G,Q491 K;A159V, T411 S,A443I,H468G,Q491 R; A159V, T411 S,A443I,H468G,Q491 E;A159V, T411 S,A443I,H468S,Q491 K;A159V, T411 S,A443 l,H468S,Q491 R;A159V, T41 1 S,A443I,H468S,Q491 E;A159V, T411 S,A443L,H468R,Q491 K;A1 59V, T411 S,A443L,H468R,Q491 R;A159V, T411 S,A443L,H468R,Q491 E;A159V, T411 S.A443L ,H468A,Q491 K;A159V, T411 S,A443L,H468A,Q491 R;A159V, T41 1 S,A443L,H468A,Q491 E;A1 59V, T411 S,A443L,H468K,Q491 K;A159V, T411 S,A443L,H468K,Q491 R;A159V, T41 1 S.A443L ,H468K,Q491 E;A159V, T411 S,A443L,H468G,Q491 K;A159V, T41 1 S,A443L,H468G,Q491 R;A 159V, T411 S,A443L,H468G,Q491 E;A159V, T411 S,A443L,H468S,Q491 K;A159V, T411 S,A443 L,H468S,Q491 R;A159V, T411 S,A443L,H468S,Q491 E;A159V, T41 1 S,A443F,H468R,Q491 K;A 159V, T411 S,A443F,H468R,Q491 R;A159V, T411 S,A443F,H468R,Q491 E;A159V, T41 1 S,A44 3F,H468A,Q491 K;A159V, T411 S,A443F,H468A,Q491 R;A159V, T41 1 S,A443F,H468A,Q491 E; A159V, T411 S,A443F,H468K,Q491 K;A159V, T41 1 S,A443F,H468K,Q491 R;A159V, T411 S,A4 43F,H468K,Q491 E;A159V, T411 S,A443F,H468G,Q491 K;A159V, T411 S,A443F,H468G,Q491 R;A159V, T411 S,A443F,H468G,Q491 E;A159V, T41 1 S,A443F,H468S,Q491 K;A159V, T411 S,A 443F,H468S,Q491 R;A159V, T411 S,A443F,H468S,Q491 E;A159V, T411 S,A443M,H468R,Q49 1 K;A159V, T411 S,A443M,H468R,Q491 R;A159V, T411 S,A443M,H468R,Q491 E;A159V, T411 S,A443M,H468A,Q491 K;A159V, T411 S,A443M,H468A,Q491 R;A159V, T41 1 S,A443M,H468A, Q491 E;A159V, T411 S,A443M,H468K,Q491 K;A159V, T411 S,A443M,H468K,Q491 R;A159V, T 411 S,A443M,H468K,Q491 E;A159V, T411 S,A443M,H468G,Q491 K;A159V, T411 S,A443M,H4 68G.Q491 R;A159V, T411 S,A443M,H468G,Q491 E;A159V, T41 1 S,A443M,H468S,Q491 K;A15 9V,T41 1 S,A443M,H468S,Q491 R;A159V, T411 S,A443M,H468S,Q491 E;A159V, T411 S.A443Y ,H468R,Q491 K;A159V, T411 S,A443Y,H468R,Q491 R;A159V, T411 S,A443Y,H468R,Q491 E;A 159V, T411 S,A443Y,H468A,Q491 K;A159V, T411 S,A443Y,H468A,Q491 R;A159V, T411 S,A44 3Y,H468A,Q491 E;A159V, T411 S,A443Y,H468K,Q491 K;A159V, T411 S,A443Y,H468K,Q491 R ;A159V, T411 S,A443Y,H468K,Q491 E;A159V, T411 S,A443Y,H468G,Q491 K;A159V, T411 S,A4 43Y,H468G,Q491 R;A159V, T411 S,A443Y,H468G,Q491 E;A159V, T41 1 S,A443Y,H468S,Q491 K;A159V, T411 S,A443Y,H468S,Q491 R;A159V, T411 S,A443Y,H468S,Q491 E;A159V, T411 S,A 443V,H468R,Q491 K;A159V, T411 S,A443V,H468R,Q491 R;A159V, T41 1 S,A443V,H468R,Q49

[0142] I E;A159V, T411 S,A443V,H468A,Q491 K;A159V, T411 S,A443V,H468A,Q491 R;A159V, T41 1 S, A443V,H468A,Q491 E;A159V, T411 S,A443V,H468K,Q491 K;A159V, T411 S,A443V,H468K,Q4 91 R;A159V, T411 S,A443V,H468K,Q491 E;A159V, T411 S,A443V,H468G,Q491 K;A159V, T41 1 S,A443V,H468G,Q491 R;A159V, T411 S,A443V,H468G,Q491 E;A159V, T411 S,A443V,H468S, Q491 K;A159V, T411 S,A443V,H468S,Q491 R;A159V, T41 1 S,A443V,H468S,Q491 E;A159V, T4

[0143] I I A,A443I,H468R,Q491 K;A159V,T411 A,A443I,H468R,Q491 R;A159V,T41 1 A,A443I,H468R, Q491 E;A159V.T411 A,A443I,H468A,Q491 K;A159V.T411 A,A443I,H468A,Q491 R;A159V, T41

[0144] I A,A443I,H468A,Q491 E;A159V,T41 1 A,A443I,H468K,Q491 K;A159V.T411 A,A443I,H468K,Q 491 R;A159V.T411 A,A443I,H468K,Q491 E;A159V.T411 A,A443I,H468G,Q491 K;A159V, T41 1 A,A443I,H468G,Q491 R;A159V,T411A,A443I,H468G,Q491 E;A159V,T411A,A443I,H468S,Q4 91 K;A159V,T411A,A443I,H468S,Q491 R;A159V,T411A,A443I,H468S,Q491 E;A159V,T411A, A443L,H468R,Q491 K;A159V.T411 A,A443L,H468R,Q491 R;A159V.T411 A,A443L,H468R,Q4 91 E;A159V, T411 A,A443L,H468A,Q491 K;A159V, T41 1 A,A443L,H468A,Q491 R;A159V.T411 A ,A443L,H468A,Q491 E;A159V,T411A,A443L,H468K,Q491 K;A159V,T411A,A443L,H468K,Q4

[0145] 91 R;A159V.T411 A,A443L,H468K,Q491 E;A159V, T411 A,A443L,H468G,Q491 K;A159V, T41 1 A,A443L,H468G,Q491 R;A159V,T411A,A443L,H468G,Q491 E;A159V,T411A,A443L,H468S, Q491 K;A159V, T41 1 A,A443L,H468S,Q491 R;A159V.T411 A,A443L,H468S,Q491 E;A159V, T4

[0146] I I A,A443F,H468R,Q491 K;A159V,T41 1 A,A443F,H468R,Q491 R;A159V.T411 A,A443F,H468 R,Q491 E;A159V, T411 A,A443F,H468A,Q491 K;A159V.T411 A,A443F,H468A,Q491 R;A159V, T41 1 A,A443F,H468A,Q491 E;A159V, T41 1 A,A443F,H468K,Q491 K;A159V.T411 A,A443F,H46 8K.Q491 R;A159V, T411 A,A443F,H468K,Q491 E;A159V, T411 A,A443F,H468G,Q491 K;A159V ,T411 A,A443F,H468G,Q491 R;A159V.T411 A,A443F,H468G,Q491 E;A159V, T411 A,A443F,H4 68S.Q491 K;A159V, T41 1 A,A443F,H468S,Q491 R;A159V, T411 A,A443F,H468S,Q491 E;A159 V,T411 A,A443M,H468R,Q491 K;A159V,T41 1 A,A443M,H468R,Q491 R;A159V,T411 A.A443M, H468R,Q491 E;A159V,T411A,A443M,H468A,Q491 K;A159V,T411A,A443M,H468A,Q491 R;A 159V.T411 A,A443M,H468A,Q491 E;A159V.T411 A,A443M,H468K,Q491 K;A159V.T411 A,A44 3M,H468K,Q491 R;A159V.T411 A,A443M,H468K,Q491 E;A159V,T41 1 A,A443M,H468G,Q491 K;A159V.T411 A,A443M,H468G,Q491 R;A159V.T411 A,A443M,H468G,Q491 E;A159V, T411 A, A443M,H468S,Q491 K;A159V,T411A,A443M,H468S,Q491 R;A159V,T411A,A443M,H468S,Q 491 E;A159V, T411 A,A443Y,H468R,Q491 K;A159V.T411 A,A443Y,H468R,Q491 R;A159V, T41

[0147] I A,A443Y,H468R,Q491 E;A159V.T411 A,A443Y,H468A,Q491 K;A159V.T411 A,A443Y,H468A, Q491 R;A159V.T411 A,A443Y,H468A,Q491 E;A159V.T411 A,A443Y,H468K,Q491 K;A159V, T4

[0148] I I A,A443Y,H468K,Q491 R;A159V.T411 A,A443Y,H468K,Q491 E;A159V,T411 A,A443Y,H468 G,Q491 K;A159V, T411 A,A443Y,H468G,Q491 R;A159V, T411 A,A443Y,H468G,Q491 E;A159V, T41 1 A,A443Y,H468S,Q491 K;A159V, T41 1 A,A443Y,H468S,Q491 R;A159V.T411 A,A443Y,H4 68S.Q491 E;A159V, T411 A,A443V,H468R,Q491 K;A159V, T41 1 A,A443V,H468R,Q491 R;A159 V,T411 A,A443V,H468R,Q491 E;A159V,T41 1 A,A443V,H468A,Q491 K;A159V,T41 1 A.A443V, H468A.Q491 R;A159V.T411 A,A443V,H468A,Q491 E;A159V.T411 A,A443V,H468K,Q491 K;A1 59V.T411 A,A443V,H468K,Q491 R;A159V.T411 A,A443V,H468K,Q491 E;A159V.T411 A,A443 V,H468G,Q491 K;A159V.T411 A,A443V,H468G,Q491 R;A159V.T411 A,A443V,H468G,Q491 E; A159V.T411 A,A443V,H468S,Q491 K;A159V.T411 A,A443V,H468S,Q491 R;A159V, T41 1 A,A4 43V,H468S,Q491 E;A159V, T411 Q,A443I,H468R,Q491 K;A159V, T411 Q,A443I,H468R,Q491 R ;A159V, T411 Q,A443I,H468R,Q491 E;A159V, T41 1 Q,A443I,H468A,Q491 K;A159V, T411 Q,A44 3I,H468A,Q491 R;A159V, T411 Q,A443I,H468A,Q491 E;A159V, T411 Q,A443I,H468K,Q491 K;A 159V, T411 Q,A443I,H468K,Q491 R;A159V, T411 Q,A443I,H468K,Q491 E;A159V, T411 Q.A443I ,H468G,Q491 K;A159V, T411 Q,A443I,H468G,Q491 R;A159V, T411 Q,A443I,H468G,Q491 E;A1 59V, T411 Q,A443I,H468S,Q491 K;A159V, T411 Q,A443I,H468S,Q491 R;A159V, T411 Q.A443I, H468S.Q491 E;A159V, T411 Q,A443L,H468R,Q491 K;A159V, T41 1 Q,A443L,H468R,Q491 R;A1 59V, T411 Q,A443L,H468R,Q491 E;A159V, T411 Q,A443L,H468A,Q491 K;A159V, T411 Q,A443 L,H468A,Q491 R;A159V, T411 Q,A443L,H468A,Q491 E;A159V, T411 Q,A443L,H468K,Q491 K; A159V, T411 Q,A443L,H468K,Q491 R;A159V, T411 Q,A443L,H468K,Q491 E;A159V, T411 Q,A4 43L,H468G,Q491 K;A159V, T411 Q,A443L,H468G,Q491 R;A159V, T411 Q,A443L,H468G,Q491 E;A159V, T411 Q,A443L,H468S,Q491 K;A159V, T41 1 Q,A443L,H468S,Q491 R;A159V, T41 1 Q, A443L,H468S,Q491 E;A159V, T411 Q,A443F,H468R,Q491 K;A159V, T41 1 Q,A443F,H468R,Q4 91 R;A159V, T411 Q,A443F,H468R,Q491 E;A159V, T411 Q,A443F,H468A,Q491 K;A159V, T411 Q,A443F,H468A,Q491 R;A159V, T411 Q,A443F,H468A,Q491 E;A159V, T411 Q,A443F,H468K, Q491 K;A159V, T411 Q,A443F,H468K,Q491 R;A159V, T411 Q,A443F,H468K,Q491 E;A159V, T4 11 Q,A443F,H468G,Q491 K;A159V, T41 1 Q,A443F,H468G,Q491 R;A159V, T41 1 Q,A443F,H468 G,Q491 E;A159V, T411 Q,A443F,H468S,Q491 K;A159V, T411 Q,A443F,H468S,Q491 R;A159V, T41 1 Q,A443F,H468S,Q491 E;A159V, T411 Q,A443M,H468R,Q491 K;A159V, T411 Q,A443M,H 468R.Q491 R;A159V, T41 1 Q,A443M,H468R,Q491 E;A159V, T41 1 Q,A443M,H468A,Q491 K;A1 59V, T411 Q,A443M,H468A,Q491 R;A159V, T411 Q,A443M,H468A,Q491 E;A159V, T411 Q,A44 3M,H468K,Q491 K;A159V, T411 Q,A443M,H468K,Q491 R;A159V, T411 Q,A443M,H468K,Q491 E;A159V, T411 Q,A443M,H468G,Q491 K;A159V, T41 1 Q,A443M,H468G,Q491 R;A159V, T411 Q ,A443M,H468G,Q491 E;A159V, T411 Q,A443M,H468S,Q491 K;A159V, T411 Q,A443M,H468S, Q491 R;A159V, T411 Q,A443M,H468S,Q491 E;A159V, T411 Q,A443Y,H468R,Q491 K;A159V, T 411 Q,A443Y,H468R,Q491 R;A159V, T411 Q,A443Y,H468R,Q491 E;A159V, T411 Q,A443Y,H4 68A.Q491 K;A159V, T411 Q,A443Y,H468A,Q491 R;A159V, T41 1 Q,A443Y,H468A,Q491 E;A159 V,T411 Q,A443Y,H468K,Q491 K;A159V, T411 Q,A443Y,H468K,Q491 R;A159V, T411 Q.A443Y, H468K.Q491 E;A159V, T411 Q,A443Y,H468G,Q491 K;A159V, T411 Q,A443Y,H468G,Q491 R;A 159V, T411 Q,A443Y,H468G,Q491 E;A159V, T41 1 Q,A443Y,H468S,Q491 K;A159V, T411 Q,A44 3Y,H468S,Q491 R;A159V, T41 1 Q,A443Y,H468S,Q491 E;A159V, T411 Q,A443V,H468R,Q491 K;A159V, T411 Q,A443V,H468R,Q491 R;A159V, T411 Q,A443V,H468R,Q491 E;A159V, T411 Q, A443V,H468A,Q491 K;A159V, T41 1 Q,A443V,H468A,Q491 R;A159V, T411 Q,A443V,H468A,Q 491 E;A159V, T41 1 Q,A443V,H468K,Q491 K;A159V, T411 Q,A443V,H468K,Q491 R;A159V, T41

[0149] I Q,A443V,H468K,Q491 E;A159V, T411 Q,A443V,H468G,Q491 K;A159V, T411 Q,A443V,H468 G,Q491 R;A159V, T411 Q,A443V,H468G,Q491 E;A159V, T411 Q,A443V,H468S,Q491 K;A159V, T41 1 Q,A443V,H468S,Q491 R;A159V, T41 1 Q,A443V,H468S,Q491 E;A159V, T411 E,A443I,H4 68R.Q491 K;A159V, T411 E,A443I,H468R,Q491 R;A159V, T41 1 E,A443I,H468R,Q491 E;A159V, T41 1 E,A443I,H468A,Q491 K;A159V, T411 E,A443I,H468A,Q491 R;A159V, T411 E,A443I,H468 A,Q491 E;A159V, T411 E,A443I,H468K,Q491 K;A159V, T41 1 E,A443I,H468K,Q491 R;A159V, T4

[0150] I I E,A443I,H468K,Q491 E;A159V, T411 E,A443I,H468G,Q491 K;A159V, T411 E,A443I,H468G, Q491 R;A159V, T411 E,A443I,H468G,Q491 E;A159V, T411 E,A443I,H468S,Q491 K;A159V, T41

[0151] I E,A443I,H468S,Q491 R;A159V, T41 1 E,A443I,H468S,Q491 E;A159V, T411 E,A443L,H468R,Q 491 K;A159V, T411 E,A443L,H468R,Q491 R;A159V, T411 E,A443L,H468R,Q491 E;A159V, T41 1 E,A443L,H468A,Q491 K;A159V, T411 E,A443L,H468A,Q491 R;A159V, T411 E,A443L,H468A,Q 491 E;A159V, T41 1 E,A443L,H468K,Q491 K;A159V, T411 E,A443L,H468K,Q491 R;A159V, T411 E,A443L,H468K,Q491 E;A159V, T411 E,A443L,H468G,Q491 K;A159V, T41 1 E,A443L,H468G, Q491 R;A159V, T411 E,A443L,H468G,Q491 E;A159V, T41 1 E,A443L,H468S,Q491 K;A159V, T4

[0152] I I E,A443L,H468S,Q491 R;A159V, T41 1 E,A443L,H468S,Q491 E;A159V, T411 E,A443F,H468 R,Q491 K;A159V, T411 E,A443F,H468R,Q491 R;A159V, T41 1 E,A443F,H468R,Q491 E;A159V, T41 1 E,A443F,H468A,Q491 K;A159V, T411 E,A443F,H468A,Q491 R;A159V, T411 E,A443F,H4 68A.Q491 E;A159V, T411 E,A443F,H468K,Q491 K;A159V, T411 E,A443F,H468K,Q491 R;A159 V,T411 E,A443F,H468K,Q491 E;A159V, T411 E,A443F,H468G,Q491 K;A159V, T41 1 E,A443F,H 468G.Q491 R;A159V, T411 E,A443F,H468G,Q491 E;A159V, T411 E,A443F,H468S,Q491 K;A15 9V,T41 1 E,A443F,H468S,Q491 R;A159V, T41 1 E,A443F,H468S,Q491 E;A159V, T411 E.A443M, H468R.Q491 K;A159V, T411 E,A443M,H468R,Q491 R;A159V, T411 E,A443M,H468R,Q491 E;A 159V, T411 E,A443M,H468A,Q491 K;A159V, T411 E,A443M,H468A,Q491 R;A159V, T41 1 E,A44 3M,H468A,Q491 E;A159V, T411 E,A443M,H468K,Q491 K;A159V, T411 E,A443M,H468K,Q491 R;A159V, T411 E,A443M,H468K,Q491 E;A159V, T411 E,A443M,H468G,Q491 K;A159V, T41 1 E, A443M,H468G,Q491 R;A159V, T41 1 E,A443M,H468G,Q491 E;A159V, T411 E,A443M,H468S,Q 491 K;A159V, T411 E,A443M,H468S,Q491 R;A159V, T411 E,A443M,H468S,Q491 E;A159V, T41

[0153] I E,A443Y,H468R,Q491 K;A159V, T411 E,A443Y,H468R,Q491 R;A159V, T41 1 E,A443Y,H468R ,Q491 E;A159V, T411 E,A443Y,H468A,Q491 K;A159V, T411 E,A443Y,H468A,Q491 R;A159V, T4

[0154] I I E,A443Y,H468A,Q491 E;A159V, T411 E,A443Y,H468K,Q491 K;A159V, T41 1 E,A443Y,H468

[0155] K,Q491 R;A159V, T411 E,A443Y,H468K,Q491 E;A159V, T411 E,A443Y,H468G,Q491 K;A159V, T41 1 E,A443Y,H468G,Q491 R;A159V, T41 1 E,A443Y,H468G,Q491 E;A159V, T41 1 E,A443Y,H4 68S.Q491 K;A159V, T411 E,A443Y,H468S,Q491 R;A159V, T41 1 E,A443Y,H468S,Q491 E;A159 V,T411 E,A443V,H468R,Q491 K;A159V, T41 1 E,A443V,H468R,Q491 R;A159V, T41 1 E.A443V, H468R.Q491 E;A159V, T41 1 E,A443V,H468A,Q491 K;A159V, T411 E,A443V,H468A,Q491 R;A1 59V, T411 E,A443V,H468A,Q491 E;A159V, T411 E,A443V,H468K,Q491 K;A159V, T411 E,A443 V,H468K,Q491 R;A159V, T411 E,A443V,H468K,Q491 E;A159V, T411 E,A443V,H468G,Q491 K; A159V, T411 E,A443V,H468G,Q491 R;A159V, T411 E,A443V,H468G,Q491 E;A159V, T411 E,A4 43V,H468S,Q491 K;A159V, T411 E,A443V,H468S,Q491 R;A159V, T411 E,A443V,H468S,Q491 E;A159V, T411 K,A443I,H468R,Q491 K;A159V, T411 K,A443I,H468R,Q491 R;A159V, T411 K,A4 43I,H468R,Q491 E;A159V, T411 K,A443I,H468A,Q491 K;A159V, T411 K,A443I,H468A,Q491 R; A159V, T411 K,A443I,H468A,Q491 E;A159V, T411 K,A443I,H468K,Q491 K;A159V, T41 1 K,A443 l,H468K,Q491 R;A159V, T41 1 K,A443I,H468K,Q491 E;A159V, T411 K,A443I,H468G,Q491 K;A1 59V, T411 K,A443I,H468G,Q491 R;A159V, T41 1 K,A443I,H468G,Q491 E;A159V, T41 1 K.A443I, H468S.Q491 K;A159V, T411 K,A443I,H468S,Q491 R;A159V, T411 K,A443I,H468S,Q491 E;A15 9V,T41 1 K,A443L,H468R,Q491 K;A159V, T411 K,A443L,H468R,Q491 R;A159V, T411 K.A443L, H468R.Q491 E;A159V, T41 1 K,A443L,H468A,Q491 K;A159V, T41 1 K,A443L,H468A,Q491 R;A1 59V, T411 K,A443L,H468A,Q491 E;A159V, T411 K,A443L,H468K,Q491 K;A159V, T411 K.A443L ,H468K,Q491 R;A159V, T411 K,A443L,H468K,Q491 E;A159V, T411 K,A443L,H468G,Q491 K;A1 59V, T411 K,A443L,H468G,Q491 R;A159V, T411 K,A443L,H468G,Q491 E;A159V, T411 K,A443

