Modified PIV5 vaccine vectors: methods of making and uses
Patent Information
- Application Number
- PCT/US2024/014505
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2023-02-06
- Filing Date
- 2024-02-05
- Publication Date
- 2025-01-09
AI Technical Summary
Current PIV5 vaccine vectors have limitations in potency and yield, necessitating the development of more effective and high-yield vectors for immunization against respiratory viruses like RSV and SARS-CoV-2.
A modified PIV5 CVB backbone with specific mutations, such as S156N or S157F in the P/V gene, and deletions or substitutions in the SH gene, enhances viral replication and transcription, improving vaccine vector yield and immunogenicity, and is used to express heterologous antigens like SARS-CoV-2 and RSV proteins for intranasal immunization.
The modified PIV5 CVB vector demonstrates enhanced growth in cell culture and immunogenicity, providing a potent vaccine platform for inducing effective immune responses against SARS-CoV-2 and RSV, with improved yield and protective efficacy.
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Figure US2024014505_09012025_PF_FP_ABST
Abstract
Description
MODIFIED PIV5 VACCINE VECTORS: METHODS OF MAKING AND USESREFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to United States Provisional Application Serial Number 63 / 483,377, filed on February 6, 2023, which is hereby incorporated by this reference in its entirety.FIELD
[0002] The invention is generally related to the field of vaccination, and more particularly to compositions and methods of using modified PIV5 vaccine vectors such as PIV5W3AASH or PIV5W3AASH with P / V gene mutation (CVB) for modulating immune responses in a subject having or susceptible to infectious agents such as RSV and SARS-CoV-2.BACKGROUND
[0003] Parainfluenza virus type 5 (Parainfluenza virus 5, PIV5) belongs to the family Paramyxoviridae and the genus Rubulavirus which also includes mumps virus, and its genome is negative single strand RNA with a length of 15246 nt. The genome full- length structure of PIV5 is 3 '-Leader-NP-V / P-M-F-SH-HN-L-Trailer-5', namely, from 3 'end to 5' end, Nucleocapsid Protein (NP), V protein / phosphorylated protein (P), Matrix protein (M), Fusion protein (F), Small hydrophobic protein (SH), Hemagglutininneuraminidase protein (HN) and polymerase protein (Large protein, L) are encoded in sequence. Wherein, the V protein and the SH protein are non- structural proteins.
[0004] PIV5 is an excellent viral vector for vaccine development, and research on PIV5 recombinant vaccines is underway. In recent years, researchers have continuously explored the feasibility of using PIV5 as a vaccine vector. A common approach is to insert a protective antigen gene from a virus or bacteria into PIV5, and to express the inserted foreign gene by replication and translation of PIV5 vector. Given that PIV5 can infect respiratory tract without causing any illness, researchers often take advantage of this and focus on controlling certain respiratory viral infections. Therefore, the deep research on the molecular biological characteristics, the replication mechanism and the like of the virus is beneficial to the comprehensive and thorough understanding of the PIV5, so that a foundation is laid for the research on the PIV5 as a genetic engineering vaccine vector and the gene function research of the virus. However, there remains a need for more potent and high yield PIV5 vaccine vectors.
[0005] Thus, the disclosure provided herein provides a more potent and high yield PIV5 CVB backbone which contains the P / V gene S156N or S157F mutation, and the generation of new SARS-CoV-2 CVB-vectored vaccines for intranasal immunization. The phosphoprotein (P) protein can be phosphorylated at serine residues at positions 36, 126, and 157 and a threonine residue at position 286. In addition, host cell Polo-like kinase 1 (PLK1) can phosphorylate a serine residue at position 308. Mutation of the serine residues to alanine residues at either position 157 or 308 prevents phosphorylation at these residues significantly enhancing the activity of the vRdRP in mini-genome assays and the replication of recombinant viruses that bear these mutations. The mutation at residue 156 and 157 are hypothesized to upregulate viral transcription and replication, improving vaccine virus yield. The change in the amino acids 155-159 TSSPI motif of the PIV5 P protein will change virus phenotype and growth property in vitro and in vivo.SUMMARY
[0006] In accordance with the purpose(s) of this invention, as embodied and broadly described herein, this invention, in one aspect, relates to a modified PIV5 (termed CVB) viral expression vector comprising a PIV5 W3A viral genome having a mutations at amino acid residue SI 57 or SI 56 of the P / V gene and a deletion of the small hydrophobic (SH) gene of the PIV5 W3A viral genome. This modified CVB backbone has been shown to grow better in cell culture such as in serum-free Vero cells and be more immunogenic, such as in the cotton rat animal model. The modified CVB backbone can be used as an effective vaccine platform.