[0156] L,H468S,Q491 K;A159V, T411 K,A443L,H468S,Q491 R;A159V, T411 K,A443L,H468S,Q491 E;A 159V, T411 K,A443F,H468R,Q491 K;A159V, T411 K,A443F,H468R,Q491 R;A159V, T41 1 K,A44 3F,H468R,Q491 E;A159V, T41 1 K,A443F,H468A,Q491 K;A159V, T411 K,A443F,H468A,Q491 R; A159V, T411 K,A443F,H468A,Q491 E;A159V, T41 1 K,A443F,H468K,Q491 K;A159V, T41 1 K,A44 3F,H468K,Q491 R;A159V, T41 1 K,A443F,H468K,Q491 E;A159V, T41 1 K,A443F,H468G,Q491 K ;A159V, T411 K,A443F,H468G,Q491 R;A159V, T411 K,A443F,H468G,Q491 E;A159V, T411 K,A4 43F,H468S,Q491 K;A159V, T411 K,A443F,H468S,Q491 R;A159V, T411 K,A443F,H468S,Q491 E;A159V, T411 K,A443M,H468R,Q491 K;A159V, T411 K,A443M,H468R,Q491 R;A159V, T411 K, A443M,H468R,Q491 E;A159V, T411 K,A443M,H468A,Q491 K;A159V, T411 K,A443M,H468A,Q 491 R;A159V, T411 K,A443M,H468A,Q491 E;A159V, T411 K,A443M,H468K,Q491 K;A159V, T41 I K,A443M,H468K,Q491 R;A159V, T411 K,A443M,H468K,Q491 E;A159V, T41 1 K,A443M,H468 G,Q491 K;A159V, T411 K,A443M,H468G,Q491 R;A159V, T411 K,A443M,H468G,Q491 E;A159V ,T411 K,A443M,H468S,Q491 K;A159V, T411 K,A443M,H468S,Q491 R;A159V, T411 K,A443M,H 468S.Q491 E;A159V, T411 K,A443Y,H468R,Q491 K;A159V, T411 K,A443Y,H468R,Q491 R;A15 9V,T41 1 K,A443Y,H468R,Q491 E;A159V, T41 1 K,A443Y,H468A,Q491 K;A159V, T41 1 K.A443Y, H468A.Q491 R;A159V, T411 K,A443Y,H468A,Q491 E;A159V, T411 K,A443Y,H468K,Q491 K;A1 59V, T411 K,A443Y,H468K,Q491 R;A159V, T411 K,A443Y,H468K,Q491 E;A159V, T411 K,A443 Y,H468G,Q491 K;A159V, T411 K,A443Y,H468G,Q491 R;A159V, T411 K,A443Y,H468G,Q491 E; A159V, T411 K,A443Y,H468S,Q491 K;A159V, T411 K,A443Y,H468S,Q491 R;A159V, T411 K,A4 43Y,H468S,Q491 E;A159V, T411 K,A443V,H468R,Q491 K;A159V, T41 1 K,A443V,H468R,Q491 R;A159V, T411 K,A443V,H468R,Q491 E;A159V, T41 1 K,A443V,H468A,Q491 K;A159V, T411 K, A443V,H468A,Q491 R;A159V, T411 K,A443V,H468A,Q491 E;A159V, T411 K,A443V,H468K,Q4 91 K;A159V, T411 K,A443V,H468K,Q491 R;A159V, T411 K,A443V,H468K,Q491 E;A159V, T41 1 K,A443V,H468G,Q491 K;A159V, T411 K,A443V,H468G,Q491 R;A159V, T41 1 K,A443V,H468G, Q491 E;A159V, T411 K,A443V,H468S,Q491 K;A159V, T41 1 K,A443V,H468S,Q491 R;A159V, T4

[0157] I I K,A443V,H468S,Q491 E;A159S,T411 V,A443I,H468R,Q491 K;A159S,T41 1 V,A443I,H468R, Q491 R;A159S.T411 V,A443I,H468R,Q491 E;A159S.T41 1 V,A443I,H468A,Q491 K;A159S.T41

[0158] 1 V,A443I,H468A,Q491 R;A159S,T41 1 V,A443I,H468A,Q491 E;A159S.T411 V,A443I,H468K,Q 491 K;A159S.T411 V,A443I,H468K,Q491 R;A159S.T41 1 V,A443I,H468K,Q491 E;A159S.T411 V ,A443I,H468G,Q491 K;A159S,T411 V,A443I,H468G,Q491 R;A159S,T411V,A443I,H468G,Q49 1 E;A159S.T411 V,A443I,H468S,Q491 K;A159S.T411 V,A443I,H468S,Q491 R;A159S.T411 V,A 443I,H468S,Q491 E;A159S.T411 V,A443L,H468R,Q491 K;A159S.T411 V,A443L,H468R,Q491 R;A159S.T411 V,A443L,H468R,Q491 E;A159S.T411 V,A443L,H468A,Q491 K;A159S.T41 1 V,A 443L,H468A,Q491 R;A159S.T411 V,A443L,H468A,Q491 E;A159S.T41 1 V,A443L,H468K,Q491 K;A159S,T411 V,A443L,H468K,Q491 R;A159S,T41 1 V,A443L,H468K,Q491 E;A159S,T411 V,A 443L,H468G,Q491 K;A159S.T411 V,A443L,H468G,Q491 R;A159S.T411 V,A443L,H468G,Q49

[0159] I E;A159S.T411 V,A443L,H468S,Q491 K;A159S.T41 1 V,A443L,H468S,Q491 R;A159S.T411 V, A443L,H468S,Q491 E;A159S.T41 1 V,A443F,H468R,Q491 K;A159S,T411 V,A443F,H468R,Q4 91 R;A159S.T411 V,A443F,H468R,Q491 E;A159S.T41 1 V,A443F,H468A,Q491 K;A159S.T411 V,A443F,H468A,Q491 R;A159S.T411 V,A443F,H468A,Q491 E;A159S.T411 V,A443F,H468K, Q491 K;A159S.T411 V,A443F,H468K,Q491 R;A159S.T41 1 V,A443F,H468K,Q491 E;A159S,T4

[0160] I I V,A443F,H468G,Q491 K;A159S,T41 1 V,A443F,H468G,Q491 R;A159S,T41 1 V,A443F,H468 G,Q491 E;A159S.T411 V,A443F,H468S,Q491 K;A159S.T41 1 V,A443F,H468S,Q491 R;A159S, T41 1 V,A443F,H468S,Q491 E;A159S.T411 V,A443M,H468R,Q491 K;A159S.T411 V,A443M,H4 68R.Q491 R;A159S.T411 V,A443M,H468R,Q491 E;A159S.T411 V,A443M,H468A,Q491 K;A15 9S,T41 1 V,A443M,H468A,Q491 R;A159S,T411 V,A443M,H468A,Q491 E;A159S.T411 V,A443 M,H468K,Q491 K;A159S.T411 V,A443M,H468K,Q491 R;A159S.T411 V,A443M,H468K,Q491 E ;A159S.T411 V,A443M,H468G,Q491 K;A159S.T411 V,A443M,H468G,Q491 R;A159S.T411 V,A 443M,H468G,Q491 E;A159S,T411V,A443M,H468S,Q491 K;A159S,T411V,A443M,H468S,Q4 91 R;A159S.T411 V,A443M,H468S,Q491 E;A159S.T41 1 V,A443Y,H468R,Q491 K;A159S.T411 V,A443Y,H468R,Q491 R;A159S,T411V,A443Y,H468R,Q491 E;A159S,T411V,A443Y,H468A, Q491 K;A159S.T411 V,A443Y,H468A,Q491 R;A159S.T411 V,A443Y,H468A,Q491 E;A159S.T4 11 V,A443Y,H468K,Q491 K;A159S,T411 V,A443Y,H468K,Q491 R;A159S,T411 V,A443Y,H468

[0161] K.Q491 E;A159S.T411 V,A443Y,H468G,Q491 K;A159S.T41 1 V,A443Y,H468G,Q491 R;A159S, T41 1 V,A443Y,H468G,Q491 E;A159S,T411 V,A443Y,H468S,Q491 K;A159S,T41 1 V,A443Y,H4 68S.Q491 R;A159S.T411 V,A443Y,H468S,Q491 E;A159S.T411 V,A443V,H468R,Q491 K;A159 S.T411 V,A443V,H468R,Q491 R;A159S.T411 V,A443V,H468R,Q491 E;A159S.T41 1 V.A443V, H468A.Q491 K;A159S.T411 V,A443V,H468A,Q491 R;A159S.T411 V,A443V,H468A,Q491 E;A1 59S.T411 V,A443V,H468K,Q491 K;A159S.T411 V,A443V,H468K,Q491 R;A159S.T411 V.A443 V,H468K,Q491 E;A159S.T41 1 V,A443V,H468G,Q491 K;A159S.T411 V,A443V,H468G,Q491 R; A159S.T411 V,A443V,H468G,Q491 E;A159S.T411 V,A443V,H468S,Q491 K;A159S.T41 1 V,A4 43V,H468S,Q491 R;A159S.T411 V,A443V,H468S,Q491 E;A159S.T41 1 S,A443I,H468R,Q491 K;A159S.T411 S,A443I,H468R,Q491 R;A159S.T411 S,A443I,H468R,Q491 E;A159S.T411 S,A4 43I.H468A.Q491 K;A159S.T411 S,A443I,H468A,Q491 R;A159S.T411 S,A443I,H468A,Q491 E;

[0162] A159S.T411 S,A443I,H468K,Q491 K;A159S.T411 S,A443I,H468K,Q491 R;A159S.T411 S.A443 l,H468K,Q491 E;A159S.T411 S,A443I,H468G,Q491 K;A159S.T411 S,A443I,H468G,Q491 R;A1 59S.T411 S,A443I,H468G,Q491 E;A159S.T411 S,A443I,H468S,Q491 K;A159S.T41 1 S.A443I, H468S.Q491 R;A159S.T411 S,A443I,H468S,Q491 E;A159S.T411 S,A443L,H468R,Q491 K;A15 9S.T41 1 S,A443L,H468R,Q491 R;A159S.T411 S,A443L,H468R,Q491 E;A159S.T411 S.A443L, H468A.Q491 K;A159S.T411 S,A443L,H468A,Q491 R;A159S.T41 1 S,A443L,H468A,Q491 E;A1 59S.T411 S,A443L,H468K,Q491 K;A159S.T411 S,A443L,H468K,Q491 R;A159S.T41 1 S.A443L ,H468K,Q491 E;A159S.T411 S,A443L,H468G,Q491 K;A159S.T41 1 S,A443L,H468G,Q491 R;A 159S.T411 S,A443L,H468G,Q491 E;A159S.T411 S,A443L,H468S,Q491 K;A159S.T411 S.A443

[0163] L,H468S,Q491 R;A159S.T411 S,A443L,H468S,Q491 E;A159S.T41 1 S,A443F,H468R,Q491 K;A 159S.T411 S,A443F,H468R,Q491 R;A159S.T411 S,A443F,H468R,Q491 E;A159S.T41 1 S,A44 3F,H468A,Q491 K;A159S.T411 S,A443F,H468A,Q491 R;A159S.T41 1 S,A443F,H468A,Q491 E; A159S.T411 S,A443F,H468K,Q491 K;A159S.T41 1 S,A443F,H468K,Q491 R;A159S.T411 S,A4 43F,H468K,Q491 E;A159S.T411 S,A443F,H468G,Q491 K;A159S.T411 S,A443F,H468G,Q491 R;A159S.T411 S,A443F,H468G,Q491 E;A159S.T41 1 S,A443F,H468S,Q491 K;A159S.T411 S,A 443F,H468S,Q491 R;A159S.T411 S,A443F,H468S,Q491 E;A159S.T411 S,A443M,H468R,Q49 1 K;A159S.T411 S,A443M,H468R,Q491 R;A159S.T411 S,A443M,H468R,Q491 E;A159S.T411 S,A443M,H468A,Q491 K;A159S.T411 S,A443M,H468A,Q491 R;A159S.T41 1 S,A443M,H468A, Q491 E;A159S.T411 S,A443M,H468K,Q491 K;A159S.T411 S,A443M,H468K,Q491 R;A159S,T 411 S,A443M,H468K,Q491 E;A159S.T411 S,A443M,H468G,Q491 K;A159S.T411 S,A443M,H4 68G.Q491 R;A159S.T411 S,A443M,H468G,Q491 E;A159S.T411 S,A443M,H468S,Q491 K;A15 9S.T41 1 S,A443M,H468S,Q491 R;A159S.T411 S,A443M,H468S,Q491 E;A159S.T411 S.A443Y ,H468R,Q491 K;A159S.T411 S,A443Y,H468R,Q491 R;A159S.T411 S,A443Y,H468R,Q491 E;A 159S.T411 S,A443Y,H468A,Q491 K;A159S.T411 S,A443Y,H468A,Q491 R;A159S.T41 1 S,A44 3Y,H468A,Q491 E;A159S.T411 S,A443Y,H468K,Q491 K;A159S.T411 S,A443Y,H468K,Q491 R ;A159S.T411 S,A443Y,H468K,Q491 E;A159S.T411 S,A443Y,H468G,Q491 K;A159S.T41 1 S,A4 43Y,H468G,Q491 R;A159S.T411 S,A443Y,H468G,Q491 E;A159S.T41 1 S,A443Y,H468S,Q491 K;A159S.T411 S,A443Y,H468S,Q491 R;A159S.T411 S,A443Y,H468S,Q491 E;A159S.T411 S,A 443V,H468R,Q491 K;A159S.T411 S,A443V,H468R,Q491 R;A159S.T41 1 S,A443V,H468R,Q49

[0164] I E;A159S.T411 S,A443V,H468A,Q491 K;A159S.T411 S,A443V,H468A,Q491 R;A159S.T41 1 S, A443V,H468A,Q491 E;A159S.T411 S,A443V,H468K,Q491 K;A159S.T411 S,A443V,H468K,Q4 91 R;A159S.T411 S,A443V,H468K,Q491 E;A159S.T411 S,A443V,H468G,Q491 K;A159S.T41 1 S,A443V,H468G,Q491 R;A159S.T411 S,A443V,H468G,Q491 E;A159S.T411 S,A443V,H468S, Q491 K;A159S.T411 S,A443V,H468S,Q491 R;A159S.T41 1 S,A443V,H468S,Q491 E;A159S.T4

[0165] I I A,A443I,H468R,Q491 K;A159S,T411 A,A443I,H468R,Q491 R;A159S,T411 A.A443I.H468R, Q491 E;A159S.T411 A,A443I,H468A,Q491 K;A159S.T411 A,A443I,H468A,Q491 R;A159S.T41

[0166] I A,A443I,H468A,Q491 E;A159S,T41 1 A,A443I,H468K,Q491 K;A159S.T411 A,A443I,H468K,Q 491 R;A159S.T411 A,A443I,H468K,Q491 E;A159S.T411 A,A443I,H468G,Q491 K;A159S.T411 A,A443I,H468G,Q491 R;A159S,T411A,A443I,H468G,Q491 E;A159S,T411A,A443I,H468S,Q4 91 K;A159S,T411A,A443I,H468S,Q491 R;A159S,T411A,A443I,H468S,Q491 E;A159S,T411A, A443L,H468R,Q491 K;A159S.T411 A,A443L,H468R,Q491 R;A159S.T411 A,A443L,H468R,Q4 91 E;A159S.T411 A,A443L,H468A,Q491 K;A159S.T41 1 A,A443L,H468A,Q491 R;A159S.T411 A ,A443L,H468A,Q491 E;A159S,T411A,A443L,H468K,Q491 K;A159S,T411A,A443L,H468K,Q4 91 R;A159S.T411 A,A443L,H468K,Q491 E;A159S.T41 1 A,A443L,H468G,Q491 K;A159S.T411 A,A443L,H468G,Q491 R;A159S,T411A,A443L,H468G,Q491 E;A159S,T411A,A443L,H468S, Q491 K;A159S.T41 1 A,A443L,H468S,Q491 R;A159S.T411 A,A443L,H468S,Q491 E;A159S.T4

[0167] I I A,A443F,H468R,Q491 K;A159S.T411 A,A443F,H468R,Q491 R;A159S.T411 A,A443F,H468

[0168] R.Q491 E;A159S.T411 A,A443F,H468A,Q491 K;A159S.T411 A,A443F,H468A,Q491 R;A159S, T41 1 A,A443F,H468A,Q491 E;A159S,T41 1 A,A443F,H468K,Q491 K;A159S,T411 A,A443F,H46 8K.Q491 R;A159S.T411 A,A443F,H468K,Q491 E;A159S.T411 A,A443F,H468G,Q491 K;A159S ,T411 A,A443F,H468G,Q491 R;A159S.T411 A,A443F,H468G,Q491 E;A159S.T411 A,A443F,H4 68S.Q491 K;A159S.T41 1 A,A443F,H468S,Q491 R;A159S.T411 A,A443F,H468S,Q491 E;A159

[0169] S.T411 A,A443M,H468R,Q491 K;A159S,T41 1 A,A443M,H468R,Q491 R;A159S,T411 A.A443M, H468R,Q491 E;A159S,T411A,A443M,H468A,Q491 K;A159S,T411A,A443M,H468A,Q491 R;A 159S.T411 A,A443M,H468A,Q491 E;A159S.T411 A,A443M,H468K,Q491 K;A159S.T411 A,A44 3M,H468K,Q491 R;A159S.T411 A,A443M,H468K,Q491 E;A159S,T41 1 A,A443M,H468G,Q491 K;A159S.T411 A,A443M,H468G,Q491 R;A159S.T411 A,A443M,H468G,Q491 E;A159S.T411 A, A443M,H468S,Q491 K;A159S,T411A,A443M,H468S,Q491 R;A159S,T411A,A443M,H468S,Q 491 E;A159S.T411 A,A443Y,H468R,Q491 K;A159S.T411 A,A443Y,H468R,Q491 R;A159S.T41

[0170] I A,A443Y,H468R,Q491 E;A159S.T411 A,A443Y,H468A,Q491 K;A159S.T411 A,A443Y,H468A, Q491 R;A159S.T411 A,A443Y,H468A,Q491 E;A159S.T411 A,A443Y,H468K,Q491 K;A159S.T4

[0171] I I A,A443Y,H468K,Q491 R;A159S.T411 A,A443Y,H468K,Q491 E;A159S,T411 A,A443Y,H468 G.Q491 K;A159S.T411 A,A443Y,H468G,Q491 R;A159S.T411 A,A443Y,H468G,Q491 E;A159S, T41 1 A,A443Y,H468S,Q491 K;A159S.T41 1 A,A443Y,H468S,Q491 R;A159S.T411 A,A443Y,H4 68S.Q491 E;A159S.T411 A,A443V,H468R,Q491 K;A159S.T41 1 A,A443V,H468R,Q491 R;A159 S.T411 A,A443V,H468R,Q491 E;A159S,T41 1 A,A443V,H468A,Q491 K;A159S,T41 1 A.A443V, H468A.Q491 R;A159S.T411 A,A443V,H468A,Q491 E;A159S.T411 A,A443V,H468K,Q491 K;A1 59S.T411 A,A443V,H468K,Q491 R;A159S.T411 A,A443V,H468K,Q491 E;A159S.T411 A.A443 V,H468G,Q491 K;A159S.T411 A,A443V,H468G,Q491 R;A159S.T411 A,A443V,H468G,Q491 E; A159S.T411 A,A443V,H468S,Q491 K;A159S.T411 A,A443V,H468S,Q491 R;A159S.T411 A,A4 43V,H468S,Q491 E;A159S.T411 Q,A443I,H468R,Q491 K;A159S.T411 Q,A443I,H468R,Q491 R ;A159S.T411 Q,A443I,H468R,Q491 E;A159S.T41 1 Q,A443I,H468A,Q491 K;A159S.T41 1 Q,A44 3I.H468A.Q491 R;A159S.T411 Q,A443I,H468A,Q491 E;A159S.T411 Q,A443I,H468K,Q491 K;A 159S.T411 Q,A443I,H468K,Q491 R;A159S.T411 Q,A443I,H468K,Q491 E;A159S.T411 Q.A443I ,H468G,Q491 K;A159S.T411 Q,A443I,H468G,Q491 R;A159S.T411 Q,A443I,H468G,Q491 E;A1 59S.T411 Q,A443I,H468S,Q491 K;A159S.T411 Q,A443I,H468S,Q491 R;A159S.T411 Q.A443I, H468S.Q491 E;A159S.T411 Q,A443L,H468R,Q491 K;A159S.T41 1 Q,A443L,H468R,Q491 R;A1 59S.T411 Q,A443L,H468R,Q491 E;A159S.T411 Q,A443L,H468A,Q491 K;A159S.T411 Q.A443 L,H468A,Q491 R;A159S.T411 Q,A443L,H468A,Q491 E;A159S.T411 Q,A443L,H468K,Q491 K; A159S.T411 Q,A443L,H468K,Q491 R;A159S.T411 Q,A443L,H468K,Q491 E;A159S.T411 Q,A4 43L,H468G,Q491 K;A159S.T411 Q,A443L,H468G,Q491 R;A159S.T411 Q,A443L,H468G,Q491 E;A159S.T411 Q,A443L,H468S,Q491 K;A159S.T41 1 Q,A443L,H468S,Q491 R;A159S.T41 1 Q, A443L,H468S,Q491 E;A159S.T411 Q,A443F,H468R,Q491 K;A159S.T41 1 Q,A443F,H468R,Q4 91 R;A159S.T411 Q,A443F,H468R,Q491 E;A159S.T411 Q,A443F,H468A,Q491 K;A159S.T411 Q,A443F,H468A,Q491 R;A159S.T411 Q,A443F,H468A,Q491 E;A159S.T411 Q,A443F,H468K, Q491 K;A159S.T411 Q,A443F,H468K,Q491 R;A159S.T411 Q,A443F,H468K,Q491 E;A159S.T4 11 Q,A443F,H468G,Q491 K;A159S.T41 1 Q,A443F,H468G,Q491 R;A159S.T41 1 Q,A443F,H468 G.Q491 E;A159S.T411 Q,A443F,H468S,Q491 K;A159S.T411 Q,A443F,H468S,Q491 R;A159S, T41 1 Q,A443F,H468S,Q491 E;A159S.T411 Q,A443M,H468R,Q491 K;A159S.T411 Q,A443M,H 468R.Q491 R;A159S.T41 1 Q,A443M,H468R,Q491 E;A159S.T41 1 Q,A443M,H468A,Q491 K;A1 59S.T411 Q,A443M,H468A,Q491 R;A159S.T411 Q,A443M,H468A,Q491 E;A159S.T411 Q,A44 3M,H468K,Q491 K;A159S.T411 Q,A443M,H468K,Q491 R;A159S.T411 Q,A443M,H468K,Q491 E;A159S.T411 Q,A443M,H468G,Q491 K;A159S.T41 1 Q,A443M,H468G,Q491 R;A159S.T411 Q ,A443M,H468G,Q491 E;A159S.T411 Q,A443M,H468S,Q491 K;A159S.T411 Q,A443M,H468S, Q491 R;A159S.T411 Q,A443M,H468S,Q491 E;A159S.T411 Q,A443Y,H468R,Q491 K;A159S,T 411 Q,A443Y,H468R,Q491 R;A159S.T411 Q,A443Y,H468R,Q491 E;A159S.T411 Q,A443Y,H4 68A.Q491 K;A159S.T411 Q,A443Y,H468A,Q491 R;A159S.T41 1 Q,A443Y,H468A,Q491 E;A159 S.T411 Q,A443Y,H468K,Q491 K;A159S.T411 Q,A443Y,H468K,Q491 R;A159S.T411 Q.A443Y, H468K.Q491 E;A159S.T411 Q,A443Y,H468G,Q491 K;A159S.T411 Q,A443Y,H468G,Q491 R;A 159S.T411 Q,A443Y,H468G,Q491 E;A159S.T41 1 Q,A443Y,H468S,Q491 K;A159S.T411 Q,A44 3Y,H468S,Q491 R;A159S.T41 1 Q,A443Y,H468S,Q491 E;A159S.T411 Q,A443V,H468R,Q491 K;A159S.T411 Q,A443V,H468R,Q491 R;A159S.T411 Q,A443V,H468R,Q491 E;A159S.T411 Q, A443V,H468A,Q491 K;A159S.T41 1 Q,A443V,H468A,Q491 R;A159S.T41 1 Q,A443V,H468A,Q 491 E;A159S.T411 Q,A443V,H468K,Q491 K;A159S.T411 Q,A443V,H468K,Q491 R;A159S.T41

[0172] I Q,A443V,H468K,Q491 E;A159S.T411 Q,A443V,H468G,Q491 K;A159S.T411 Q,A443V,H468 G.Q491 R;A159S.T411 Q,A443V,H468G,Q491 E;A159S.T411 Q,A443V,H468S,Q491 K;A159S, T41 1 Q,A443V,H468S,Q491 R;A159S.T411 Q,A443V,H468S,Q491 E;A159S.T411 E.A443I.H4 68R.Q491 K;A159S.T411 E,A443I,H468R,Q491 R;A159S.T411 E,A443I,H468R,Q491 E;A159S, T41 1 E,A443I,H468A,Q491 K;A159S.T411 E,A443I,H468A,Q491 R;A159S.T411 E.A443I.H468 A.Q491 E;A159S.T411 E,A443I,H468K,Q491 K;A159S.T41 1 E,A443I,H468K,Q491 R;A159S.T4

[0173] I I E,A443I,H468K,Q491 E;A159S.T411 E,A443I,H468G,Q491 K;A159S.T41 1 E.A443I.H468G, Q491 R;A159S.T411 E.A443I.H468G.Q491 E;A159S.T411 E,A443I,H468S,Q491 K;A159S.T41

[0174] I E,A443I,H468S,Q491 R;A159S.T41 1 E,A443I,H468S,Q491 E;A159S.T411 E,A443L,H468R,Q 491 K;A159S.T411 E,A443L,H468R,Q491 R;A159S.T411 E,A443L,H468R,Q491 E;A159S.T41 1 E,A443L,H468A,Q491 K;A159S.T411 E,A443L,H468A,Q491 R;A159S.T411 E,A443L,H468A,Q 491 E;A159S.T411 E,A443L,H468K,Q491 K;A159S.T411 E,A443L,H468K,Q491 R;A159S.T411 E,A443L,H468K,Q491 E;A159S.T411 E,A443L,H468G,Q491 K;A159S.T41 1 E,A443L,H468G, Q491 R;A159S.T411 E,A443L,H468G,Q491 E;A159S.T41 1 E,A443L,H468S,Q491 K;A159S.T4

[0175] I I E,A443L,H468S,Q491 R;A159S.T41 1 E,A443L,H468S,Q491 E;A159S.T411 E,A443F,H468

[0176] R.Q491 K;A159S.T411 E,A443F,H468R,Q491 R;A159S.T41 1 E,A443F,H468R,Q491 E;A159S, T41 1 E,A443F,H468A,Q491 K;A159S.T41 1 E,A443F,H468A,Q491 R;A159S.T41 1 E,A443F,H4 68A.Q491 E;A159S.T411 E,A443F,H468K,Q491 K;A159S.T411 E,A443F,H468K,Q491 R;A159

[0177] S.T411 E,A443F,H468K,Q491 E;A159S.T411 E,A443F,H468G,Q491 K;A159S.T41 1 E,A443F,H 468G.Q491 R;A159S.T411 E,A443F,H468G,Q491 E;A159S.T411 E,A443F,H468S,Q491 K;A15 9S.T41 1 E,A443F,H468S,Q491 R;A159S.T41 1 E,A443F,H468S,Q491 E;A159S.T411 E.A443M, H468R.Q491 K;A159S.T411 E,A443M,H468R,Q491 R;A159S.T411 E,A443M,H468R,Q491 E;A 159S.T411 E,A443M,H468A,Q491 K;A159S.T411 E,A443M,H468A,Q491 R;A159S.T41 1 E,A44 3M,H468A,Q491 E;A159S.T411 E,A443M,H468K,Q491 K;A159S.T411 E,A443M,H468K,Q491 R;A159S.T411 E,A443M,H468K,Q491 E;A159S.T411 E,A443M,H468G,Q491 K;A159S.T41 1 E, A443M,H468G,Q491 R;A159S.T41 1 E,A443M,H468G,Q491 E;A159S.T411 E,A443M,H468S,Q 491 K;A159S.T411 E,A443M,H468S,Q491 R;A159S.T411 E,A443M,H468S,Q491 E;A159S.T41 I E,A443Y,H468R,Q491 K;A159S.T411 E,A443Y,H468R,Q491 R;A159S.T41 1 E,A443Y,H468R ,Q491 E;A159S.T411 E,A443Y,H468A,Q491 K;A159S.T411 E,A443Y,H468A,Q491 R;A159S.T4

[0178] I I E,A443Y,H468A,Q491 E;A159S.T411 E,A443Y,H468K,Q491 K;A159S.T41 1 E,A443Y,H468

[0179] K.Q491 R;A159S.T411 E,A443Y,H468K,Q491 E;A159S.T411 E,A443Y,H468G,Q491 K;A159S, T41 1 E,A443Y,H468G,Q491 R;A159S.T41 1 E,A443Y,H468G,Q491 E;A159S.T411 E,A443Y,H4 68S.Q491 K;A159S.T411 E,A443Y,H468S,Q491 R;A159S.T41 1 E,A443Y,H468S,Q491 E;A159 S.T411 E,A443V,H468R,Q491 K;A159S.T411 E,A443V,H468R,Q491 R;A159S.T411 E.A443V, H468R.Q491 E;A159S.T41 1 E,A443V,H468A,Q491 K;A159S.T411 E,A443V,H468A,Q491 R;A1 59S.T411 E,A443V,H468A,Q491 E;A159S.T411 E,A443V,H468K,Q491 K;A159S.T411 E.A443 V,H468K,Q491 R;A159S.T411 E,A443V,H468K,Q491 E;A159S.T411 E,A443V,H468G,Q491 K; A159S.T411 E,A443V,H468G,Q491 R;A159S.T411 E,A443V,H468G,Q491 E;A159S.T411 E,A4 43V,H468S,Q491 K;A159S.T411 E,A443V,H468S,Q491 R;A159S.T411 E,A443V,H468S,Q491 E;A159S.T411 K,A443I,H468R,Q491 K;A159S.T411 K,A443I,H468R,Q491 R;A159S.T411 K,A4 43I.H468R.Q491 E;A159S.T411 K,A443I,H468A,Q491 K;A159S.T411 K,A443I,H468A,Q491 R; A159S.T411 K,A443I,H468A,Q491 E;A159S.T411 K,A443I,H468K,Q491 K;A159S.T41 1 K.A443 l,H468K,Q491 R;A159S.T41 1 K,A443I,H468K,Q491 E;A159S.T411 K,A443I,H468G,Q491 K;A1 59S.T411 K,A443I,H468G,Q491 R;A159S.T41 1 K,A443I,H468G,Q491 E;A159S.T41 1 K.A443I, H468S.Q491 K;A159S.T411 K,A443I,H468S,Q491 R;A159S.T411 K,A443I,H468S,Q491 E;A15 9S.T41 1 K,A443L,H468R,Q491 K;A159S.T411 K,A443L,H468R,Q491 R;A159S.T411 K.A443L, H468R.Q491 E;A159S.T41 1 K,A443L,H468A,Q491 K;A159S.T41 1 K,A443L,H468A,Q491 R;A1 59S.T411 K,A443L,H468A,Q491 E;A159S.T411 K,A443L,H468K,Q491 K;A159S.T411 K.A443L ,H468K,Q491 R;A159S.T411 K,A443L,H468K,Q491 E;A159S.T411 K,A443L,H468G,Q491 K;A1 59S.T411 K,A443L,H468G,Q491 R;A159S.T411 K,A443L,H468G,Q491 E;A159S.T411 K.A443

[0180] L,H468S,Q491 K;A159S.T411 K,A443L,H468S,Q491 R;A159S.T411 K,A443L,H468S,Q491 E;A 159S.T411 K,A443F,H468R,Q491 K;A159S.T411 K,A443F,H468R,Q491 R;A159S.T41 1 K,A44 3F,H468R,Q491 E;A159S.T41 1 K,A443F,H468A,Q491 K;A159S.T411 K,A443F,H468A,Q491 R; A159S.T411 K,A443F,H468A,Q491 E;A159S.T41 1 K,A443F,H468K,Q491 K;A159S.T41 1 K,A44 3F,H468K,Q491 R;A159S.T41 1 K,A443F,H468K,Q491 E;A159S.T41 1 K,A443F,H468G,Q491 K ;A159S.T411 K,A443F,H468G,Q491 R;A159S.T411 K,A443F,H468G,Q491 E;A159S.T411 K,A4 43F,H468S,Q491 K;A159S.T411 K,A443F,H468S,Q491 R;A159S.T411 K,A443F,H468S,Q491 E;A159S.T411 K,A443M,H468R,Q491 K;A159S.T411 K,A443M,H468R,Q491 R;A159S.T411 K, A443M,H468R,Q491 E;A159S.T411 K,A443M,H468A,Q491 K;A159S.T411 K,A443M,H468A,Q 491 R;A159S.T411 K,A443M,H468A,Q491 E;A159S.T411 K,A443M,H468K,Q491 K;A159S.T41 1 K,A443M,H468K,Q491 R;A159S.T411 K,A443M,H468K,Q491 E;A159S.T41 1 K,A443M,H468 G.Q491 K;A159S.T411 K,A443M,H468G,Q491 R;A159S.T411 K,A443M,H468G,Q491 E;A159S ,T411 K,A443M,H468S,Q491 K;A159S.T411 K,A443M,H468S,Q491 R;A159S.T411 K,A443M,H 468S.Q491 E;A159S.T411 K,A443Y,H468R,Q491 K;A159S.T411 K,A443Y,H468R,Q491 R;A15 9S.T41 1 K,A443Y,H468R,Q491 E;A159S.T41 1 K,A443Y,H468A,Q491 K;A159S.T41 1 K.A443Y, H468A.Q491 R;A159S.T411 K,A443Y,H468A,Q491 E;A159S.T411 K,A443Y,H468K,Q491 K;A1 59S.T411 K,A443Y,H468K,Q491 R;A159S.T411 K,A443Y,H468K,Q491 E;A159S.T411 K.A443 Y,H468G,Q491 K;A159S.T411 K,A443Y,H468G,Q491 R;A159S.T411 K,A443Y,H468G,Q491 E; A159S.T411 K,A443Y,H468S,Q491 K;A159S.T411 K,A443Y,H468S,Q491 R;A159S.T411 K,A4 43Y,H468S,Q491 E;A159S.T411 K,A443V,H468R,Q491 K;A159S.T41 1 K,A443V,H468R,Q491 R;A159S.T411 K,A443V,H468R,Q491 E;A159S.T41 1 K,A443V,H468A,Q491 K;A159S.T411 K, A443V,H468A,Q491 R;A159S.T411 K,A443V,H468A,Q491 E;A159S.T411 K,A443V,H468K,Q4 91 K;A159S.T411 K,A443V,H468K,Q491 R;A159S.T411 K,A443V,H468K,Q491 E;A159S.T41 1 K,A443V,H468G,Q491 K;A159S.T411 K,A443V,H468G,Q491 R;A159S.T411 K,A443V,H468G, Q491 E;A159S.T411 K,A443V,H468S,Q491 K;A159S.T41 1 K,A443V,H468S,Q491 R; or

[0181] A159S.T411 K,A443V,H468S,Q491 E.

[0182] In some embodiments, the glucose oxidase variant (which comprises an amino acid substitution at any one of positions 159, 411 , 443, 468, and / or 491) comprises, at position 92, a naturally occurring amino acid residue that is different from D. The glucose oxidase variant comprising a substitution at position 92 can include, in some embodiments, at least one further substitution at any one of positions 433, 440, and / or 503. The glucose oxidase variant comprising a substitution at position 92 can include, in some embodiments, at least two further substitutions at any one of positions 433, 440, and / or 503. The glucose oxidase variant comprising a substitution at position 92 can include, in some embodiments, substitutions at positions 433, 440, and 503. For example, the glucose oxidase variant can include, at position 92, one of the following amino acid residue: A (D92A), R (D92R), N (D92N), C (D92C), E M (D92M), F (D92F), P r example, the glucose oxidase variant can include, at position 92, one of the following amino acid residues: A (D92A), R (D92R), E (D92E), Q (D92Q), K (D92K), S (D92S), or Y (D92Y). In another example, the glucose oxidase variant can include, at position 92, one of the following amino acid residues: A (D92A), R (D92R), E (D92E), S (D92S), or Y (D92Y). In a further example, the glucose oxidase variant can include, at position 92, one of the following amino acid residues E (D92E), or Q (D92Q). In yet a further example, the glucose oxidase variant can include, at position 92, E (D92E). In some embodiments, the glucose oxidase variant does not include, at position 92, Q (D92Q). In some embodiments, the glucose oxidase variant does not include, at position 92, K (D92K). In some embodiments, the glucose oxidase variant does not include, at position 992, Q (D92Q) or K (D92K). Specific embodiments of the glucose oxidase comprising, at position 92, a substitution include, without limitation, a polypeptide comprising the amino acid sequence of SEQ ID NO: 5 or a variant thereof (including fragments thereof comprising, in some embodiments, the amino acid residues 25-605 of the amino acid sequence of SEQ ID NO: 5).

[0183] In some embodiments, the glucose oxidase variant (which comprises an amino acid substitution at any one of positions 159, 41 1 , 443, 468, and / or 491 ) comprises, at position 433, a naturally occurring amino acid residue that is different from S. The glucose oxidase variant comprising a substitution at position 433 can include, in some embodiments, at least one further substitution at any one of positions 92, 440, and / or 503. The glucose oxidase variant comprising a substitution at position 433 can include, in some embodiments, at least two further substitutions at any one of positions 92, 440, and / or 503. The glucose oxidase variant comprising a substitution at position 433 can include, in some embodiments, substitutions at positions 92, 440, and 503. For example, the glucose oxidase variant can include, at position 433, one of the following amino acid residue: A (S433A), R (S433R), N (S433N), D (S433D), C (S433C), E (S433E), Q (S433Q), G (S433G), H (S433H), I (S433I), L (S433L), K (S433K), M (S433M), F (S433F), P (S433P), T (S433T), W (S433W), Y (S433Y), or V (S433V). For example, the glucose oxidase variant can include, at position 433, one of the following amino acid residues: A (S433A), G (S433G), I (S433I), L (S433L), F (S433F), Y (S433Y), or V (S433V). In another example, the glucose oxidase variant can include, at position 433, one of the following amino acid residues: G (S433G), I (S433I), L (S433L), F (S433F), Y (S433Y), or V (S433V). In a further example, the glucose oxidase variant can include, at position 433, one of the following amino acid residues A (S433A), or V (S433V). In yet a further example, the glucose oxidase variant can include, at position 433, A (S433A). In some embodiments, the glucose oxidase variant does not include, at position 433, A (S433A). Specific embodiments of the glucose oxidase comprising, at position 433, a substitution include, without limitation, a polypeptide comprising the amino acid sequence of SEQ ID NO: 5 or a variant thereof (including fragments thereof comprising, in some embodiments, the amino acid residues 25- 605 of the amino acid sequence of SEQ ID NO: 5).

[0184] In some embodiments, the glucose oxidase variant (which comprise an amino acid substitution at any one of positions 159, 411 , 443, 468, and / or 491) comprises, at position 440, a naturally occurring amino acid residue that is different from A. The glucose oxidase variant comprising a substitution at position 440 can include, in some embodiments, at least one further substitution at any one of positions 92, 433, and / or 503. The glucose oxidase variant comprising a substitution at position 440 can include, in some embodiments, at least two further substitutions at any one of positions 92, 433, and / or 503. The glucose oxidase variant comprising a substitution at position 440 can include, in some embodiments, substitutions at positions 92, 433, and 503. For example, the glucose oxidase variant can include, at position 440, one of the following amino acid residue: R (A440R), N (A440N), D (A440D), C (A440C), E (A440E), Q (A440Q), G (A440G), H (A440H), I (A440I), L (A440L), K (A440K), M (A440M), F (A440F), P (A440P), S (A440S), T (A440T), W (A440W), Y (A440Y), or V (A440V). For example, the glucose oxidase variant can include, at position 440, one of the following amino acid residues: D (A440D), E (A440E), G (A440G), K (A440K), F (A440F), or S (A440S). In another example, the glucose oxidase variant can include, at position 440, one of the following amino acid residues: D (A440D), E (A440E), G (A440G), F (A440F), or S (A440S). In a further example, the glucose oxidase variant can include, at position 440, one of the following amino acid residues E (A440E), or G (A440G). In yet a further example, the glucose oxidase variant can include, at position 440, G (A440G). In some embodiments, the glucose oxidase variant does not include, at position 440, K (A440K). Specific embodiments of the glucose oxidase comprising, at position 440, a substitution include, without limitation, a polypeptide comprising the amino acid sequence of SEQ ID NO: 5 or a variant thereof (including fragments thereof comprising, in some embodiments, the amino acid residues 25-605 of the amino acid sequence of SEQ ID NO: 5).

[0185] In embodiments in which the glucose oxidase variants include A159L, the glucose oxidase variants do not include one or a combination of the following amino acid substitutions: A114E, Y271 L, and / or P530K. In embodiments in which the glucose oxidase variants include A159L and Q491 R, the glucose oxidase variants do not include one or a combination of the following amino acid substitutions: Q164K, H388T, D462S, and / or Q475N. In further embodiments in which the glucose oxidase variants include D92K, A159L, T411 S, S433G, A440G, A443F, H468A, Q491 R, and Q503A, the glucose oxidase variants do not include one or a combination of the following amino acid substitutions: Q164K, K224D, P238Q, H242R, H388T, D462S, K463A, Q475N, and / or D514P.

[0186] In some embodiments, the glucose oxidase variant (which comprises an amino acid substitution at any one of positions 159, 411 , 443, 468, and / or 491 ) comprises, at position 503, a naturally occurring amino acid residue that is different from Q. The glucose oxidase variant comprising a substitution at position 503 can include, in some embodiments, at least one further substitution at any one of positions 92, 433, and / or 440. The glucose oxidase variant comprising a substitution at position 503 can include, in some embodiments, at least two further substitutions at any one of positions 92, 433, and / or 440. The glucose oxidase variant comprising a substitution at position 503 can include, in some embodiments, substitutions at positions 92, 433, and 440. For example, the glucose oxidase variant can include, at position 503, one of the following amino acid residue: A (Q503A), R (Q503R), N (Q503N), D (Q503D), C (Q503C), E (Q503E), G (Q503G), H (Q503H), I (Q503I), L (Q503L), K (Q503K), M (Q503M), F (Q503F), P (Q503P), S (Q503S), T (Q503T), W (Q503W), Y (Q503Y), or V (Q503V). For example, the glucose oxidase variant can include, at position 503, one of the following amino acid residues: A (Q503A), R (Q503R), E (Q503E), K (Q503K), or S (Q503S). In another example, the glucose oxidase variant can include, at position 503, one of the following amino acid residues: A (Q503A), R (Q503R), E (Q503E), or S (Q503S). In a further example, the glucose oxidase variant can include, at position 503, one of the following amino acid residues A (Q503A), or K (Q503K). In yet a further example, the glucose oxidase variant can include, at position 503, K (Q503K). In some embodiments, the glucose oxidase variant does not include, at position 503, K (Q503K). Specific embodiments of the glucose oxidase comprising, at position 503, a substitution include, without limitation, a polypeptide comprising the amino acid sequence of SEQ ID NO: 5 or a variant thereof (including fragments thereof comprising, in some embodiments, the amino acid residues 25-605 of the amino acid sequence of SEQ ID NO: 5).