[0007] In some embodiments, the mutation at amino acid residue SI 57 or SI 56 comprises the substitution of serine (S) with an amino acid residue selected from a group consisting of alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), selenocysteine (U), valine (V), tryptophan (W), and tyrosine (Y). In one embodiment, the amino acid substitution at amino acid residue SI 57 comprises a substitution of serine (S) to phenylalanine (F) or SI 56 comprises a substitution of serine (S) to asparagine (N).
[0008] In further embodiments, the SH gene has a deletion of the SH open reading frame or a deletion of an entire SH gene transcript unit.
[0009] In one embodiment, the CVB viral expression vector expresses a heterologous polypeptide comprising a viral antigen selected from a group consisting of SARS-CoV-2, RSV or other viral or bacterial antigens. In another embodiment, the PIV5 genome has a heterologous nucleic acid sequence with at least 98% sequence identity to SEQ ID NOs: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 and wherein the viral expression vector expresses a heterologous polypeptide comprising a coronavirus spike (S) and / or nucleocapsid (N) proteins, RSV-F proteins, or viral or bacterial antigens.
[0010] In one embodiment, the coronavirus S protein is a coronavirus S protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a variant of interest or a variant of concern of SARS-CoV-2 and the coronavirus N protein is the coronavirus N protein of SARS-CoV-2, a variant of interest or a variant of concern of SARS-CoV-2. In some embodiment, the coronavirus S protein is the coronavirus S protein of a SARS- CoV-2 Wuhan strain, a SARS-CoV-2 beta variant, a SARS-CoV-2 gamma variant, a SARS-CoV-2 delta variant, or a SARS-CoV-2 omicron variant and the coronavirus N protein is the coronavirus N protein of a SARS-CoV-2 Wuhan strain, a SARS-CoV-2 beta variant, a SARS-CoV-2 gamma variant, a SARS-CoV-2 delta variant, or a SARS-CoV-2 omicron variant. In some embodiments, the SARS-CoV-2 omicron variant is SARS- CoV-2 Omicron BA.1 or SARS-CoV-2 Omicron BA.5, BQ1 or XBB1 or any future emerging variants.
[0011] In one embodiment, the coronavirus S protein comprises the coronavirus S protein of SARS-CoV-2 and wherein the cytoplasmic tail of the coronavirus S protein has been replaced with the cytoplasmic tail of the fusion (F) protein of CVB.
[0012] In one embodiment, the PIV5 W3 A viral genome comprises open reading frame deletion mutations of the SH gene and the S gene of SARS-CoV-2 Wuhan strain is inserted between the PIV5 hemagglutinin (HN) and polymerase (L) genes of CVB.
[0013] In some embodiments, the entire SH gene transcript unit of PIV5 W3A viral genome is deleted and the S gene of the SARS-CoV-2 Wuhan strain is placed between the HN and L genes of CVB.
[0014] In some embodiments, the N gene of SARS-CoV-2 Wuhan strain is inserted to replace the SH gene of PIV5, and the S gene of SARS-CoV-2 Wuhan strain is inserted between the HN and L genes of CVB.
[0015] In some embodiments, the N gene of SARS-CoV-2 Wuhan strain is inserted to replace the SH gene of PIV5, and the S gene of SARS-CoV-2 Omicron BA.l variant is inserted between the HN and L genes of CVB
[0016] In some embodiments, the S gene of SARS-CoV-2 Omicron BA.5 variant is inserted between the HN and L genes of CVB.
[0017] In some embodiments, the S gene of SARS-CoV-2 Omicron BA.5 variant is inserted between the HN and L genes and the N gene of SARS-CoV-2 Wuhan strain is inserted to replace the SH gene of CVB.