[0187] Glucose oxidase variants having amino acid substitutions at positions 92, 433, 440, and / or 503 can be used with the embodiments described herein for glucose oxidase variants having amino acid substitutions at positions 159, 411 , 443, 468, and / or 491 described herein and include, including the following combinations of substitutions: D92E,S433A,A440G,Q503K;D92E,S433A,A440G,Q503A;D92E,S433A,A440G,Q503R;D92E ,S433A,A440G,Q503S;D92E,S433A,A440G,Q503E;D92E,S433A,A440E,Q503K;D92E,S433 A,A440E,Q503A;D92E,S433A,A440E,Q503R;D92E,S433A,A440E,Q503S;D92E,S433A,A44 0E,Q503E;D92E,S433A,A440D,Q503K;D92E,S433A,A440D,Q503A;D92E,S433A,A440D,Q5 03R;D92E,S433A,A440D,Q503S;D92E,S433A,A440D,Q503E;D92E,S433A,A440S,Q503K;D 92E,S433A,A440S,Q503A;D92E,S433A,A440S,Q503R;D92E,S433A,A440S,Q503S;D92E,S 433A,A440S,Q503E;D92E,S433A,A440F,Q503K;D92E,S433A,A440F,Q503A;D92E,S433A, A440F,Q503R;D92E,S433A,A440F,Q503S;D92E,S433A,A440F,Q503E;D92E,S433A,A440K ,Q503K;D92E,S433A,A440K,Q503A;D92E,S433A,A440K,Q503R;D92E,S433A,A440K,Q503 S;D92E,S433A,A440K,Q503E;D92E,S433V,A440G,Q503K;D92E,S433V,A440G,Q503A;D92 E,S433V,A440G,Q503R;D92E,S433V,A440G,Q503S;D92E,S433V,A440G,Q503E;D92E,S4 33V,A440E,Q503K;D92E,S433V,A440E,Q503A;D92E,S433V,A440E,Q503R;D92E,S433V,A 440E,Q503S;D92E,S433V,A440E,Q503E;D92E,S433V,A440D,Q503K;D92E,S433V,A440D, Q503A;D92E,S433V,A440D,Q503R;D92E,S433V,A440D,Q503S;D92E,S433V,A440D,Q503 E;D92E,S433V,A440S,Q503K;D92E,S433V,A440S,Q503A;D92E,S433V,A440S,Q503R;D92 E,S433V,A440S,Q503S;D92E,S433V,A440S,Q503E;D92E,S433V,A440F,Q503K;D92E,S43 3V,A440F,Q503A;D92E,S433V,A440F,Q503R;D92E,S433V,A440F,Q503S;D92E,S433V,A4 40F,Q503E;D92E,S433V,A440K,Q503K;D92E,S433V,A440K,Q503A;D92E,S433V,A440K,Q 503R;D92E,S433V,A440K,Q503S;D92E,S433V,A440K,Q503E;D92E,S433L,A440G,Q503K; D92E,S433L,A440G,Q503A;D92E,S433L,A440G,Q503R;D92E,S433L,A440G,Q503S;D92E, S433L,A440G,Q503E;D92E,S433L,A440E,Q503K;D92E,S433L,A440E,Q503A;D92E,S433L, A440E,Q503R;D92E,S433L,A440E,Q503S;D92E,S433L,A440E,Q503E;D92E,S433L,A440D ,Q503K;D92E,S433L,A440D,Q503A;D92E,S433L,A440D,Q503R;D92E,S433L,A440D,Q503 S;D92E,S433L,A440D,Q503E;D92E,S433L,A440S,Q503K;D92E,S433L,A440S,Q503A;D92 E,S433L,A440S,Q503R;D92E,S433L,A440S,Q503S;D92E,S433L,A440S,Q503E;D92E,S433

[0188] L,A440F,Q503K;D92E,S433L,A440F,Q503A;D92E,S433L,A440F,Q503R;D92E,S433L,A440

[0189] F,Q503S;D92E,S433L,A440F,Q503E;D92E,S433L,A440K,Q503K;D92E,S433L,A440K,Q503

[0190] A;D92E,S433L,A440K,Q503R;D92E,S433L,A440K,Q503S;D92E,S433L,A440K,Q503E;D92

[0191] E,S433G,A440G,Q503K;D92E,S433G,A440G,Q503A;D92E,S433G,A440G,Q503R;D92E,S4

[0192] 33G,A440G,Q503S;D92E,S433G,A440G,Q503E;D92E,S433G,A440E,Q503K;D92E,S433G,

[0193] A440E,Q503A;D92E,S433G,A440E,Q503R;D92E,S433G,A440E,Q503S;D92E,S433G,A440

[0194] E,Q503E;D92E,S433G,A440D,Q503K;D92E,S433G,A440D,Q503A;D92E,S433G,A440D,Q5

[0195] 03R;D92E,S433G,A440D,Q503S;D92E,S433G,A440D,Q503E;D92E,S433G,A440S,Q503K;

[0196] D92E,S433G,A440S,Q503A;D92E,S433G,A440S,Q503R;D92E,S433G,A440S,Q503S;D92E

[0197] ,S433G,A440S,Q503E;D92E,S433G,A440F,Q503K;D92E,S433G,A440F,Q503A;D92E,S433

[0198] G,A440F,Q503R;D92E,S433G,A440F,Q503S;D92E,S433G,A440F,Q503E;D92E,S433G,A4

[0199] 40K,Q503K;D92E,S433G,A440K,Q503A;D92E,S433G,A440K,Q503R;D92E,S433G,A440K,

[0200] Q503S;D92E,S433G,A440K,Q503E;D92E,S433F,A440G,Q503K;D92E,S433F,A440G,Q503

[0201] A;D92E,S433F,A440G,Q503R;D92E,S433F,A440G,Q503S;D92E,S433F,A440G,Q503E;D92

[0202] E,S433F,A440E,Q503K;D92E,S433F,A440E,Q503A;D92E,S433F,A440E,Q503R;D92E,S43

[0203] 3F,A440E,Q503S;D92E,S433F,A440E,Q503E;D92E,S433F,A440D,Q503K;D92E,S433F,A4

[0204] 40D,Q503A;D92E,S433F,A440D,Q503R;D92E,S433F,A440D,Q503S;D92E,S433F,A440D,Q

[0205] 503E;D92E,S433F,A440S,Q503K;D92E,S433F,A440S,Q503A;D92E,S433F,A440S,Q503R;

[0206] D92E,S433F,A440S,Q503S;D92E,S433F,A440S,Q503E;D92E,S433F,A440F,Q503K;D92E,

[0207] S433F,A440F,Q503A;D92E,S433F,A440F,Q503R;D92E,S433F,A440F,Q503S;D92E,S433F,

[0208] A440F,Q503E;D92E,S433F,A440K,Q503K;D92E,S433F,A440K,Q503A;D92E,S433F,A440K

[0209] ,Q503R;D92E,S433F,A440K,Q503S;D92E,S433F,A440K,Q503E;D92E,S433Y,A440G,Q503

[0210] K;D92E,S433Y,A440G,Q503A;D92E,S433Y,A440G,Q503R;D92E,S433Y,A440G,Q503S;D9

[0211] 2E,S433Y,A440G,Q503E;D92E,S433Y,A440E,Q503K;D92E,S433Y,A440E,Q503A;D92E,S4

[0212] 33Y,A440E,Q503R;D92E,S433Y,A440E,Q503S;D92E,S433Y,A440E,Q503E;D92E,S433Y,A

[0213] 440D,Q503K;D92E,S433Y,A440D,Q503A;D92E,S433Y,A440D,Q503R;D92E,S433Y,A440D,

[0214] Q503S;D92E,S433Y,A440D,Q503E;D92E,S433Y,A440S,Q503K;D92E,S433Y,A440S,Q503

[0215] A;D92E,S433Y,A440S,Q503R;D92E,S433Y,A440S,Q503S;D92E,S433Y,A440S,Q503E;D92

[0216] E,S433Y,A440F,Q503K;D92E,S433Y,A440F,Q503A;D92E,S433Y,A440F,Q503R;D92E,S43

[0217] 3Y,A440F,Q503S;D92E,S433Y,A440F,Q503E;D92E,S433Y,A440K,Q503K;D92E,S433Y,A4

[0218] 40K,Q503A;D92E,S433Y,A440K,Q503R;D92E,S433Y,A440K,Q503S;D92E,S433Y,A440K,Q

[0219] 503E;D92E,S433l,A440G,Q503K;D92E,S433l,A440G,Q503A;D92E,S433l,A440G,Q503R;D

[0220] 92E,S433l,A440G,Q503S;D92E,S433l,A440G,Q503E;D92E,S433l,A440E,Q503K;D92E,S43

[0221] 3l,A440E,Q503A;D92E,S433l,A440E,Q503R;D92E,S433l,A440E,Q503S;D92E,S433l,A440E

[0222] ,Q503E;D92E,S433l,A440D,Q503K;D92E,S433l,A440D,Q503A;D92E,S433l,A440D,Q503R;

[0223] D92E,S433l,A440D,Q503S;D92E,S433l,A440D,Q503E;D92E,S433l,A440S,Q503K;D92E,S4 33l,A440S,Q503A;D92E,S433l,A440S,Q503R;D92E,S433l,A440S,Q503S;D92E,S433l,A440

[0224] S,Q503E;D92E,S433l,A440F,Q503K;D92E,S433l,A440F,Q503A;D92E,S433l,A440F,Q503R

[0225] ;D92E,S433l,A440F,Q503S;D92E,S433l,A440F,Q503E;D92E,S433l,A440K,Q503K;D92E,S4

[0226] 33l,A440K,Q503A;D92E,S433l,A440K,Q503R;D92E,S433l,A440K,Q503S;D92E,S433l,A440

[0227] K,Q503E;D92Q,S433A,A440G,Q503K;D92Q,S433A,A440G,Q503A;D92Q,S433A,A440G,Q5

[0228] 03R;D92Q,S433A,A440G,Q503S;D92Q,S433A,A440G,Q503E;D92Q,S433A,A440E,Q503K;

[0229] D92Q,S433A,A440E,Q503A;D92Q,S433A,A440E,Q503R;D92Q,S433A,A440E,Q503S;D92Q

[0230] ,S433A,A440E,Q503E;D92Q,S433A,A440D,Q503K;D92Q,S433A,A440D,Q503A;D92Q,S43

[0231] 3A,A440D,Q503R;D92Q,S433A,A440D,Q503S;D92Q,S433A,A440D,Q503E;D92Q,S433A,A

[0232] 440S,Q503K;D92Q,S433A,A440S,Q503A;D92Q,S433A,A440S,Q503R;D92Q,S433A,A440S,

[0233] Q503S;D92Q,S433A,A440S,Q503E;D92Q,S433A,A440F,Q503K;D92Q,S433A,A440F,Q503

[0234] A;D92Q,S433A,A440F,Q503R;D92Q,S433A,A440F,Q503S;D92Q,S433A,A440F,Q503E;D92

[0235] Q,S433A,A440K,Q503K;D92Q,S433A,A440K,Q503A;D92Q,S433A,A440K,Q503R;D92Q,S4

[0236] 33A,A440K,Q503S;D92Q,S433A,A440K,Q503E;D92Q,S433V,A440G,Q503K;D92Q,S433V,

[0237] A440G,Q503A;D92Q,S433V,A440G,Q503R;D92Q,S433V,A440G,Q503S;D92Q,S433V,A44

[0238] 0G,Q503E;D92Q,S433V,A440E,Q503K;D92Q,S433V,A440E,Q503A;D92Q,S433V,A440E,Q

[0239] 503R;D92Q,S433V,A440E,Q503S;D92Q,S433V,A440E,Q503E;D92Q,S433V,A440D,Q503K

[0240] ;D92Q,S433V,A440D,Q503A;D92Q,S433V,A440D,Q503R;D92Q,S433V,A440D,Q503S;D92

[0241] Q,S433V,A440D,Q503E;D92Q,S433V,A440S,Q503K;D92Q,S433V,A440S,Q503A;D92Q,S4

[0242] 33V,A440S,Q503R;D92Q,S433V,A440S,Q503S;D92Q,S433V,A440S,Q503E;D92Q,S433V,

[0243] A440F,Q503K;D92Q,S433V,A440F,Q503A;D92Q,S433V,A440F,Q503R;D92Q,S433V,A440

[0244] F,Q503S;D92Q,S433V,A440F,Q503E;D92Q,S433V,A440K,Q503K;D92Q,S433V,A440K,Q5

[0245] 03A;D92Q,S433V,A440K,Q503R;D92Q,S433V,A440K,Q503S;D92Q,S433V,A440K,Q503E;

[0246] D92Q,S433L,A440G,Q503K;D92Q,S433L,A440G,Q503A;D92Q,S433L,A440G,Q503R;D92Q

[0247] ,S433L,A440G,Q503S;D92Q,S433L,A440G,Q503E;D92Q,S433L,A440E,Q503K;D92Q,S433

[0248] L,A440E,Q503A;D92Q,S433L,A440E,Q503R;D92Q,S433L,A440E,Q503S;D92Q,S433L,A44

[0249] 0E,Q503E;D92Q,S433L,A440D,Q503K;D92Q,S433L,A440D,Q503A;D92Q,S433L,A440D,Q5

[0250] 03R;D92Q,S433L,A440D,Q503S;D92Q,S433L,A440D,Q503E;D92Q,S433L,A440S,Q503K;D

[0251] 92Q,S433L,A440S,Q503A;D92Q,S433L,A440S,Q503R;D92Q,S433L,A440S,Q503S;D92Q,S

[0252] 433L,A440S,Q503E;D92Q,S433L,A440F,Q503K;D92Q,S433L,A440F,Q503A;D92Q,S433L,

[0253] A440F,Q503R;D92Q,S433L,A440F,Q503S;D92Q,S433L,A440F,Q503E;D92Q,S433L,A440K

[0254] ,Q503K;D92Q,S433L,A440K,Q503A;D92Q,S433L,A440K,Q503R;D92Q,S433L,A440K,Q503

[0255] S;D92Q,S433L,A440K,Q503E;D92Q,S433G,A440G,Q503K;D92Q,S433G,A440G,Q503A;D9

[0256] 2Q,S433G,A440G,Q503R;D92Q,S433G,A440G,Q503S;D92Q,S433G,A440G,Q503E;D92Q,

[0257] S433G,A440E,Q503K;D92Q,S433G,A440E,Q503A;D92Q,S433G,A440E,Q503R;D92Q,S43

[0258] 3G,A440E,Q503S;D92Q,S433G,A440E,Q503E;D92Q,S433G,A440D,Q503K;D92Q,S433G,A

[0259] 440D,Q503A;D92Q,S433G,A440D,Q503R;D92Q,S433G,A440D,Q503S;D92Q,S433G,A440 D,Q503E;D92Q,S433G,A440S,Q503K;D92Q,S433G,A440S,Q503A;D92Q,S433G,A440S,Q5

[0260] 03R;D92Q,S433G,A440S,Q503S;D92Q,S433G,A440S,Q503E;D92Q,S433G,A440F,Q503K;

[0261] D92Q,S433G,A440F,Q503A;D92Q,S433G,A440F,Q503R;D92Q,S433G,A440F,Q503S;D92

[0262] Q,S433G,A440F,Q503E;D92Q,S433G,A440K,Q503K;D92Q,S433G,A440K,Q503A;D92Q,S4

[0263] 33G,A440K,Q503R;D92Q,S433G,A440K,Q503S;D92Q,S433G,A440K,Q503E;D92Q,S433F,

[0264] A440G,Q503K;D92Q,S433F,A440G,Q503A;D92Q,S433F,A440G,Q503R;D92Q,S433F,A440

[0265] G,Q503S;D92Q,S433F,A440G,Q503E;D92Q,S433F,A440E,Q503K;D92Q,S433F,A440E,Q5

[0266] 03A;D92Q,S433F,A440E,Q503R;D92Q,S433F,A440E,Q503S;D92Q,S433F,A440E,Q503E;D

[0267] 92Q,S433F,A440D,Q503K;D92Q,S433F,A440D,Q503A;D92Q,S433F,A440D,Q503R;D92Q,

[0268] S433F,A440D,Q503S;D92Q,S433F,A440D,Q503E;D92Q,S433F,A440S,Q503K;D92Q,S433

[0269] F,A440S,Q503A;D92Q,S433F,A440S,Q503R;D92Q,S433F,A440S,Q503S;D92Q,S433F,A44

[0270] 0S,Q503E;D92Q,S433F,A440F,Q503K;D92Q,S433F,A440F,Q503A;D92Q,S433F,A440F,Q5

[0271] 03R;D92Q,S433F,A440F,Q503S;D92Q,S433F,A440F,Q503E;D92Q,S433F,A440K,Q503K;D

[0272] 92Q,S433F,A440K,Q503A;D92Q,S433F,A440K,Q503R;D92Q,S433F,A440K,Q503S;D92Q,

[0273] S433F,A440K,Q503E;D92Q,S433Y,A440G,Q503K;D92Q,S433Y,A440G,Q503A;D92Q,S433

[0274] Y,A440G,Q503R;D92Q,S433Y,A440G,Q503S;D92Q,S433Y,A440G,Q503E;D92Q,S433Y,A4

[0275] 40E,Q503K;D92Q,S433Y,A440E,Q503A;D92Q,S433Y,A440E,Q503R;D92Q,S433Y,A440E,

[0276] Q503S;D92Q,S433Y,A440E,Q503E;D92Q,S433Y,A440D,Q503K;D92Q,S433Y,A440D,Q503

[0277] A;D92Q,S433Y,A440D,Q503R;D92Q,S433Y,A440D,Q503S;D92Q,S433Y,A440D,Q503E;D9

[0278] 2Q,S433Y,A440S,Q503K;D92Q,S433Y,A440S,Q503A;D92Q,S433Y,A440S,Q503R;D92Q,S

[0279] 433Y,A440S,Q503S;D92Q,S433Y,A440S,Q503E;D92Q,S433Y,A440F,Q503K;D92Q,S433Y,

[0280] A440F,Q503A;D92Q,S433Y,A440F,Q503R;D92Q,S433Y,A440F,Q503S;D92Q,S433Y,A440

[0281] F,Q503E;D92Q,S433Y,A440K,Q503K;D92Q,S433Y,A440K,Q503A;D92Q,S433Y,A440K,Q5

[0282] 03R;D92Q,S433Y,A440K,Q503S;D92Q,S433Y,A440K,Q503E;D92Q,S433l,A440G,Q503K;D

[0283] 92Q,S433l,A440G,Q503A;D92Q,S433l,A440G,Q503R;D92Q,S433l,A440G,Q503S;D92Q,S4

[0284] 33l,A440G,Q503E;D92Q,S433l,A440E,Q503K;D92Q,S433l,A440E,Q503A;D92Q,S433l,A44

[0285] 0E,Q503R;D92Q,S433l,A440E,Q503S;D92Q,S433l,A440E,Q503E;D92Q,S433l,A440D,Q50

[0286] 3K;D92Q,S433l,A440D,Q503A;D92Q,S433l,A440D,Q503R;D92Q,S433l,A440D,Q503S;D92

[0287] Q,S433l,A440D,Q503E;D92Q,S433l,A440S,Q503K;D92Q,S433l,A440S,Q503A;D92Q,S433l

[0288] ,A440S,Q503R;D92Q,S433l,A440S,Q503S;D92Q,S433l,A440S,Q503E;D92Q,S433l,A440F,

[0289] Q503K;D92Q,S433l,A440F,Q503A;D92Q,S433l,A440F,Q503R;D92Q,S433l,A440F,Q503S;

[0290] D92Q,S433l,A440F,Q503E;D92Q,S433l,A440K,Q503K;D92Q,S433l,A440K,Q503A;D92Q,S

[0291] 433l,A440K,Q503R;D92Q,S433l,A440K,Q503S;D92Q,S433l,A440K,Q503E;D92A,S433A,A4

[0292] 40G,Q503K;D92A,S433A,A440G,Q503A;D92A,S433A,A440G,Q503R;D92A,S433A,A440G,

[0293] Q503S;D92A,S433A,A440G,Q503E;D92A,S433A,A440E,Q503K;D92A,S433A,A440E,Q503

[0294] A;D92A,S433A,A440E,Q503R;D92A,S433A,A440E,Q503S;D92A,S433A,A440E,Q503E;D92

[0295] A,S433A,A440D,Q503K;D92A,S433A,A440D,Q503A;D92A,S433A,A440D,Q503R;D92A,S43 3A,A440D,Q503S;D92A,S433A,A440D,Q503E;D92A,S433A,A440S,Q503K;D92A,S433A,A4

[0296] 40S,Q503A;D92A,S433A,A440S,Q503R;D92A,S433A,A440S,Q503S;D92A,S433A,A440S,Q

[0297] 503E;D92A,S433A,A440F,Q503K;D92A,S433A,A440F,Q503A;D92A,S433A,A440F,Q503R;

[0298] D92A,S433A,A440F,Q503S;D92A,S433A,A440F,Q503E;D92A,S433A,A440K,Q503K;D92A,

[0299] S433A,A440K,Q503A;D92A,S433A,A440K,Q503R;D92A,S433A,A440K,Q503S;D92A,S433

[0300] A,A440K,Q503E;D92A,S433V,A440G,Q503K;D92A,S433V,A440G,Q503A;D92A,S433V,A44

[0301] 0G,Q503R;D92A,S433V,A440G,Q503S;D92A,S433V,A440G,Q503E;D92A,S433V,A440E,Q

[0302] 503K;D92A,S433V,A440E,Q503A;D92A,S433V,A440E,Q503R;D92A,S433V,A440E,Q503S;

[0303] D92A,S433V,A440E,Q503E;D92A,S433V,A440D,Q503K;D92A,S433V,A440D,Q503A;D92A,

[0304] S433V,A440D,Q503R;D92A,S433V,A440D,Q503S;D92A,S433V,A440D,Q503E;D92A,S433

[0305] V,A440S,Q503K;D92A,S433V,A440S,Q503A;D92A,S433V,A440S,Q503R;D92A,S433V,A44

[0306] 0S,Q503S;D92A,S433V,A440S,Q503E;D92A,S433V,A440F,Q503K;D92A,S433V,A440F,Q5

[0307] 03A;D92A,S433V,A440F,Q503R;D92A,S433V,A440F,Q503S;D92A,S433V,A440F,Q503E;D

[0308] 92A,S433V,A440K,Q503K;D92A,S433V,A440K,Q503A;D92A,S433V,A440K,Q503R;D92A,S

[0309] 433V,A440K,Q503S;D92A,S433V,A440K,Q503E;D92A,S433L,A440G,Q503K;D92A,S433L,

[0310] A440G,Q503A;D92A,S433L,A440G,Q503R;D92A,S433L,A440G,Q503S;D92A,S433L,A440

[0311] G,Q503E;D92A,S433L,A440E,Q503K;D92A,S433L,A440E,Q503A;D92A,S433L,A440E,Q50

[0312] 3R;D92A,S433L,A440E,Q503S;D92A,S433L,A440E,Q503E;D92A,S433L,A440D,Q503K;D9

[0313] 2A,S433L,A440D,Q503A;D92A,S433L,A440D,Q503R;D92A,S433L,A440D,Q503S;D92A,S4

[0314] 33L,A440D,Q503E;D92A,S433L,A440S,Q503K;D92A,S433L,A440S,Q503A;D92A,S433L,A4

[0315] 40S,Q503R;D92A,S433L,A440S,Q503S;D92A,S433L,A440S,Q503E;D92A,S433L,A440F,Q

[0316] 503K;D92A,S433L,A440F,Q503A;D92A,S433L,A440F,Q503R;D92A,S433L,A440F,Q503S;D

[0317] 92A,S433L,A440F,Q503E;D92A,S433L,A440K,Q503K;D92A,S433L,A440K,Q503A;D92A,S4

[0318] 33L,A440K,Q503R;D92A,S433L,A440K,Q503S;D92A,S433L,A440K,Q503E;D92A,S433G,A

[0319] 440G,Q503K;D92A,S433G,A440G,Q503A;D92A,S433G,A440G,Q503R;D92A,S433G,A440

[0320] G,Q503S;D92A,S433G,A440G,Q503E;D92A,S433G,A440E,Q503K;D92A,S433G,A440E,Q5

[0321] 03A;D92A,S433G,A440E,Q503R;D92A,S433G,A440E,Q503S;D92A,S433G,A440E,Q503E;

[0322] D92A,S433G,A440D,Q503K;D92A,S433G,A440D,Q503A;D92A,S433G,A440D,Q503R;D92

[0323] A,S433G,A440D,Q503S;D92A,S433G,A440D,Q503E;D92A,S433G,A440S,Q503K;D92A,S4

[0324] 33G,A440S,Q503A;D92A,S433G,A440S,Q503R;D92A,S433G,A440S,Q503S;D92A,S433G,

[0325] A440S,Q503E;D92A,S433G,A440F,Q503K;D92A,S433G,A440F,Q503A;D92A,S433G,A440

[0326] F,Q503R;D92A,S433G,A440F,Q503S;D92A,S433G,A440F,Q503E;D92A,S433G,A440K,Q5

[0327] 03K;D92A,S433G,A440K,Q503A;D92A,S433G,A440K,Q503R;D92A,S433G,A440K,Q503S;

[0328] D92A,S433G,A440K,Q503E;D92A,S433F,A440G,Q503K;D92A,S433F,A440G,Q503A;D92A,

[0329] S433F,A440G,Q503R;D92A,S433F,A440G,Q503S;D92A,S433F,A440G,Q503E;D92A,S433

[0330] F,A440E,Q503K;D92A,S433F,A440E,Q503A;D92A,S433F,A440E,Q503R;D92A,S433F,A44

[0331] 0E,Q503S;D92A,S433F,A440E,Q503E;D92A,S433F,A440D,Q503K;D92A,S433F,A440D,Q5 03A;D92A,S433F,A440D,Q503R;D92A,S433F,A440D,Q503S;D92A,S433F,A440D,Q503E;D

[0332] 92A,S433F,A440S,Q503K;D92A,S433F,A440S,Q503A;D92A,S433F,A440S,Q503R;D92A,S 433F,A440S,Q503S;D92A,S433F,A440S,Q503E;D92A,S433F,A440F,Q503K;D92A,S433F,A 440F,Q503A;D92A,S433F,A440F,Q503R;D92A,S433F,A440F,Q503S;D92A,S433F,A440F,

[0333] Q503E;D92A,S433F,A440K,Q503K;D92A,S433F,A440K,Q503A;D92A,S433F,A440K,Q503R

[0334] ;D92A,S433F,A440K,Q503S;D92A,S433F,A440K,Q503E;D92A,S433Y,A440G,Q503K;D92A

[0335] ,S433Y,A440G,Q503A;D92A,S433Y,A440G,Q503R;D92A,S433Y,A440G,Q503S;D92A,S433

[0336] Y,A440G,Q503E;D92A,S433Y,A440E,Q503K;D92A,S433Y,A440E,Q503A;D92A,S433Y,A44

[0337] 0E,Q503R;D92A,S433Y,A440E,Q503S;D92A,S433Y,A440E,Q503E;D92A,S433Y,A440D,Q5

[0338] 03K;D92A,S433Y,A440D,Q503A;D92A,S433Y,A440D,Q503R;D92A,S433Y,A440D,Q503S;D

[0339] 92A,S433Y,A440D,Q503E;D92A,S433Y,A440S,Q503K;D92A,S433Y,A440S,Q503A;D92A,S

[0340] 433Y,A440S,Q503R;D92A,S433Y,A440S,Q503S;D92A,S433Y,A440S,Q503E;D92A,S433Y,

[0341] A440F,Q503K;D92A,S433Y,A440F,Q503A;D92A,S433Y,A440F,Q503R;D92A,S433Y,A440F

[0342] ,Q503S;D92A,S433Y,A440F,Q503E;D92A,S433Y,A440K,Q503K;D92A,S433Y,A440K,Q503

[0343] A;D92A,S433Y,A440K,Q503R;D92A,S433Y,A440K,Q503S;D92A,S433Y,A440K,Q503E;D92

[0344] A,S433l,A440G,Q503K;D92A,S433l,A440G,Q503A;D92A,S433l,A440G,Q503R;D92A,S433l

[0345] ,A440G,Q503S;D92A,S433l,A440G,Q503E;D92A,S433l,A440E,Q503K;D92A,S433l,A440E,

[0346] Q503A;D92A,S433l,A440E,Q503R;D92A,S433l,A440E,Q503S;D92A,S433l,A440E,Q503E;D

[0347] 92A,S433l,A440D,Q503K;D92A,S433l,A440D,Q503A;D92A,S433l,A440D,Q503R;D92A,S43

[0348] 3l,A440D,Q503S;D92A,S433l,A440D,Q503E;D92A,S433l,A440S,Q503K;D92A,S433l,A440

[0349] S,Q503A;D92A,S433l,A440S,Q503R;D92A,S433l,A440S,Q503S;D92A,S433l,A440S,Q503E

[0350] ;D92A,S433l,A440F,Q503K;D92A,S433l,A440F,Q503A;D92A,S433l,A440F,Q503R;D92A,S4

[0351] 33l,A440F,Q503S;D92A,S433l,A440F,Q503E;D92A,S433l,A440K,Q503K;D92A,S433l,A440

[0352] K,Q503A;D92A,S433l,A440K,Q503R;D92A,S433l,A440K,Q503S;D92A,S433l,A440K,Q503E

[0353] ;D92K,S433A,A440G,Q503K;D92K,S433A,A440G,Q503A;D92K,S433A,A440G,Q503R;D92

[0354] K,S433A,A440G,Q503S;D92K,S433A,A440G,Q503E;D92K,S433A,A440E,Q503K;D92K,S43

[0355] 3A,A440E,Q503A;D92K,S433A,A440E,Q503R;D92K,S433A,A440E,Q503S;D92K,S433A,A4

[0356] 40E,Q503E;D92K,S433A,A440D,Q503K;D92K,S433A,A440D,Q503A;D92K,S433A,A440D,Q

[0357] 503R;D92K,S433A,A440D,Q503S;D92K,S433A,A440D,Q503E;D92K,S433A,A440S,Q503K;

[0358] D92K,S433A,A440S,Q503A;D92K,S433A,A440S,Q503R;D92K,S433A,A440S,Q503S;D92K,

[0359] S433A,A440S,Q503E;D92K,S433A,A440F,Q503K;D92K,S433A,A440F,Q503A;D92K,S433A

[0360] ,A440F,Q503R;D92K,S433A,A440F,Q503S;D92K,S433A,A440F,Q503E;D92K,S433A,A440

[0361] K,Q503K;D92K,S433A,A440K,Q503A;D92K,S433A,A440K,Q503R;D92K,S433A,A440K,Q50

[0362] 3S;D92K,S433A,A440K,Q503E;D92K,S433V,A440G,Q503K;D92K,S433V,A440G,Q503A;D9

[0363] 2K,S433V,A440G,Q503R;D92K,S433V,A440G,Q503S;D92K,S433V,A440G,Q503E;D92K,S 433V,A440E,Q503K;D92K,S433V,A440E,Q503A;D92K,S433V,A440E,Q503R;D92K,S433V,

[0364] A440E,Q503S;D92K,S433V,A440E,Q503E;D92K,S433V,A440D,Q503K;D92K,S433V,A440 D,Q503A;D92K,S433V,A440D,Q503R;D92K,S433V,A440D,Q503S;D92K,S433V,A440D,Q5

[0365] 03E;D92K,S433V,A440S,Q503K;D92K,S433V,A440S,Q503A;D92K,S433V,A440S,Q503R;D

[0366] 92K,S433V,A440S,Q503S;D92K,S433V,A440S,Q503E;D92K,S433V,A440F,Q503K;D92K,S

[0367] 433V,A440F,Q503A;D92K,S433V,A440F,Q503R;D92K,S433V,A440F,Q503S;D92K,S433V,

[0368] A440F,Q503E;D92K,S433V,A440K,Q503K;D92K,S433V,A440K,Q503A;D92K,S433V,A440K

[0369] ,Q503R;D92K,S433V,A440K,Q503S;D92K,S433V,A440K,Q503E;D92K,S433L,A440G,Q503

[0370] K;D92K,S433L,A440G,Q503A;D92K,S433L,A440G,Q503R;D92K,S433L,A440G,Q503S;D92

[0371] K,S433L,A440G,Q503E;D92K,S433L,A440E,Q503K;D92K,S433L,A440E,Q503A;D92K,S43

[0372] 3L,A440E,Q503R;D92K,S433L,A440E,Q503S;D92K,S433L,A440E,Q503E;D92K,S433L,A44

[0373] 0D,Q503K;D92K,S433L,A440D,Q503A;D92K,S433L,A440D,Q503R;D92K,S433L,A440D,Q5

[0374] 03S;D92K,S433L,A440D,Q503E;D92K,S433L,A440S,Q503K;D92K,S433L,A440S,Q503A;D

[0375] 92K,S433L,A440S,Q503R;D92K,S433L,A440S,Q503S;D92K,S433L,A440S,Q503E;D92K,S4

[0376] 33L,A440F,Q503K;D92K,S433L,A440F,Q503A;D92K,S433L,A440F,Q503R;D92K,S433L,A4

[0377] 40F,Q503S;D92K,S433L,A440F,Q503E;D92K,S433L,A440K,Q503K;D92K,S433L,A440K,Q5

[0378] 03A;D92K,S433L,A440K,Q503R;D92K,S433L,A440K,Q503S;D92K,S433L,A440K,Q503E;D

[0379] 92K,S433G,A440G,Q503K;D92K,S433G,A440G,Q503A;D92K,S433G,A440G,Q503R;D92K,

[0380] S433G,A440G,Q503S;D92K,S433G,A440G,Q503E;D92K,S433G,A440E,Q503K;D92K,S433

[0381] G,A440E,Q503A;D92K,S433G,A440E,Q503R;D92K,S433G,A440E,Q503S;D92K,S433G,A4

[0382] 40E,Q503E;D92K,S433G,A440D,Q503K;D92K,S433G,A440D,Q503A;D92K,S433G,A440D,

[0383] Q503R;D92K,S433G,A440D,Q503S;D92K,S433G,A440D,Q503E;D92K,S433G,A440S,Q503

[0384] K;D92K,S433G,A440S,Q503A;D92K,S433G,A440S,Q503R;D92K,S433G,A440S,Q503S;D9

[0385] 2K,S433G,A440S,Q503E;D92K,S433G,A440F,Q503K;D92K,S433G,A440F,Q503A;D92K,S4

[0386] 33G,A440F,Q503R;D92K,S433G,A440F,Q503S;D92K,S433G,A440F,Q503E;D92K,S433G,

[0387] A440K,Q503K;D92K,S433G,A440K,Q503A;D92K,S433G,A440K,Q503R;D92K,S433G,A440

[0388] K,Q503S;D92K,S433G,A440K,Q503E;D92K,S433F,A440G,Q503K;D92K,S433F,A440G,Q5

[0389] 03A;D92K,S433F,A440G,Q503R;D92K,S433F,A440G,Q503S;D92K,S433F,A440G,Q503E;D

[0390] 92K,S433F,A440E,Q503K;D92K,S433F,A440E,Q503A;D92K,S433F,A440E,Q503R;D92K,S

[0391] 433F,A440E,Q503S;D92K,S433F,A440E,Q503E;D92K,S433F,A440D,Q503K;D92K,S433F,

[0392] A440D,Q503A;D92K,S433F,A440D,Q503R;D92K,S433F,A440D,Q503S;D92K,S433F,A440

[0393] D,Q503E;D92K,S433F,A440S,Q503K;D92K,S433F,A440S,Q503A;D92K,S433F,A440S,Q50

[0394] 3R;D92K,S433F,A440S,Q503S;D92K,S433F,A440S,Q503E;D92K,S433F,A440F,Q503K;D9

[0395] 2K,S433F,A440F,Q503A;D92K,S433F,A440F,Q503R;D92K,S433F,A440F,Q503S;D92K,S43

[0396] 3F,A440F,Q503E;D92K,S433F,A440K,Q503K;D92K,S433F,A440K,Q503A;D92K,S433F,A44

[0397] 0K,Q503R;D92K,S433F,A440K,Q503S;D92K,S433F,A440K,Q503E;D92K,S433Y,A440G,Q5

[0398] 03K;D92K,S433Y,A440G,Q503A;D92K,S433Y,A440G,Q503R;D92K,S433Y,A440G,Q503S;

[0399] D92K,S433Y,A440G,Q503E;D92K,S433Y,A440E,Q503K;D92K,S433Y,A440E,Q503A;D92K,

[0400] S433Y,A440E,Q503R;D92K,S433Y,A440E,Q503S;D92K,S433Y,A440E,Q503E;D92K,S433 Y,A440D,Q503K;D92K,S433Y,A440D,Q503A;D92K,S433Y,A440D,Q503R;D92K,S433Y,A44

[0401] 0D,Q503S;D92K,S433Y,A440D,Q503E;D92K,S433Y,A440S,Q503K;D92K,S433Y,A440S,Q5

[0402] 03A;D92K,S433Y,A440S,Q503R;D92K,S433Y,A440S,Q503S;D92K,S433Y,A440S,Q503E;D

[0403] 92K,S433Y,A440F,Q503K;D92K,S433Y,A440F,Q503A;D92K,S433Y,A440F,Q503R;D92K,S

[0404] 433Y,A440F,Q503S;D92K,S433Y,A440F,Q503E;D92K,S433Y,A440K,Q503K;D92K,S433Y,

[0405] A440K,Q503A;D92K,S433Y,A440K,Q503R;D92K,S433Y,A440K,Q503S;D92K,S433Y,A440

[0406] K,Q503E;D92K,S433l,A440G,Q503K;D92K,S433l,A440G,Q503A;D92K,S433l,A440G,Q503

[0407] R;D92K,S433l,A440G,Q503S;D92K,S433l,A440G,Q503E;D92K,S433l,A440E,Q503K;D92K,

[0408] S433l,A440E,Q503A;D92K,S433l,A440E,Q503R;D92K,S433l,A440E,Q503S;D92K,S433l,A4

[0409] 40E,Q503E;D92K,S433l,A440D,Q503K;D92K,S433l,A440D,Q503A;D92K,S433l,A440D,Q50

[0410] 3R;D92K,S433l,A440D,Q503S;D92K,S433l,A440D,Q503E;D92K,S433l,A440S,Q503K;D92K

[0411] ,S433l,A440S,Q503A;D92K,S433l,A440S,Q503R;D92K,S433l,A440S,Q503S;D92K,S433l,A

[0412] 440S,Q503E;D92K,S433l,A440F,Q503K;D92K,S433l,A440F,Q503A;D92K,S433l,A440F,Q5

[0413] 03R;D92K,S433l,A440F,Q503S;D92K,S433l,A440F,Q503E;D92K,S433l,A440K,Q503K;D92

[0414] K,S433l,A440K,Q503A;D92K,S433l,A440K,Q503R;D92K,S433l,A440K,Q503S;D92K,S433l,

[0415] A440K,Q503E;D92R,S433A,A440G,Q503K;D92R,S433A,A440G,Q503A;D92R,S433A,A440

[0416] G,Q503R;D92R,S433A,A440G,Q503S;D92R,S433A,A440G,Q503E;D92R,S433A,A440E,Q5

[0417] 03K;D92R,S433A,A440E,Q503A;D92R,S433A,A440E,Q503R;D92R,S433A,A440E,Q503S;D

[0418] 92R,S433A,A440E,Q503E;D92R,S433A,A440D,Q503K;D92R,S433A,A440D,Q503A;D92R,

[0419] S433A,A440D,Q503R;D92R,S433A,A440D,Q503S;D92R,S433A,A440D,Q503E;D92R,S433

[0420] A,A440S,Q503K;D92R,S433A,A440S,Q503A;D92R,S433A,A440S,Q503R;D92R,S433A,A44

[0421] 0S,Q503S;D92R,S433A,A440S,Q503E;D92R,S433A,A440F,Q503K;D92R,S433A,A440F,Q5

[0422] 03A;D92R,S433A,A440F,Q503R;D92R,S433A,A440F,Q503S;D92R,S433A,A440F,Q503E;D

[0423] 92R,S433A,A440K,Q503K;D92R,S433A,A440K,Q503A;D92R,S433A,A440K,Q503R;D92R,S

[0424] 433A,A440K,Q503S;D92R,S433A,A440K,Q503E;D92R,S433V,A440G,Q503K;D92R,S433V,

[0425] A440G,Q503A;D92R,S433V,A440G,Q503R;D92R,S433V,A440G,Q503S;D92R,S433V,A440

[0426] G,Q503E;D92R,S433V,A440E,Q503K;D92R,S433V,A440E,Q503A;D92R,S433V,A440E,Q5

[0427] 03R;D92R,S433V,A440E,Q503S;D92R,S433V,A440E,Q503E;D92R,S433V,A440D,Q503K;

[0428] D92R,S433V,A440D,Q503A;D92R,S433V,A440D,Q503R;D92R,S433V,A440D,Q503S;D92R

[0429] ,S433V,A440D,Q503E;D92R,S433V,A440S,Q503K;D92R,S433V,A440S,Q503A;D92R,S433

[0430] V,A440S,Q503R;D92R,S433V,A440S,Q503S;D92R,S433V,A440S,Q503E;D92R,S433V,A44

[0431] 0F,Q503K;D92R,S433V,A440F,Q503A;D92R,S433V,A440F,Q503R;D92R,S433V,A440F,Q5

[0432] 03S;D92R,S433V,A440F,Q503E;D92R,S433V,A440K,Q503K;D92R,S433V,A440K,Q503A;D

[0433] 92R,S433V,A440K,Q503R;D92R,S433V,A440K,Q503S;D92R,S433V,A440K,Q503E;D92R,S

[0434] 433L,A440G,Q503K;D92R,S433L,A440G,Q503A;D92R,S433L,A440G,Q503R;D92R,S433L,

[0435] A440G,Q503S;D92R,S433L,A440G,Q503E;D92R,S433L,A440E,Q503K;D92R,S433L,A440

[0436] E,Q503A;D92R,S433L,A440E,Q503R;D92R,S433L,A440E,Q503S;D92R,S433L,A440E,Q50 3E;D92R,S433L,A440D,Q503K;D92R,S433L,A440D,Q503A;D92R,S433L,A440D,Q503R;D9

[0437] 2R,S433L,A440D,Q503S;D92R,S433L,A440D,Q503E;D92R,S433L,A440S,Q503K;D92R,S4

[0438] 33L,A440S,Q503A;D92R,S433L,A440S,Q503R;D92R,S433L,A440S,Q503S;D92R,S433L,A

[0439] 440S,Q503E;D92R,S433L,A440F,Q503K;D92R,S433L,A440F,Q503A;D92R,S433L,A440F,

[0440] Q503R;D92R,S433L,A440F,Q503S;D92R,S433L,A440F,Q503E;D92R,S433L,A440K,Q503K

[0441] ;D92R,S433L,A440K,Q503A;D92R,S433L,A440K,Q503R;D92R,S433L,A440K,Q503S;D92R,

[0442] S433L,A440K,Q503E;D92R,S433G,A440G,Q503K;D92R,S433G,A440G,Q503A;D92R,S433

[0443] G,A440G,Q503R;D92R,S433G,A440G,Q503S;D92R,S433G,A440G,Q503E;D92R,S433G,A

[0444] 440E,Q503K;D92R,S433G,A440E,Q503A;D92R,S433G,A440E,Q503R;D92R,S433G,A440E

[0445] ,Q503S;D92R,S433G,A440E,Q503E;D92R,S433G,A440D,Q503K;D92R,S433G,A440D,Q50

[0446] 3A;D92R,S433G,A440D,Q503R;D92R,S433G,A440D,Q503S;D92R,S433G,A440D,Q503E;D

[0447] 92R,S433G,A440S,Q503K;D92R,S433G,A440S,Q503A;D92R,S433G,A440S,Q503R;D92R,

[0448] S433G,A440S,Q503S;D92R,S433G,A440S,Q503E;D92R,S433G,A440F,Q503K;D92R,S433

[0449] G,A440F,Q503A;D92R,S433G,A440F,Q503R;D92R,S433G,A440F,Q503S;D92R,S433G,A4

[0450] 40F,Q503E;D92R,S433G,A440K,Q503K;D92R,S433G,A440K,Q503A;D92R,S433G,A440K,

[0451] Q503R;D92R,S433G,A440K,Q503S;D92R,S433G,A440K,Q503E;D92R,S433F,A440G,Q503

[0452] K;D92R,S433F,A440G,Q503A;D92R,S433F,A440G,Q503R;D92R,S433F,A440G,Q503S;D9

[0453] 2R,S433F,A440G,Q503E;D92R,S433F,A440E,Q503K;D92R,S433F,A440E,Q503A;D92R,S4

[0454] 33F,A440E,Q503R;D92R,S433F,A440E,Q503S;D92R,S433F,A440E,Q503E;D92R,S433F,A

[0455] 440D,Q503K;D92R,S433F,A440D,Q503A;D92R,S433F,A440D,Q503R;D92R,S433F,A440D,

[0456] Q503S;D92R,S433F,A440D,Q503E;D92R,S433F,A440S,Q503K;D92R,S433F,A440S,Q503

[0457] A;D92R,S433F,A440S,Q503R;D92R,S433F,A440S,Q503S;D92R,S433F,A440S,Q503E;D92

[0458] R,S433F,A440F,Q503K;D92R,S433F,A440F,Q503A;D92R,S433F,A440F,Q503R;D92R,S43

[0459] 3F,A440F,Q503S;D92R,S433F,A440F,Q503E;D92R,S433F,A440K,Q503K;D92R,S433F,A4

[0460] 40K,Q503A;D92R,S433F,A440K,Q503R;D92R,S433F,A440K,Q503S;D92R,S433F,A440K,Q

[0461] 503E;D92R,S433Y,A440G,Q503K;D92R,S433Y,A440G,Q503A;D92R,S433Y,A440G,Q503R

[0462] ;D92R,S433Y,A440G,Q503S;D92R,S433Y,A440G,Q503E;D92R,S433Y,A440E,Q503K;D92

[0463] R,S433Y,A440E,Q503A;D92R,S433Y,A440E,Q503R;D92R,S433Y,A440E,Q503S;D92R,S43

[0464] 3Y,A440E,Q503E;D92R,S433Y,A440D,Q503K;D92R,S433Y,A440D,Q503A;D92R,S433Y,A4

[0465] 40D,Q503R;D92R,S433Y,A440D,Q503S;D92R,S433Y,A440D,Q503E;D92R,S433Y,A440S,

[0466] Q503K;D92R,S433Y,A440S,Q503A;D92R,S433Y,A440S,Q503R;D92R,S433Y,A440S,Q503

[0467] S;D92R,S433Y,A440S,Q503E;D92R,S433Y,A440F,Q503K;D92R,S433Y,A440F,Q503A;D92

[0468] R,S433Y,A440F,Q503R;D92R,S433Y,A440F,Q503S;D92R,S433Y,A440F,Q503E;D92R,S43

[0469] 3Y,A440K,Q503K;D92R,S433Y,A440K,Q503A;D92R,S433Y,A440K,Q503R;D92R,S433Y,A4

[0470] 40K,Q503S;D92R,S433Y,A440K,Q503E;D92R,S433l,A440G,Q503K;D92R,S433l,A440G,Q5

[0471] 03A;D92R,S433l,A440G,Q503R;D92R,S433l,A440G,Q503S;D92R,S433l,A440G,Q503E;D9

[0472] 2R,S433l,A440E,Q503K;D92R,S433l,A440E,Q503A;D92R,S433l,A440E,Q503R;D92R,S433 l,A440E,Q503S;D92R,S433l,A440E,Q503E;D92R,S433l,A440D,Q503K;D92R,S433l,A440D,