[0018] In some embodiments, the PIV5 F and HN genes are deleted and wherein the S gene of SARS-CoV-2 Wuhan strain is between M and L genes of CVB.
[0019] In some embodiments, the N gene of the SARS-CoV-2 Wuhan strain is inserted between F and HN, and the S gene of the SARS-CoV-2 Wuhan strain is inserted between the HN and L genes of CVB.
[0020] In some embodiments, the M gene from the SARS-CoV-2 Wuhan strain is inserted between F and HN, and the S gene of the SARS-CoV-2 Wuhan strain is inserted between HN and L of CVB.
[0021] In some embodiments, the M gene from the SARS-CoV-2 Wuhan strain is inserted after F of PIV5, the E gene from the SARS-CoV-2 Wuhan strain inserted between the M gene of SARS-CoV-2 and HN, and the S gene of SARS-CoV-2 Wuhan strain is inserted between HN and L of CVB.
[0022] In some embodiments, the M gene from the SARS-CoV-2 Wuhan strain is inserted after F of PIV5, the N gene from the SARS-CoV-2 Wuhan strain is inserted between the M gene and the E gene of SARS-CoV-2, the E gene from the SARS-CoV-2 Wuhan strain inserted between the N gene of SARS-CoV-2 and HN, and the S gene of SARS-CoV-2 Wuhan strain is inserted between HN and L of CVB.
[0023] In some embodiments, the F gene from respiratory syncytial virus (RSV) is inserted between the SH and HN genes of CVB backbone.
[0024] In one embodiment, a viral particle comprises the viral expression vector.
[0025] In another aspect, the invention relates to a composition comprising a CVB viral expression vector having a nucleic acid sequence with at least 98%sequence identity to SEQ ID NOs: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 and wherein the viral expressionvector expresses a heterologous polypeptide comprising a coronavirus spike (S) and / or nucleocapsid (N) proteins. In one embodiment, the heterologous coronavirus spike (S) and nucleocapsid (N) proteins are expressed in a cell by contacting the cell with the composition.
[0026] In yet another aspect, the invention relates to a method of inducing an immune response in a subject having or at risk of having SARS-COV-2, RSV or other viral or bacterial infections, the method comprising administering the composition of to the subject, wherein the immune response comprises a humoral immune response and / or a cellular immune response.
[0027] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. In one embodiment, the subject is vaccinated against COVID-19, RSV or other viral or bacterial infections the method comprising administering the composition to the subject, wherein the composition is administered intranasally, intramuscularly, topically, or orally. The method further comprises administering a PIV5 booster vaccine composition comprising a viral expression vector or a viral particle having a PIV5 genome comprising a heterologous nucleic acid sequence with at least 98% sequence identity to SEQ ID NOs: 27, 28, 29, 30, 31, 32, or 33, wherein said subject has previously received a primary vaccination against SARS- COV-2, RSV or other viral or bacterial infections.BRIEF DESCRIPTIONS OF THE DRAWINGS
[0028] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate (one) several embodiment(s) of the invention and together with the description, serve to explain the principles of the invention.
[0029] Figure 1 is a diagram of W3AASH, CPI and CVB genomic structure.
[0030] Figures 2A-2B show RSV F-specific cellular immune responses inW3AASH-RSV-F vs CPI-RSV-F-immunized AGMs. RSV F-specific cellular immune response in immunized African green monkeys (AGMs). PBMCs were isolated fromimmunized AGMs one day prior to vaccination, and at 14 and 28 days postimmunization. The PBMCs were stimulated with an RSV F peptide pool, and different cytokine levels in CD4+(FIG. 2A) and CD8+(FIG. 2B) cells were quantified by ICS and expressed at % sum of all cytokines.
[0031] Figure 3 shows a lung RSV viral titer following RSV challenge following immunization with indicated controls or antigens.
[0032] Figure 4 shows a RSV titer following RSV challenge in nasal wash.
[0033] Figure 5 shows RSV neutralizing antibody responses.
[0034] Figure 6 shows anti-RSV F protein IgG antibody responses by ELISA.
[0035] Figure 7 shows an illustrative overview of virus rescue.