[0473] Q503A;D92R,S433l,A440D,Q503R;D92R,S433l,A440D,Q503S;D92R,S433l,A440D,Q503E;

[0474] D92R,S433l,A440S,Q503K;D92R,S433l,A440S,Q503A;D92R,S433l,A440S,Q503R;D92R,S 433l,A440S,Q503S;D92R,S433l,A440S,Q503E;D92R,S433l,A440F,Q503K;D92R,S433l,A44

[0475] 0F,Q503A;D92R,S433l,A440F,Q503R;D92R,S433l,A440F,Q503S;D92R,S433l,A440F,Q503

[0476] E;D92R,S433l,A440K,Q503K;D92R,S433l,A440K,Q503A;D92R,S433l,A440K,Q503R;D92R,

[0477] S433l,A440K,Q503S;D92R,S433l,A440K,Q503E;D92S,S433A,A440G,Q503K;D92S,S433A,

[0478] A440G,Q503A;D92S,S433A,A440G,Q503R;D92S,S433A,A440G,Q503S;D92S,S433A,A440

[0479] G,Q503E;D92S,S433A,A440E,Q503K;D92S,S433A,A440E,Q503A;D92S,S433A,A440E,Q50

[0480] 3R;D92S,S433A,A440E,Q503S;D92S,S433A,A440E,Q503E;D92S,S433A,A440D,Q503K;D9

[0481] 2S,S433A,A440D,Q503A;D92S,S433A,A440D,Q503R;D92S,S433A,A440D,Q503S;D92S,S4

[0482] 33A,A440D,Q503E;D92S,S433A,A440S,Q503K;D92S,S433A,A440S,Q503A;D92S,S433A,A

[0483] 440S,Q503R;D92S,S433A,A440S,Q503S;D92S,S433A,A440S,Q503E;D92S,S433A,A440F,

[0484] Q503K;D92S,S433A,A440F,Q503A;D92S,S433A,A440F,Q503R;D92S,S433A,A440F,Q503S

[0485] ;D92S,S433A,A440F,Q503E;D92S,S433A,A440K,Q503K;D92S,S433A,A440K,Q503A;D92S,

[0486] S433A,A440K,Q503R;D92S,S433A,A440K,Q503S;D92S,S433A,A440K,Q503E;D92S,S433

[0487] V,A440G,Q503K;D92S,S433V,A440G,Q503A;D92S,S433V,A440G,Q503R;D92S,S433V,A4

[0488] 40G,Q503S;D92S,S433V,A440G,Q503E;D92S,S433V,A440E,Q503K;D92S,S433V,A440E,

[0489] Q503A;D92S,S433V,A440E,Q503R;D92S,S433V,A440E,Q503S;D92S,S433V,A440E,Q503

[0490] E;D92S,S433V,A440D,Q503K;D92S,S433V,A440D,Q503A;D92S,S433V,A440D,Q503R;D92

[0491] S,S433V,A440D,Q503S;D92S,S433V,A440D,Q503E;D92S,S433V,A440S,Q503K;D92S,S43

[0492] 3V,A440S,Q503A;D92S,S433V,A440S,Q503R;D92S,S433V,A440S,Q503S;D92S,S433V,A4

[0493] 40S,Q503E;D92S,S433V,A440F,Q503K;D92S,S433V,A440F,Q503A;D92S,S433V,A440F,Q

[0494] 503R;D92S,S433V,A440F,Q503S;D92S,S433V,A440F,Q503E;D92S,S433V,A440K,Q503K;

[0495] D92S,S433V,A440K,Q503A;D92S,S433V,A440K,Q503R;D92S,S433V,A440K,Q503S;D92S,

[0496] S433V,A440K,Q503E;D92S,S433L,A440G,Q503K;D92S,S433L,A440G,Q503A;D92S,S433L

[0497] ,A440G,Q503R;D92S,S433L,A440G,Q503S;D92S,S433L,A440G,Q503E;D92S,S433L,A440

[0498] E,Q503K;D92S,S433L,A440E,Q503A;D92S,S433L,A440E,Q503R;D92S,S433L,A440E,Q50

[0499] 3S;D92S,S433L,A440E,Q503E;D92S,S433L,A440D,Q503K;D92S,S433L,A440D,Q503A;D9

[0500] 2S,S433L,A440D,Q503R;D92S,S433L,A440D,Q503S;D92S,S433L,A440D,Q503E;D92S,S4

[0501] 33L,A440S,Q503K;D92S,S433L,A440S,Q503A;D92S,S433L,A440S,Q503R;D92S,S433L,A4

[0502] 40S,Q503S;D92S,S433L,A440S,Q503E;D92S,S433L,A440F,Q503K;D92S,S433L,A440F,Q5

[0503] 03A;D92S,S433L,A440F,Q503R;D92S,S433L,A440F,Q503S;D92S,S433L,A440F,Q503E;D9

[0504] 2S,S433L,A440K,Q503K;D92S,S433L,A440K,Q503A;D92S,S433L,A440K,Q503R;D92S,S43

[0505] 3L,A440K,Q503S;D92S,S433L,A440K,Q503E;D92S,S433G,A440G,Q503K;D92S,S433G,A4

[0506] 40G,Q503A;D92S,S433G,A440G,Q503R;D92S,S433G,A440G,Q503S;D92S,S433G,A440G,

[0507] Q503E;D92S,S433G,A440E,Q503K;D92S,S433G,A440E,Q503A;D92S,S433G,A440E,Q503 R;D92S,S433G,A440E,Q503S;D92S,S433G,A440E,Q503E;D92S,S433G,A440D,Q503K;D9

[0508] 2S,S433G,A440D,Q503A;D92S,S433G,A440D,Q503R;D92S,S433G,A440D,Q503S;D92S,S 433G,A440D,Q503E;D92S,S433G,A440S,Q503K;D92S,S433G,A440S,Q503A;D92S,S433G ,A440S,Q503R;D92S,S433G,A440S,Q503S;D92S,S433G,A440S,Q503E;D92S,S433G,A440

[0509] F,Q503K;D92S,S433G,A440F,Q503A;D92S,S433G,A440F,Q503R;D92S,S433G,A440F,Q50

[0510] 3S;D92S,S433G,A440F,Q503E;D92S,S433G,A440K,Q503K;D92S,S433G,A440K,Q503A;D

[0511] 92S,S433G,A440K,Q503R;D92S,S433G,A440K,Q503S;D92S,S433G,A440K,Q503E;D92S,

[0512] S433F,A440G,Q503K;D92S,S433F,A440G,Q503A;D92S,S433F,A440G,Q503R;D92S,S433

[0513] F,A440G,Q503S;D92S,S433F,A440G,Q503E;D92S,S433F,A440E,Q503K;D92S,S433F,A44

[0514] OE,Q503A;D92S,S433F,A440E,Q503R;D92S,S433F,A440E,Q503S;D92S,S433F,A440E,Q5

[0515] 03E;D92S,S433F,A440D,Q503K;D92S,S433F,A440D,Q503A;D92S,S433F,A440D,Q503R;D

[0516] 92S,S433F,A440D,Q503S;D92S,S433F,A440D,Q503E;D92S,S433F,A440S,Q503K;D92S,S

[0517] 433F,A440S,Q503A;D92S,S433F,A440S,Q503R;D92S,S433F,A440S,Q503S;D92S,S433F,

[0518] A440S,Q503E;D92S,S433F,A440F,Q503K;D92S,S433F,A440F,Q503A;D92S,S433F,A440F,

[0519] Q503R;D92S,S433F,A440F,Q503S;D92S,S433F,A440F,Q503E;D92S,S433F,A440K,Q503K ;D92S,S433F,A440K,Q503A;D92S,S433F,A440K,Q503R;D92S,S433F,A440K,Q503S;D92S, S433F,A440K,Q503E;D92S,S433Y,A440G,Q503K;D92S,S433Y,A440G,Q503A;D92S,S433

[0520] Y,A440G,Q503R;D92S,S433Y,A440G,Q503S;D92S,S433Y,A440G,Q503E;D92S,S433Y,A4 40E,Q503K;D92S,S433Y,A440E,Q503A;D92S,S433Y,A440E,Q503R;D92S,S433Y,A440E,Q 503S;D92S,S433Y,A440E,Q503E;D92S,S433Y,A440D,Q503K;D92S,S433Y,A440D,Q503A;

[0521] D92S,S433Y,A440D,Q503R;D92S,S433Y,A440D,Q503S;D92S,S433Y,A440D,Q503E;D92S, S433Y,A440S,Q503K;D92S,S433Y,A440S,Q503A;D92S,S433Y,A440S,Q503R;D92S,S433 Y,A440S,Q503S;D92S,S433Y,A440S,Q503E;D92S,S433Y,A440F,Q503K;D92S,S433Y,A44

[0522] OF,Q503A;D92S,S433Y,A440F,Q503R;D92S,S433Y,A440F,Q503S;D92S,S433Y,A440F,Q5

[0523] 03E;D92S,S433Y,A440K,Q503K;D92S,S433Y,A440K,Q503A;D92S,S433Y,A440K,Q503R;D

[0524] 92S,S433Y,A440K,Q503S;D92S,S433Y,A440K,Q503E;D92S,S433l,A440G,Q503K;D92S,S4

[0525] 33l,A440G,Q503A;D92S,S433l,A440G,Q503R;D92S,S433l,A440G,Q503S;D92S,S433l,A44

[0526] OG,Q503E;D92S,S433l,A440E,Q503K;D92S,S433l,A440E,Q503A;D92S,S433l,A440E,Q503

[0527] R;D92S,S433l,A440E,Q503S;D92S,S433l,A440E,Q503E;D92S,S433l,A440D,Q503K;D92S,

[0528] S433l,A440D,Q503A;D92S,S433l,A440D,Q503R;D92S,S433l,A440D,Q503S;D92S,S433l,A

[0529] 440D,Q503E;D92S,S433l,A440S,Q503K;D92S,S433l,A440S,Q503A;D92S,S433l,A440S,Q5

[0530] 03R;D92S,S433l,A440S,Q503S;D92S,S433l,A440S,Q503E;D92S,S433l,A440F,Q503K;D92

[0531] S,S433l,A440F,Q503A;D92S,S433l,A440F,Q503R;D92S,S433l,A440F,Q503S;D92S,S433l,

[0532] A440F,Q503E;D92S,S433l,A440K,Q503K;D92S,S433l,A440K,Q503A;D92S,S433l,A440K,Q

[0533] 503R;D92S,S433l,A440K,Q503S;D92S,S433l,A440K,Q503E;D92Y,S433A,A440G,Q503K;D 92Y,S433A,A440G,Q503A;D92Y,S433A,A440G,Q503R;D92Y,S433A,A440G,Q503S;D92Y, S433A,A440G,Q503E;D92Y,S433A,A440E,Q503K;D92Y,S433A,A440E,Q503A;D92Y,S433 A,A440E,Q503R;D92Y,S433A,A440E,Q503S;D92Y,S433A,A440E,Q503E;D92Y,S433A,A44

[0534] 0D,Q503K;D92Y,S433A,A440D,Q503A;D92Y,S433A,A440D,Q503R;D92Y,S433A,A440D,Q 503S;D92Y,S433A,A440D,Q503E;D92Y,S433A,A440S,Q503K;D92Y,S433A,A440S,Q503A;

[0535] D92Y,S433A,A440S,Q503R;D92Y,S433A,A440S,Q503S;D92Y,S433A,A440S,Q503E;D92Y,

[0536] S433A,A440F,Q503K;D92Y,S433A,A440F,Q503A;D92Y,S433A,A440F,Q503R;D92Y,S433A

[0537] ,A440F,Q503S;D92Y,S433A,A440F,Q503E;D92Y,S433A,A440K,Q503K;D92Y,S433A,A440

[0538] K,Q503A;D92Y,S433A,A440K,Q503R;D92Y,S433A,A440K,Q503S;D92Y,S433A,A440K,Q50

[0539] 3E;D92Y,S433V,A440G,Q503K;D92Y,S433V,A440G,Q503A;D92Y,S433V,A440G,Q503R;D

[0540] 92Y,S433V,A440G,Q503S;D92Y,S433V,A440G,Q503E;D92Y,S433V,A440E,Q503K;D92Y,S

[0541] 433V,A440E,Q503A;D92Y,S433V,A440E,Q503R;D92Y,S433V,A440E,Q503S;D92Y,S433V,

[0542] A440E,Q503E;D92Y,S433V,A440D,Q503K;D92Y,S433V,A440D,Q503A;D92Y,S433V,A440

[0543] D,Q503R;D92Y,S433V,A440D,Q503S;D92Y,S433V,A440D,Q503E;D92Y,S433V,A440S,Q5

[0544] 03K;D92Y,S433V,A440S,Q503A;D92Y,S433V,A440S,Q503R;D92Y,S433V,A440S,Q503S;D

[0545] 92Y,S433V,A440S,Q503E;D92Y,S433V,A440F,Q503K;D92Y,S433V,A440F,Q503A;D92Y,S

[0546] 433V,A440F,Q503R;D92Y,S433V,A440F,Q503S;D92Y,S433V,A440F,Q503E;D92Y,S433V,

[0547] A440K,Q503K;D92Y,S433V,A440K,Q503A;D92Y,S433V,A440K,Q503R;D92Y,S433V,A440

[0548] K,Q503S;D92Y,S433V,A440K,Q503E;D92Y,S433L,A440G,Q503K;D92Y,S433L,A440G,Q50

[0549] 3A;D92Y,S433L,A440G,Q503R;D92Y,S433L,A440G,Q503S;D92Y,S433L,A440G,Q503E;D9

[0550] 2Y,S433L,A440E,Q503K;D92Y,S433L,A440E,Q503A;D92Y,S433L,A440E,Q503R;D92Y,S43

[0551] 3L,A440E,Q503S;D92Y,S433L,A440E,Q503E;D92Y,S433L,A440D,Q503K;D92Y,S433L,A44

[0552] 0D,Q503A;D92Y,S433L,A440D,Q503R;D92Y,S433L,A440D,Q503S;D92Y,S433L,A440D,Q5

[0553] 03E;D92Y,S433L,A440S,Q503K;D92Y,S433L,A440S,Q503A;D92Y,S433L,A440S,Q503R;D

[0554] 92Y,S433L,A440S,Q503S;D92Y,S433L,A440S,Q503E;D92Y,S433L,A440F,Q503K;D92Y,S4

[0555] 33L,A440F,Q503A;D92Y,S433L,A440F,Q503R;D92Y,S433L,A440F,Q503S;D92Y,S433L,A4

[0556] 40F,Q503E;D92Y,S433L,A440K,Q503K;D92Y,S433L,A440K,Q503A;D92Y,S433L,A440K,Q5

[0557] 03R;D92Y,S433L,A440K,Q503S;D92Y,S433L,A440K,Q503E;D92Y,S433G,A440G,Q503K;D

[0558] 92Y,S433G,A440G,Q503A;D92Y,S433G,A440G,Q503R;D92Y,S433G,A440G,Q503S;D92Y,

[0559] S433G,A440G,Q503E;D92Y,S433G,A440E,Q503K;D92Y,S433G,A440E,Q503A;D92Y,S433

[0560] G,A440E,Q503R;D92Y,S433G,A440E,Q503S;D92Y,S433G,A440E,Q503E;D92Y,S433G,A4

[0561] 40D,Q503K;D92Y,S433G,A440D,Q503A;D92Y,S433G,A440D,Q503R;D92Y,S433G,A440D,

[0562] Q503S;D92Y,S433G,A440D,Q503E;D92Y,S433G,A440S,Q503K;D92Y,S433G,A440S,Q503

[0563] A;D92Y,S433G,A440S,Q503R;D92Y,S433G,A440S,Q503S;D92Y,S433G,A440S,Q503E;D9 2Y,S433G,A440F,Q503K;D92Y,S433G,A440F,Q503A;D92Y,S433G,A440F,Q503R;D92Y,S4 33G,A440F,Q503S;D92Y,S433G,A440F,Q503E;D92Y,S433G,A440K,Q503K;D92Y,S433G,

[0564] A440K,Q503A;D92Y,S433G,A440K,Q503R;D92Y,S433G,A440K,Q503S;D92Y,S433G,A440

[0565] K,Q503E;D92Y,S433F,A440G,Q503K;D92Y,S433F,A440G,Q503A;D92Y,S433F,A440G,Q50

[0566] 3R;D92Y,S433F,A440G,Q503S;D92Y,S433F,A440G,Q503E;D92Y,S433F,A440E,Q503K;D9 2Y,S433F,A440E,Q503A;D92Y,S433F,A440E,Q503R;D92Y,S433F,A440E,Q503S;D92Y,S4 33F,A440E,Q503E;D92Y,S433F,A440D,Q503K;D92Y,S433F,A440D,Q503A;D92Y,S433F,A 440D,Q503R;D92Y,S433F,A440D,Q503S;D92Y,S433F,A440D,Q503E;D92Y,S433F,A440S, Q503K;D92Y,S433F,A440S,Q503A;D92Y,S433F,A440S,Q503R;D92Y,S433F,A440S,Q503S ;D92Y,S433F,A440S,Q503E;D92Y,S433F,A440F,Q503K;D92Y,S433F,A440F,Q503A;D92Y, S433F,A440F,Q503R;D92Y,S433F,A440F,Q503S;D92Y,S433F,A440F,Q503E;D92Y,S433F, A440K,Q503K;D92Y,S433F,A440K,Q503A;D92Y,S433F,A440K,Q503R;D92Y,S433F,A440K ,Q503S;D92Y,S433F,A440K,Q503E;D92Y,S433Y,A440G,Q503K;D92Y,S433Y,A440G,Q503 A;D92Y,S433Y,A440G,Q503R;D92Y,S433Y,A440G,Q503S;D92Y,S433Y,A440G,Q503E;D9 2Y,S433Y,A440E,Q503K;D92Y,S433Y,A440E,Q503A;D92Y,S433Y,A440E,Q503R;D92Y,S4 33Y,A440E,Q503S;D92Y,S433Y,A440E,Q503E;D92Y,S433Y,A440D,Q503K;D92Y,S433Y,A 440D,Q503A;D92Y,S433Y,A440D,Q503R;D92Y,S433Y,A440D,Q503S;D92Y,S433Y,A440D, Q503E;D92Y,S433Y,A440S,Q503K;D92Y,S433Y,A440S,Q503A;D92Y,S433Y,A440S,Q503 R;D92Y,S433Y,A440S,Q503S;D92Y,S433Y,A440S,Q503E;D92Y,S433Y,A440F,Q503K;D92 Y,S433Y,A440F,Q503A;D92Y,S433Y,A440F,Q503R;D92Y,S433Y,A440F,Q503S;D92Y,S43 3Y,A440F,Q503E;D92Y,S433Y,A440K,Q503K;D92Y,S433Y,A440K,Q503A;D92Y,S433Y,A4

[0567] 40K,Q503R;D92Y,S433Y,A440K,Q503S;D92Y,S433Y,A440K,Q503E;D92Y,S433l,A440G,Q 503K;D92Y,S433l,A440G,Q503A;D92Y,S433l,A440G,Q503R;D92Y,S433l,A440G,Q503S;D 92Y,S433l,A440G,Q503E;D92Y,S433l,A440E,Q503K;D92Y,S433l,A440E,Q503A;D92Y,S43 3l,A440E,Q503R;D92Y,S433l,A440E,Q503S;D92Y,S433l,A440E,Q503E;D92Y,S433l,A440 D,Q503K;D92Y,S433l,A440D,Q503A;D92Y,S433l,A440D,Q503R;D92Y,S433l,A440D,Q503 S;D92Y,S433l,A440D,Q503E;D92Y,S433l,A440S,Q503K;D92Y,S433l,A440S,Q503A;D92Y, S433l,A440S,Q503R;D92Y,S433l,A440S,Q503S;D92Y,S433l,A440S,Q503E;D92Y,S433l,A4 40F,Q503K;D92Y,S433l,A440F,Q503A;D92Y,S433l,A440F,Q503R;D92Y,S433l,A440F,Q50 3S;D92Y,S433l,A440F,Q503E;D92Y,S433l,A440K,Q503K;D92Y,S433l,A440K,Q503A;D92Y ,S433l,A440K,Q503R;D92Y,S433l,A440K,Q503S; or D92Y,S433l,A440K,Q503E.

[0568] The glucose oxidase variants of the present disclosure include conserved amino acid residues which are involved, amongst other things, in substrate binding and catalytic activity which should preferably not be substituted. Conserved amino acid residues involved in substrate binding include, but are not limited to Y90, T132, N536, R534, H538, and H581 (all in reference to the numbering of the amino acid sequence of SEQ ID NO: 1). As such glucose oxidase variants of the present disclosure include Y90, T132, N536, R534, H538, and H581 (numbering with respect to the amino acid sequence of SEQ ID NO: 1). Conserved amino acid residues involved in catalytic activity include, but are not limited to E434, H538, and H581 (numbering with respect to the amino acid sequence of SEQ ID NO: 1). As such glucose oxidase variants of the present disclosure include E434, H538, and H581 (numbering with respect to the amino acid sequence of SEQ ID NO: 1). It was also reported that some amino acid residues (Y90, F346, and W448; numbering with respect to the amino acid sequence of SEQ ID NO: 1), when mutated to A, lead to an almost complete reduction of the glucose oxidation rate. As such, in some embodiments, the glucose oxidase variants of the present disclosure do no include A at positions 90, 346, and 448 (numbering with respect to the amino acid sequence of SEQ ID NO: 1). In some embodiments, the glucose variants of the present disclosure include the following amino acid residues: Y90, F346, and W448 (numbering with respect to the amino acid sequence of SEQ ID NO: 1).

[0569] It is also known that some residues of the wildtype glucose oxidase are or can be glycosylated and can play a role in thermostability of the enzyme. Putatively N-linked glycosylated amino acid residues include, but are not limited to, N65, N111 , N183, N190, N377, N410, and N495 (numbering with respect to the amino acid sequence of SEQ ID NO: 1). As such, the glucose oxidase variants of the present disclosure can include, in some embodiments, N65, N111 , N183, N190, N377, N410, and / or N495 (numbering with respect to the amino acid sequence of SEQ ID NO: 1). In other embodiments, the glucose oxidase variants of the present disclosure can include, in some embodiments, at positions 65, 111 , 183, 190, 377, 410, or 495 (numbering with respect to the amino acid sequence of SEQ ID NO: 1) an amino acid residue different than N, but which allows the N-glycosylation of the enzyme. Putatively O-linked glycosylated amino acid residues include, but are not limited to, S185, T192, and T411 (numbering with respect to the amino acid sequence of SEQ ID NO: 1). As such, the glucose oxidase variants of the present disclosure can include, in some embodiments S185, T192, and / or T411 (numbering with respect to the amino acid sequence of SEQ ID NO: 1). In other embodiments, the glucose oxidase variants of the present disclosure can include, in some embodiments, at positions 185, 192 or 41 1 (numbering with respect to the amino acid sequence of SEQ ID NO: 1), an amino acid residue different than S or T, but which allows the O-glycosylation of the enzyme.

[0570] Glucose oxidase variants of the present disclosure can include one or any combinations of the following additional conserved residues: D43, G48, G50, G53, A57, R59, L60, V68, E72, G74, G119, G123, G124, N129, R135, D142, W144, G149, W153, E166, G188, G191 , G219, D225, G233, R247, R261 , N263, L264, A286, G288, V289, A303, E306, V307, G312, P317, L320, S323, G324, G326, L331 , I336, P343, V344, G345, N347, L348, D350, P452, R455, G456, D482, P512, T542, M545, V553, V554, D555, V560, G562, L566, R567, V568, D570, S572, P575, and / or I597. Alternatively, or in combination, glucose oxidase variants of the present disclosure can include one or any combinations of the following additional conserved residue: T52, S73, L87, H100, S1 18, T126, P136, A140, S162, G227, Q351 , T454, D46, A470, Y472, M546, A558, L591 , and / or S594.

[0571] Systems for producing the glucose oxidase variants The present disclosure provides recombinant microbial host cells for the expression one or more of the glucose oxidase variants described herein. The recombinant microbial host cell is obtained from a microbial cell which can be a bacterium, a yeast, or a fungus. In an embodiment, the recombinant microbial host cell is obtained from a microbial cell which is a bacterium. In some embodiments, the bacterium is a Gram-positive bacterium. In other embodiments, the bacterium is a Gram-negative bacterium. In an embodiment, the recombinant microbial host cell / microbial cell is from Actinoplanes sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Actinoplanes missouriensis. In an embodiment, the recombinant microbial host cell / microbial cell is from Aeribacillus sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Aeribacillus pallidus. In an embodiment, the recombinant microbial host cell / microbial cell is from Anoxybacillus sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Anoxybacillus caldiproteolyticus. In an embodiment, the recombinant microbial host cell / microbial cell is from Bacillus sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Bacillus acidopullulyticus. In another embodiment, the recombinant microbial host cell / microbial cell is from Bacillus amyloliquefaciens. In another embodiment, the recombinant microbial host cell / microbial cell is from Bacillus licheniformis. In another embodiment, the recombinant microbial host cell / microbial cell is from Bacillus pumilus. In another embodiment, the recombinant microbial host cell / microbial cell is from Bacillus subtilis. In an embodiment, the recombinant microbial host cell / microbial cell is from Chryseobacterium sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Chryseobacterium proteolyticum. In an embodiment, the recombinant microbial host cell / microbial cell is from Escherichia sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Escherichia coll. In an embodiment, the recombinant microbial host cell / microbial cell is from Geobacillus sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Geobacillus stearothermophilus. In an embodiment, the recombinant microbial host cell / microbial cell is from Lactobacillus sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Lactobacillus fermentum. In an embodiment, the recombinant microbial host cell / microbial cell is from Lactococcus sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Lactococcus lactis. In an embodiment, the recombinant microbial host cell / microbial cell is from Macrococcus sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Macrococcus caseolyticus. In an embodiment, the recombinant microbial host cell / microbial cell is from Microbacterium sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Microbacterium arborescens. In an embodiment, the recombinant microbial host cell / microbial cell is from Micrococcus sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Micrococcus lysodeikticus. In an embodiment, the recombinant microbial host cell / microbial cell is from Priestia sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Priestia flexa. In an embodiment, the recombinant microbial host cell / microbial cell is from Streptomyces sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Streptomyces mobaraensis. In another embodiment, the recombinant microbial host cell / microbial cell is from Streptomyces murinus. In another embodiment, the recombinant microbial host cell / microbial cell is from Streptomyces olivaceus. In another embodiment, the recombinant microbial host cell / microbial cell is from Streptomyces olivochromogenes. In another embodiment, the recombinant microbial host cell / microbial cell is from Streptomyces rubiginosus. In another embodiment, the recombinant microbial host cell / microbial cell is from Streptomyces violaceoruber. In an embodiment, the recombinant microbial host cell / microbial cell is from Pseudomonas sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Pseudomonas fluorescens. In an embodiment, the recombinant microbial host cell / microbial cell is from Weizmannia sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Weizmannia coagulans.

[0572] In an embodiment, the recombinant microbial host cell is obtained from a microbial cell which is a yeast. In some embodiments, the yeast is a budding yeast. In other embodiments, the yeast is methylotrophic (e.g., yeast able to utilize methanol as the sole carbon and energy source). Embodiments of methylotrophic yeasts include, but are not limited to Komagataella sp. and Ogataea sp. In some embodiments, the yeast is an oleaginous yeast (e.g., a yeast capable of accumulating more than 20% of its dry cell weight as lipids or triglycerides).

[0573] In an embodiment, the recombinant microbial host cell / microbial cell is from Blastobotrys sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Blastobotrys adeninivorans (basonym Trichosporon adeninivorans). In an embodiment, the recombinant microbial host cell / microbial cell is from Candida sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Candida albicans. In an embodiment, the recombinant microbial host cell / microbial cell is from Cyberlindnera sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Cyberlindnera jadinii (basonym Saccharomyces jadinii). In an embodiment, the recombinant microbial host cell / microbial cell is from the Debaryomyces sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Debaryomyces hansenii. In another embodiment, the recombinant microbial host cell / microbial cell is from Debaryomyces hansenii. In an embodiment, the recombinant microbial host cell / microbial cell is from Hanseniaspora sp. (also known as Kloeckera sp.). In another embodiment, the recombinant microbial host cell / microbial cell is from Hanseniaspora guilliermondii. In another embodiment, the recombinant microbial host cell / microbial cell is from Hanseniaspora pseudoguilliermondii. In an embodiment, the recombinant microbial host cell / microbial cell is from the Kazachstania sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Kazachstania bulderi (basonym Saccharomyces bulderi). In another embodiment, the recombinant microbial host cell / microbial cell is from Kazachstania barnettii (basonym Saccharomyces barnettii). In another embodiment, the recombinant microbial host cell / microbial cell is from Kazachstania exigua (basonym Saccharomyces exiguus). In an embodiment, the recombinant microbial host cell / microbial cell is from Kluyveromyces sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Kluyveromyces lactis (basonym Torulaspora lactis). In another embodiment, the recombinant microbial host cell / microbial cell is from Kluyveromyces marxianus also known as Kluyveromyces fragilis (basonym Saccharomyces marxianus). In an embodiment, the recombinant microbial host cell / microbial cell is from Komagataella sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Komagataella phaffii. In an embodiment, the recombinant microbial host cell / microbial cell is from Limtongozyma sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Limtongozyma cylindracea (basonym Candida cylindracea). In an embodiment, the recombinant microbial host cell / microbial cell is from Lipomyces sp. In an embodiment, the recombinant microbial host cell / microbial cell is from Metschnikowia sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Metschnikowia sinensis. In another embodiment, the recombinant microbial host cell / microbial cell is from Metschnikowia fructicola. In another embodiment, the recombinant microbial host cell / microbial cell is from Metschnikowia pulcherrima. In another embodiment, the recombinant microbial host cell / microbial cell is from Metschnikowia zobellii. In another embodiment, the recombinant microbial host cell / microbial cell is from Metschnikowia shanxiensis. In an embodiment, the recombinant microbial host cell / microbial cell is from Ogataea sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Ogataea polymorpha (basonym Hansenula polymorpha). In another embodiment, the recombinant microbial host cell / microbial cell is from Ogataea methanolica (basonym Pichia methanolica). In an embodiment, the recombinant microbial host cell / microbial cell is from Pichia sp. (also known as Hansenula sp.). In an embodiment, the recombinant microbial host cell / microbial cell is from Rasamsonia sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Rasamsonia emersonii. In an embodiment, the recombinant microbial host cell / microbial cell is from Saccharomyces sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Saccharomyces cerevisiae. In yet another embodiment, the recombinant microbial host cell / microbial cell is from Saccharomyces cerevisiae var. diastaticus. In another embodiment, the recombinant microbial host cell / microbial cell is from Saccharomyces uvarum. In another embodiment, the recombinant microbial host cell / microbial cell is from Saccharomyces boulardii. In an embodiment, the recombinant microbial host cell / microbial cell is from Scheffersomyces sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Scheffersomyces stipitis (basonym Pichia stipitis). In an embodiment, the recombinant microbial host cell / microbial cell is from Schwanniomyces sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Schwanniomyces polymorphus (basonym Pichia polymorpha). In another embodiment, the recombinant microbial host cell / microbial cell is from Schwanniomyces occidentalis. In an embodiment, the recombinant microbial host cell / microbial cell is from Wickerhamomyces sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Wickerhamomyces anomalus. In an embodiment, the recombinant microbial host cell / microbial cell is from Yarrowia sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Yarrowia lipolytica.

[0574] In an embodiment, the recombinant microbial host cell is obtained from a microbial cell which is a fungus. In some embodiments, the fungus is an ascomycete fungus. In alternative embodiments, the fungus is a basidiomycete fungus. In a further embodiment, the fungus is an oleaginous fungus (e.g., a fungus capable of accumulating more than 20% of its dry cell weight as lipids or triglycerides). In an embodiment, the recombinant microbial host cell / microbial cell is from Aspergillus sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Aspergillus acidus. In another embodiment, the recombinant microbial host cell / microbial cell is from Aspergillus fijiensis. In another embodiment, the recombinant microbial host cell / microbial cell is from Aspergillus japonicus. In another embodiment, the recombinant microbial host cell / microbial cell is from Aspergillus luchuensis. In another embodiment, the recombinant microbial host cell / microbial cell is from Aspergillus melleus. In another embodiment, the recombinant microbial host cell / microbial cell is from Aspergillus niger. In another embodiment, the recombinant microbial host cell / microbial cell is from Aspergillus oryzae. In another embodiment, the recombinant microbial host cell / microbial cell is from Aspergillus flavus. In an embodiment, the recombinant microbial host cell / microbial cell is from Blakeslea sp. In an embodiment, the recombinant microbial host cell / microbial cell is from Cunninghamella sp. In an embodiment, the recombinant microbial host cell / microbial cell is from Cryphonectria sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Cryphonectria parasitica. In an embodiment, the recombinant microbial host cell / microbial cell is from Cryptococcus sp. In an embodiment, the recombinant microbial host cell / microbial cell is from Disporotrichum sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Disporotrichum dimorphosporum. In an embodiment, the recombinant microbial host cell / microbial cell is from Fusarium sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Fusarium venenatum. In an embodiment, the recombinant microbial host cell / microbial cell is from Humicola sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Humicola insolens. In an embodiment, the recombinant microbial host cell / microbial cell is from Mortierella sp. In an embodiment, the recombinant microbial host cell / microbial cell is from Mucor sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Mucor circinelloides. In an embodiment, the recombinant microbial host cell / microbial cell is from Mycothermus sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Mycothermus thermophiloides. In an embodiment, the recombinant microbial host cell / microbial cell is from Penicillum sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Penicillium camemberti. In another embodiment, the recombinant microbial host cell / microbial cell is from Penicillum chrysogenum. In another embodiment, the recombinant microbial host cell / microbial cell is from Penicillium rubens. In another embodiment, the recombinant microbial host cell / microbial cell is from Penicillium roquefortii. In an embodiment, the recombinant microbial host cell / microbial cell is from Phaffia sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Phaffia rhodozyma. In an embodiment, the recombinant microbial host cell / microbial cell is from Phycomyces sp. In an embodiment, the recombinant microbial host cell / microbial cell is from Rhizomucor sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Rhizomucor miehei. In another embodiment, the recombinant microbial host cell / microbial cell is from Rhizomucor pusillus. In an embodiment, the recombinant microbial host cell / microbial cell is from Rhizopus sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Rhizopus arrhizus (also know as Rhizopus oryzae). In another embodiment, the recombinant microbial host cell / microbial cell is from Rhizopus delemar. In another embodiment, the recombinant microbial host cell / microbial cell is from Rhizopus niveus. In an embodiment, the recombinant microbial host cell / microbial cell is from Rhodotorula sp. (also known as Rhodosporidum sp.). In an embodiment, the recombinant microbial host cell / microbial cell is from Schizosaccharomyces sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Schizosaccharomyces pombe. In an embodiment, the recombinant microbial host cell / microbial cell is from Talaromyces sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Talaromyces funiculosus (also known as Penicillium funiculosum). In an embodiment, the recombinant microbial host cell / microbial cell is from Trichoderma sp. In another embodiment, the recombinant microbial host cell / microbial cell is from Trichoderma reesei. In an embodiment, the recombinant microbial host cell / microbial cell is from Trichosporon sp.

[0575] The recombinant microbial host cells of the present disclosure include a heterologous nucleic acid molecule encoding at least one glucose oxidase variant. In some embodiments, the recombinant microbial host cells of the present disclosure include a plurality of heterologous nucleic acid molecules each encoding the same glucose oxidase variant. For example, the recombinant microbial host cell can include at least one copy of a heterologous nucleic acid molecule encoding the glucose oxidase variant having the amino acid sequence of SEQ ID NO: 5 (or a variant / fragment thereof). In this example, the recombinant microbial host cell can include one or more copies of the heterologous nucleic acid molecules having the nucleic acid sequence of SEQ ID NO: 6 or a degenerate nucleic acid sequence encoding the glucose oxidase variant having the amino acid sequence having the amino acid sequence of SEQ ID NO: 5 (or a variant / fragment thereof). In another example, the recombinant microbial host cell can include at least one copy of a heterologous nucleic acid molecule encoding the glucose oxidase variant having the amino acid sequence of SEQ ID NO: 7 (or a variant / fragment thereof). In this other example, the recombinant microbial host cell can include one or more copies of the heterologous nucleic acid molecules having the nucleic acid sequence of SEQ ID NO: 8 or a degenerate nucleic acid sequence encoding the glucose oxidase variant having the amino acid sequence having the amino acid sequence of SEQ ID NO: 7 (or a variant / fragment thereof). In some embodiments, the recombinant microbial host cells of the present disclosure include a plurality of heterologous nucleic acid molecules each encoding a different glucose oxidase variant. In still a further embodiment, the recombinant microbial host cells of the present disclosure include at least two heterologous nucleic acid molecules each encoding a different glucose oxidase variant. In yet another example, the recombinant yeast host cell of the present disclosure can include at least one copy of a first heterologous nucleic acid molecule encoding the glucose oxidase variant having the amino acid sequence of SEQ ID NO: 5 (or a variant / fragment thereof) and at least one copy of a second heterologous nucleic acid molecule encoding the glucose oxidase variant having the amino acid sequence of SEQ ID NO: 7 (or a variant / fragment thereof). In this further example, the recombinant microbial host cell can include one or more copies of the heterologous nucleic acid molecules having the nucleic acid sequence of SEQ ID NO: 6 or a degenerate nucleic acid sequence encoding the glucose oxidase variant having the amino acid sequence having the amino acid sequence of SEQ ID NO: 5 (or a variant / fragment thereof) and one or more copies of the heterologous nucleic acid molecules having the nucleic acid sequence of SEQ ID NO: 8 or a degenerate nucleic acid sequence encoding the glucose oxidase variant having the amino acid sequence having the amino acid sequence of SEQ ID NO: 7 (or a variant / fragment thereof).

[0576] As used herein, the term “heterologous” when used in reference to a nucleic acid molecule (such as a promoter, a terminator, or a coding sequence) or a polypeptide refers to a nucleic acid molecule or a polypeptide that is not natively found in the recombinant microbial host cell. “Heterologous” also includes a native coding region / promoter / terminator, or portion thereof, that was introduced into the source organism in a form and / or at a location that is different from the corresponding native gene, e.g., not in its natural location in the organism's genome. The one or more heterologous nucleic acid molecule(s) is / are purposively introduced into the recombinant microbial host cell. For example, a heterologous nucleic acid element could be derived from a different strain of host cell, or from an organism of a different taxonomic group (e.g., different domain, kingdom, phylum, class, order, family, genus, or species, or any subgroup within one of these classifications).

[0577] The one or more heterologous nucleic acid molecule(s) encoding glucose oxidase variants are introduced in the recombinant microbial host cell to allow them to express the enzymes. The expression of the heterologous or control polypeptide can be constitutive or induced. The expression of the glucose oxidase variants from the one or more heterologous nucleic acid molecule(s) can occur during the growth phase and / or the stationary phase of the recombinant microbial host cell.

[0578] In some embodiments, the one or more nucleic acid molecules encoding the glucose oxidase variants that are introduced into the recombinant microbial host cells are codon-optimized with respect to the intended recipient recombinant microbial host cell. As used herein the term “codon-optimized coding region” means a nucleic acid coding region that has been adapted for expression in the cells of a given organism by replacing at least one, or more than one, codons with one or more codons that are more frequently used in the genes of that organism. In general, highly expressed genes in an organism are biased towards codons that are recognized by the most abundant tRNA species in that organism. One measure of this bias is the “codon adaptation index” or “CAI,” which measures the extent to which the codons used to encode each amino acid in a particular gene are those which occur most frequently in a reference set of highly expressed genes from an organism. The CAI of codon optimized heterologous nucleic acid molecule described herein corresponds to between about 0.8 and 1 .0, between about 0.8 and 0.9, or about 1 .0.

[0579] The heterologous nucleic acid molecules of the present disclosure comprise a coding region for a glucose oxidase variant. A DNA or RNA “coding region” is a DNA or RNA molecule which is transcribed and / or translated into a polypeptide in a cell in vitro or in vivo when placed under the control of appropriate regulatory sequences. “Suitable regulatory regions” refer to nucleic acid regions located upstream (5' non-coding sequences), within, or downstream (3' noncoding sequences) of a coding region, and which influence the transcription, RNA processing or stability, or translation of the associated coding region. Regulatory regions may include promoters, translation leader sequences, RNA processing site, effector binding site and stemloop structure. The boundaries of the coding region are determined by a start codon at the 5' (amino) terminus and a translation stop codon at the 3' (carboxyl) terminus. A coding region can include, but is not limited to, prokaryotic regions, cDNA from mRNA, genomic DNA molecules, synthetic DNA molecules, or RNA molecules. If the coding region is intended for expression in a eukaryotic cell, a polyadenylation signal and transcription termination sequence will usually be located 3' to the coding region. In an embodiment, the coding region can be referred to as an open reading frame. “Open reading frame" is abbreviated ORF and means a length of nucleic acid, either DNA, cDNA, or RNA, that comprises a translation start signal or initiation codon, such as an ATG or AUG, and a termination codon and can be potentially translated into a polypeptide sequence.

[0580] The heterologous nucleic acid molecules described herein can comprise transcriptional and / or translational control regions. “Transcriptional and translational control regions” are DNA regulatory regions, such as promoters, enhancers, terminators, and the like, that provide for the expression of a coding region in a host cell. In eukaryotic cells, polyadenylation signals are control regions.

[0581] The heterologous nucleic acid molecule can be introduced in the recombinant microbial host cell using a vector. A “vector,” e.g., a “plasmid”, “cosmid” or “artificial chromosome” (such as, for example, a yeast artificial chromosome) refers to an extra chromosomal element and is usually in the form of a circular double-stranded DNA molecule. Such vectors may be autonomously replicating sequences, genome integrating sequences, phage or nucleotide sequences, linear, circular, or supercoiled, of a single- or double-stranded DNA or RNA, derived from any source, in which a number of nucleotide sequences have been joined or recombined into a unique construction.

[0582] In the heterologous nucleic acid molecule described herein, the promoter and the nucleic acid molecule coding for the glucose oxidase variant are operatively linked to one another. In the context of the present disclosure, the expressions “operatively linked” or “operatively associated” refers to fact that the promoter is physically associated to the nucleic acid molecule coding for the polypeptide in a manner that allows, under certain conditions, for expression of the polypeptide from the nucleic acid molecule. In an embodiment, the promoter can be located upstream (5’) of the nucleic acid sequence coding for the heterologous polypeptide. In the context of the present disclosure, one or more than one promoter can be included in the nucleic acid molecule. When more than one promoter is included in the nucleic acid molecule, each of the promoters is operatively linked to the nucleic acid sequence coding for the polypeptide. The promoters can be located, in view of the nucleic acid molecule coding for the polypeptide, upstream, downstream as well as both upstream and downstream.

[0583] “Promoter” refers to a DNA fragment capable of controlling the expression of a coding sequence or functional RNA. The term “expression,” as used herein, refers to the transcription and stable accumulation of sense (mRNA) from the heterologous nucleic acid molecule described herein. Expression may also refer to translation of mRNA into a polypeptide. Promoters may be derived in their entirety from a native gene, or be composed of different elements derived from different promoters found in nature, or even comprise synthetic DNA segments. It is understood by those skilled in the art that different promoters may direct the expression at different stages of development, or in response to different environmental or physiological conditions. Promoters which cause a gene to be expressed in most cells at most times at a substantial similar level are commonly referred to as “constitutive promoters.” It is further recognized that since in most cases the exact boundaries of regulatory sequences have not been completely defined, DNA fragments of different lengths may have identical promoter activity. A promoter is generally bounded at its 3' terminus by the transcription initiation site and extends upstream (5' direction) to include the minimum number of bases or elements necessary to initiate transcription at levels detectable above background. Within the promoter will be found a transcription initiation site (conveniently defined for example, by mapping with nuclease S1), as well as polypeptide binding domains (consensus sequences) responsible for the binding of the polymerase.

[0584] The promoter can be heterologous to the nucleic acid molecule encoding the heterologous polypeptide. The promoter can be heterologous or derived from a strain being from the same genus or species as the recombinant microbial host cell. In an embodiment, the promoter is derived from the same genus, or species than the recombinant microbial host cell and the polypeptide is derived from different genera from the recombinant microbial host cell. One or more promoters can be used to allow the expression of the polypeptides in the recombinant yeast host cell.

[0585] The heterologous nucleic acid molecule can include, in some embodiments, one or more terminators to end the translation of the glucose oxidase variant. In some embodiments, the one or more terminators used are terminators derived from genes found in yeasts (such as for example Saccharomyces or Komagataella). In some embodiments, the terminator comprises the terminator derived from is from the dit1 gene (ditit, a functional variant or a functional fragment thereof), from the idp1 gene (idplt, a functional variant or a functional fragment thereof), from the gpm1 gene (gpmlt, a functional variant or a functional fragment thereof), from the pma1 gene (pamlt, a functional variant or a functional fragment thereof), from the tdh3 gene (tdh3t, a functional variant or a functional fragment thereof), from the hxt2 gene (a functional variant or a functional fragment thereof), from the adh3 gene (adh3t, a functional variant or a functional fragment thereof), from the ira2 gene (ira2t, a functional variant or a functional fragment thereof), from the rpl3 gene (rpl3t, a functional variant thereof or a functional fragment thereof), from the bna4 gene (bna4t, a functional variant thereof or a functional fragment thereof), from the pgk1 gene (pgklt, a functional variant thereof or a functional fragment thereof), from the fur4 gene (fur4t, a functional variant thereof or a functional fragment thereof), from the mig2 gene (mig2t, a functional variant thereof or a functional fragment thereof), from the icy2 gene (icy2t, a functional variant thereof or a functional fragment thereof), from the gic1 gene (gidt, a functional variant thereof or a functional fragment thereof), from the aox1 gene (aoxlt, a functional variant thereof or a functional fragment thereof), from the gap1 gene (gaplt, a functional variant thereof or a functional fragment thereof), from the gapdh gene (gapdht, a functional variant thereof or a functional fragment thereof), from the dhas gene (dhast, a functional variant thereof or a functional fragment thereof), from the fdh gene (fdht, a functional variantthereof or a functional fragment thereof), from the fid gene (fldt, a functional variant thereof or a functional fragment thereof), from the act gene (actt, a functional variant thereof or a functional fragment thereof), from the arg4 gene (arg4t, a functional variant thereof or a functional fragment thereof), from the icl1 gene (icllt, a functional variant thereof or a functional fragment thereof), from the prm9 gene (prm9t, a functional variantthereof or a functional fragment thereof), from the vps13 gene (vps13t, a functional variant thereof or a functional fragment thereof), and / or from the Iac4 gene (Iac4t, a functional variant thereof or a functional fragment thereof).

[0586] In some embodiments, the promoter or the combination of promoters present in the heterologous nucleic acid is capable of allowing the expression of the glucose oxidase variant during the growth phase of the recombinant microbial host cell. In some embodiments, the promoter also allows the expression of the polypeptide during the stationary phase of the recombinant microbial host cell.

[0587] The promoters that can be included in the heterologous nucleic acid molecule can be constitutive or inducible promoters. In some embodiments, the promoter is derived from a promoter that is present in Saccharomyces cerevisiae. Inducible promoters include, but are not limited to glucose-regulated promoters (e.g., the promoter of the hxt7 gene (referred to as hxt7p), a functional variant or a functional fragment thereof; the promoter of the ctt1 gene (referred to as ctt1 p), a functional variant or a functional fragment thereof; the promoter of the glo1 gene (referred to as glol p), a functional variant or a functional fragment thereof; the promoter of the ygp1 gene (referred to as ygp1 p), a functional variant or a functional fragment thereof; the promoter of the gsy2 gene (referred to as gsy2p), a functional variant or a functional fragment thereof), the promoter of the gpm1 gene (referred to as gpml p), a functional variant or a functional fragment thereof, the promoter of the pgk1 gene (referred to as pgkl p)), molasses-regulated promoters (e.g., the promoter of the moll gene (referred to as mol1 p), a functional variant or a functional fragment thereof), heat shock-regulated promoters (e.g., the promoter of the glo1 gene (referred to as glol p), a functional variant or a functional fragment thereof; the promoter of the sti1 gene (referred to as stil p), a functional variant or a functional fragment thereof; the promoter of the ygp1 gene (referred to as ygpl p), a functional variant or a functional fragment thereof; the promoter of the gsy2 gene (referred to as gsy2p), a functional variant or a functional fragment thereof), oxidative stress response promoters (e.g., the promoter of the cup1 gene (referred to as cup1 p), a functional variant or a functional fragment thereof; the promoter of the ctt1 gene (referred to as cttl p), a functional variant or a functional fragment thereof; the promoter of the trx2 gene (referred to as trx2p), a functional variant or a functional fragment thereof; the promoter of the gpd1 gene (referred to as gpdl p), a functional variant or a functional fragment thereof; the promoter of the hsp12 gene (referred to as hsp12p), a functional variant or a functional fragment thereof, the promoter of the hsp150 gene (referred to as hsp150p), a functional variant or a functional fragment thereof; the promoter of the ssc1 gene (referred to as ssd p), a functional variant or a functional fragment thereof), osmotic stress response promoters (e.g., the promoter of the ctt1 gene (referred to as cttl p), a functional variant or a functional fragment thereof; the promoter of the glo1 gene (referred to as glol p), a functional variant or a functional fragment thereof; the promoter of the gpd1 gene (referred to as gpdl p), a functional variant or a functional fragment thereof; the promoter of the ygp1 gene (referred to as ygp1 p), a functional variant or a functional fragment thereof, the promoter of the hor7 gene (referred to as hor7p), a functional variant or a functional fragment thereof; the promoter of the stl1 gene (referred to as stH p), a functional variant or a functional fragment thereof), nitrogen-regulated promoters (e.g., the promoter of the ygp1 gene (referred to as ygpl p), a functional variant or a functional fragment thereof), anaerobic- regulated promoters (e.g., the promoter from the aox1 gene (referred to as aox1 p), a functional variant or a functional fragment thereof, the promoter of the tir1 gene (referred to as tirl p), a functional variant or a functional fragment thereof, the promoter of the pau5 gene (referred to as pau5p), a functional variant or a functional fragment thereof the promoter of the dan1 gene (referred to as dan1 p), the promoter of the tdh1 gene (referred to as tdh 1 p), a functional variant or a functional fragment thereof, the promoter of the spi1 gene (referred to as spil p), a functional variant or a functional fragment thereof, the promoter of the hxk1 gene (referred to as hxkl p), a functional variant or a functional fragment thereof, the promoter of the anb1 gene (referred to as anb1 p), a functional variant or a functional fragment thereof, the promoter of the hxt6 gene (referred to as hxt6p), a functional variant or a functional fragment thereof, the promoter of the trx1 gene (referred to as trxl p), a functional variant or a functional fragment thereof, the promoter of the aac3 gene (referred to as aac3p), a functional variant or a functional fragment thereof, the promoter of the hor7 gene (referred to as hor7p), a functional variant or a functional fragment thereof, the promoter of the adh1 gene (referred to as adhl p), a functional variant or a functional fragment thereof, the promoter of the tdh2 gene (referred to as tdh2p), a functional variant or a functional fragment thereof, the promoter of the tdh3 gene (referred to as tdh3p), a functional variant or a functional fragment thereof, the promoter of the gdp1 gene (referred to as gpdl p), a functional variant or a functional fragment thereof, the promoter of the cdc19 gene (referred to as cdc19p), a functional variant or a functional fragment thereof, the promoter of the eno2 gene (referred to as eno2p), a functional variant or a functional fragment thereof, the promoter of the pdc1 gene (referred to as pdd p), a functional variant or a functional fragment thereof, the promoter of the hxt3 gene (referred to as hxt3p), a functional variant or a functional fragment thereof, or the promoter of the tpi1 gene (referred to tpil p)), ethanol-regulated promoters (including ethanol responsive promoters), redox- regulated promoters (e.g., including, but not limited to the promoter of the gpd2 gene (referred as gpd2p), a functional variant or a functional fragment thereof), sulfite-regulated promoters (e.g., including, but not limited to the promoter of the fzf1 gene (referred to as the fzfl p), a functional variant or a functional fragment thereof, the promoter of the ssu1 gene (referred to as ssul p), a functional variant or a functional fragment thereof, and the promoter of the ssu1- r gene (referred to as the ssu1-rp), a functional variant or a functional fragment thereof), and stress-response promoters (e.g., including, but not limited to the promoter of the yap1 gene (referred to as yap1 p), a functional variant or a functional fragment thereof, the promoter of the ssa3 gene (referred to as ssa3p), a functional variant or a functional fragment thereof, and the promoter of the hsp104 gene (referred to as hsp104p), a functional variant or a functional fragment thereof). Constitutive promoters include, but are not limited to the promoter of the tef2 gene (referred to as tef2p), the promoter of the cwp2 gene (referred to as cwp2p), the promoter of the ssa1 gene (referred to as ssal p), the promoter of the enol gene (referred to as enol p), the promoter of the hxk1 gene (referred to as hxkl p), the promoter of the pgk1 gene (referred to as pgk1 p), the promoter of the adh1 gene (referred to as adh1 p), the promoter of the rev1 gene (referred to as revl p), the promoter of the cyc1 gene (referred to as cyd p), and the promoter of the ste5 gene (referred to as ste5p) as well as functional variants or a functional fragments thereof.

[0588] In some embodiments, the promoter can be obtained or derived from a native promoter present in Komagataella phaffii. Inducible promoters include, but are not limited to glucose-regulated promoters, fructose-regulated promoters, glycerol-regulated promoters, heat shock-regulated promoters, oxidative stress response promoters, osmotic stress response promoters, nitrogen- regulated promoters, and ethanol-regulated promoters. In an embodiment, ethanol-regulated promoters include, without limitation, the promoter from the adh2 gene, which is also known as the adh3 gene (referred to as adh2p). Constitutive promoters include, without limitation, the promoter from the spi1 gene (referred to as spil p). In an embodiment, the parental promoter is a promoter from the gap1 gene (referred to as gapl p). In an embodiment, the parental promoter is a promoter from the hgt1 gene (referred to as hgtl p). In an embodiment, the parental promoter is a promoter from the glc3 gene (referred to as glc3p). In an embodiment, the parental promoter is a promoter from the acb2 gene (referred to as acb2p). In an embodiment, the parental promoter is a promoter from the pex8 gene (referred to as pex8p). In an embodiment, the parental promoter is a promoter from the urc1 gene (referred to as urc1 p). In an embodiment, the parental promoter is a promoter from the tpo3 gene (referred to as top3p). In an embodiment, the parental promoter is a promoter from the bio2 gene (referred to as bio2p). In an embodiment, the parental promoter is a promoter from the gut1 gene (referred to as gutl p). In an embodiment, the parental promoter is a promoter from the cat1 gene (referred to as catl p). In an embodiment, the parental promoter is a promoter from the icl1 gene (referred to as icll p). In an embodiment, the parental promoter is a promoter from the gcw14 gene (referred to as gcw14p). In some embodiments, the promoter can be obtained or derived from a native promoter present in Ogataea polymorpha. In an embodiment, the promoter is a promoter from the sori gene (referred to as sori p), the O. polymorpha methanol oxidase mox1 gene (referred to as mox1 p), the O. polymorpha promoter from the gap1 gene (referred to as OpGAPI p), the O. polymorpha promoter from the gapdh gene (referred to as OpGAPDHp), the O. polymorpha promoter from the gcw14 gene (referred to as OpGCW14p), the O. Polymorpha promoter from the adh1 gene (referred to as OpADHI p), the O. polymorpha promoter from the Icl1 gene (referred to as OpICLI p), or the O. polymorpha promoter from the tef1 gene (referred to as OpTEFI p).

[0589] In specific embodiments, the heterologous nucleic acid molecule encoding the glucose oxidase variant comprises at least one of the adh2 and / or spi1 variant promoters described in US regular patent application 18 / 740,964 filed on June 12, 2023 and herewith incorporated by reference. In yet another specific embodiment, the heterologous nucleic acid molecule encoding the glucose oxidase variant comprises the nucleic acid sequence of SEQ ID NO: 11 , a variant thereof or a fragment thereof.

[0590] Promoters that can be included in the heterologous nucleic acid molecule of the present disclosure include, without limitation, the promoter of the tdh1 gene (referred to as tdhl p, a functional variant or a functional fragment thereof), of the hor7 gene (referred to as hor7p, a functional variant or a functional fragment thereof), of the hsp150 gene (referred to as hsp150p, a functional variant or a functional fragment thereof), of the hxt7 gene (referred to as hxt7p, a functional variant or a functional fragment thereof), of the gpm1 gene (referred to as gpml p, a functional variant or a functional fragment thereof), of the pgk1 gene (referred to as pgkl p, a functional variant or a functional fragment thereof), of the stl1 gene (referred to as stH p, a functional variant or a functional fragment thereof), of the tef2 gene (referred to as tef2p, a functional variant or a functional fragment thereof), of the tdh3 gene (referred to as tdh3p, a functional variant or fragment thereof), of the fba1 gene (referred to as fbal p, a functional variant or fragment thereof), of the eno2 gene (referred to as eno2p, a functional variant or fragment thereof), and / or of the hyp2 gene (referred to as hyp2p, a functional variant or fragment thereof). In some specific embodiments, the heterologous nucleic acid comprises a constitutive promoter, such as, for example, from the tef2 gene comprising the nucleic acid sequence of SEQ ID NO: 12, or a functional variant / fragment thereof. In some specific embodiments, the heterologous nucleic acid comprises a promoter from the tdh3 gene comprising the nucleic acid sequence of SEQ ID NO: 13, or a functional variant / fragment thereof. In some specific embodiments, the heterologous nucleic acid comprises a promoter from the fba1 gene comprising the nucleic acid sequence of SEQ ID NO: 14, or a functional variant / fragment thereof. In some specific embodiments, the heterologous nucleic acid comprises promoters from the tdh3 gene comprising the nucleic acid sequence of SEQ ID NO: 13, or a functional variant / fragment thereof and from the fba1 gene comprising the nucleic acid sequence of SEQ ID NO: 14, or a functional variant / fragment thereof. In some specific embodiments, the heterologous nucleic acid comprises a promoter from the eno2 gene comprising the nucleic acid sequence of SEQ ID NO: 15, or a functional variant / fragment thereof. In some specific embodiments, the heterologous nucleic acid comprises a promoter from the hyp2 gene comprising the nucleic acid sequence of SEQ ID NO: 16, or a functional variant / fragment thereof. In some specific embodiments, the heterologous nucleic acid comprises promoters from the eno2 gene comprising the nucleic acid sequence of SEQ ID NO: 15, or a functional variant / fragment thereof, and from the hyp2 gene comprising the nucleic acid sequence of SEQ ID NO: 16, or a functional variant / fragment thereof.

[0591] In the context of the present disclosure, the expression “functional fragment of a promoter” refers to a shorter nucleic acid sequence than the native promoter which retains the ability to control the expression of the nucleic acid sequence encoding the glucose oxidase variant. Usually, functional fragments are either 5’ and / or 3’ truncation of one or more nucleic acid residue from the native promoter nucleic acid sequence. In the context of the present disclosure, the expression “functional variant of a promoter” refers to a nucleic acid sequence which differs in at least one position and still retains the ability to control the expression of the nucleic acid sequence encoding the glucose oxidase variant.

[0592] In some embodiments, the heterologous nucleic acid molecules include one or a combination of terminator sequence(s) to end the transcription of the glucose oxidase variant. The terminator can be native or heterologous to the nucleic acid sequence encoding the heterologous polypeptide. In some embodiments, one or more terminators can be used. In some embodiments, the terminator comprises the terminator derived from is from the dit1 gene (ditit, a functional variant or a functional fragment thereof), from the idp1 gene (idplt, a functional variant or a functional fragment thereof), from the gpm1 gene (gpmlt, a functional variant or a functional fragment thereof), from the pma1 gene (pamlt, a functional variant or a functional fragment thereof), from the tdh3 gene (tdh3t, a functional variant or a functional fragment thereof), from the hxt2 gene (a functional variant or a functional fragment thereof), from the adh3 gene (adh3t, a functional variant or a functional fragment thereof), and / or from the ira2 gene (ira2t, a functional variant or a functional fragment thereof). In an embodiment, the terminator comprises or is derived from the dit1 gene (ditit, a functional variant or a functional fragment thereof). In another embodiment, the terminator comprises or is derived adh3t and / or idplt.

[0593] In the context of the present disclosure, the expression “functional variant of a terminator” refers to a nucleic acid sequence that has been substituted in at least one nucleic acid position when compared to the native terminator which retain the ability to end the expression of the nucleic acid sequence coding for the glucose oxidase variant. In the context of the present disclosure, the expression “functional fragment of a terminator” refers to a shorter nucleic acid sequence than the native terminator which retain the ability to end the expression of the nucleic acid sequence coding for glucose oxidase variant.

[0594] The glucose oxidase variants of the present disclosure can also be obtained in cell-free systems using the heterologous nucleic acid molecule described herein.

[0595] Methods for making the compositions comprising the glucose oxidase variants

[0596] The present disclosure provides methods for making the glucose oxidase variants as well as compositions comprising the same. In some embodiments, a cell-free system is used to express the glucose oxidase variants encoded by one or more heterologous nucleic acid molecule(s). In other embodiments, the methods comprises using one or more recombinant microbial host cells to express the glucose oxidase. In such processes, recombinant microbial host cells comprising the one or more heterologous nucleic acid molecule(s) encoding (directly or indirectly) the glucose oxidase variants can be cultured or propagated to allow the expression and the accumulation of the glucose oxidase variants. The growth phase as well as the stationary phase can be conducted in a culture medium allowing the cell growth and division of the recombinant microbial host cells under conditions (agitation, temperature, oxygen concentration, etc.) to favor the expression and accumulation, and optionally the secreti...

Claims

WHAT IS CLAIMED IS:1 . A glucose oxidase variant (i) having at least 90% identity with the amino acid sequence of SEQ ID NO: 1 , and (ii) comprising an amino acid substitution at any one of positions 159, 411 , 443, 468, and / or 491.

2. The glucose oxidase variant of claim 1 comprising the amino acid substitution at position 159.

3. The glucose oxidase variant of claim 2 comprising the amino acid substitution A159F, A159L, A159K, A159R, A159Y, A159T, A159V, or A159S.

4. The glucose oxidase variant of any one of claims 1 to 3 comprising the amino acid substitution at position 411 .

5. The glucose oxidase variant of claim 4 comprising the amino acid substitution T411V, T411S, T411A, T411 Q, T411 E, or T411 K.

6. The glucose oxidase variant of any one of claims 1 to 5 comprising the amino acid substitution at position 443.

7. The glucose oxidase variant of claim 6 comprising the amino acid substitution A443I, A443L, A443F, A443M, A443Y, or A443V.

8. The glucose oxidase variant of any one of claims 1 to 7 comprising the amino acid substitution at position 468.

9. The glucose oxidase variant of claim 8 comprising the amino acid substitution H468R, H468A, H468K, H468G, or H468S.

10. The glucose oxidase variant of any one of claims 1 to 9 comprising the amino acid substitution at position 491.11 . The glucose oxidase variant of claim 10 comprising the amino acid substitution Q491 K, Q491 R, or Q491 E.

12. The glucose oxidase variant of claim 1 , further comprising one or more additional amino acid substitution at any one of positions 92, 433, 440, and / or 503.

13. The glucose oxidase variant of claim 12 comprising the amino acid substitution at position 92.

14. The glucose oxidase variant of claim 13 comprising the amino acid substitution D92E, D92Q, D92A, D92K, D92R, D92S, or D92Y.

15. The glucose oxidase variant of any one of claims 12 to 14 comprising the amino acid substitution at position 433.

16. The glucose oxidase variant of claim 15 comprising the amino acid substitution S433A, S433V, S433L, S433G, S433F, S433Y, or S433l.

17. The glucose oxidase variant of any one of claims 12 to 16 comprising the amino acid substitution at position 440.

18. The glucose oxidase of claim 17 comprising the amino acid substitution A440G, A440E, A440D, A440S, A440F, or A440K.

19. The glucose oxidase variant of any one of claims 12 to 17 comprising the amino acid substitution at position 503.

20. The glucose oxidase variant of claim 19 comprising the amino acid substitution Q503K, Q503A, Q503R, Q503S, or Q503E.

21. A heterologous nucleic acid molecule comprising an open reading frame encoding the glucose oxidase variant of any one of claims 1 to 20.

22. The heterologous nucleic acid molecule of claim 21 further comprising at least one promoter operably associated with the open reading frame.

23. A vector comprising the heterologous nucleic acid molecule of claim 21 or 22.

24. An expression cassette comprising the heterologous nucleic acid molecule of claim 21 or 22.

25. A recombinant microbial host cell expressing the glucose oxidase variant of any one of claims 1 to 20.

26. The recombinant microbial host cell of claim 25 comprising the heterologous nucleic acid molecule of claim 21 or 22, the vector of claim 23 or the expression cassette of claim 24.

27. The recombinant microbial host cell of claim 25 or 26 being a yeast.

28. The recombinant microbial host cell of claim 27 being from Saccharomyces sp.

29. The recombinant microbial host cell of claim 28 being from Saccharomyces cerevisiae.

30. The recombinant microbial host cell of claim 27 being from Komagatealla sp.31 . The recombinant microbial host cell of claim 30 being from Komagataella phaffii.

32. A method for making the glucose oxidase variant of any one of claims 1 to 20, the process comprises (i) expressing the heterologous nucleic acid molecule of claim 21 or 22, the vector of claim 23 or the expression cassette of claim 24 in the recombinant microbial host cell of any one of claims 25 to 29.

33. The method of claim 32, wherein the glucose oxidase variant is an intracellular polypeptide or a secreted polypeptide.

34. The method of claim 33, wherein the secreted polypeptide is in a free form or is associated to the surface of the recombinant microbial host cell.

35. The method of claim 34, wherein the polypeptide associated to the surface of the recombinant yeast host cell is a tethered polypeptide.

36. The method of any one of claims 32 to 35, further comprising, after step (i), (ii) substantially separating the glucose oxidase variant from the recombinant microbial host cell.

37. The method of any one of claims 32 to 36, further comprising, after step (i) or (ii), drying the glucose oxidase variant.

38. A composition comprising the glucose oxidase variant of any one of claims 1 to 20, and a carrier.

39. The composition of claim 38, wherein the glucose oxidase variant is obtainable or obtained by the method of any one of claims 32 to 37.

40. The composition of claim 38 or 39 further comprising another enzyme.

41. A process for preparing a dough or a baked product prepared from the dough, the process comprising adding an effective amount of the glucose oxidase variant of any one of claims 1 to 20, optionally in combination with a fermenting yeast, to the dough.

42. The process of claim 41 , further comprising, prior to, during and / or after the addition, leavening the dough.

43. The process of claim 41 or 42, further comprising, after the addition, baking the dough.

44. The process of any one of claims 41 to 43 for increasing the softness and / or the resilience of the baked product.

45. The process of any one of claims 41 to 44 for increasing the strength of the dough.

46. The process of any one of claims 41 to 45 for reducing, at least in part, the amount of a chemical dough strengthener in the dough.

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