[0036] Figures 8 shows schematic diagrams of the PIV5 CVB based SARS-CoV-2 vaccine constructs indicating the location of SARS-CoV-2 genes and their corresponding variant of origin.
[0037] Figures 9A-9D show immune responses in animals induced by CVXGA16, CVXGA17 and CVXGA18. IgG antibodies against SARS-CoV-2 S protein (FIG. 9A) or S-RBD (FIG. 9B) in mice. The mice were immunized intranasally with 50 pL of PBS or 105PFU CVXGA1, CVXGA16, CVXGA17 and CVXGA18. At D32, blood was collected. Anti-S WAI or S WAI RBD IgG antibodies were determined using ELISA. Figure 9C shows T-cell responses against S or N peptides in mice. The mice were immunized as above. Spleen was collected at D32. S or N protein-specific IFNy-secreting cells were determined using ELISPOT. Figure 9D shows IgG antibodies against S protein in hamsters. The hamsters were immunized intramuscularly with 50 pL of PBS or with 2 pg of COVID-19 mRNA vaccine. After boost at D21, hamsters from Group 1 were boosted intranasally with 50 pL of PBS, and hamsters from Group 2 were boosted a second time intramuscularly with 2 pg of CO VID-19 mRNA (Group 2 A), or intranasally with 2X106PFU of CVXGA1 (Group 2B), or CVXGA18 (Group 2C) at D42. At 63 days post-immunization, blood was collected. Anti-S IgG antibodies were determined using ELISA.
[0038] Figure 10 shows growth curves of CVXGA29, CVXGA30, CVXGA31, and CVXGA32 expressing wt SARS-CoV-2 S compared to CVXGA17 expressing SARS- CoV-2 S with PIV5 F tail.
[0039] Figures 11 A-l IB show anti-SARS-CoV-2 S immunogenicity (Fig. 11 A) and anti-SARS-CoV-2 N immunogenicity (Fig. 1 IB) for CVXGA1, CVXGA18, CVXGA29, CVXGA30, CVXGA31, or CVXGA32
[0040] Figures 12 show the determination of percent RSV F protein expression in CVB-F-infected cells. Vero-SF cells were infected with CVB-F pre-MVS virus at dilutions -3 to -5. After 1-hour incubation at 37°C, media was changed, and cells were incubated for 18 hours at 37°C. Immunostaining was performed using mouse anti-CVB- HN and human anti-F (Palivizumab) antibodies followed by anti-mouse Alexa 488 and anti-human Cy3 secondary antibodies, respectively. Three representative images of wells infected with CVB-F pre-MVS showing both green and red cells. 100% CVB-infected cells expressed both PIV5 and RSV F proteins. Images were taken at 10X.
[0041] Figures 13A-13E show the replication of CVB-F at 35°C vs 37°C and day 2 vs day 4 serum free Vero cells.DETAILED DESCRIPTION
[0042] The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the Examples included therein and to the Figures and their previous and following description.I. Definitions
[0043] To facilitate an understanding of the principles and features of the various embodiments of the disclosure, various illustrative embodiments are explained herein. Although exemplary embodiments of the disclosure are explained in detail, it is to be understood that other embodiments are contemplated. Accordingly, it is not intended that the disclosure is limited in its scope to the details of construction and arrangement of components set forth in the description or examples. The disclosure is capable of other embodiments and of being practiced or carried out in various ways.
[0044] In describing the exemplary embodiments, specific terminology will be resorted to for the sake of clarity. As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. For example, reference to a component is intended also to include composition of a plurality of components. References to a composition containing “a” constituent is intended to include other constituents in addition to the one named.
[0045] Ranges may be expressed herein as from “about” or “approximately” or “substantially” one particular value and / or to “about” or “approximately” or “substantially” another particular value. When such a range is expressed, other exemplary embodiments include from the one particular value and / or to the other particular value.
[0046] Similarly, as used herein, “substantially free” of something, or “substantially pure”, and like characterizations, can include both being “at least substantially free” of something, or “at least substantially pure”, and being “completely free” of something, or “completely pure.”
[0047] The terms “patient”, “individual”, “subject”, and “animal” are used interchangeably herein and refer to mammals, including, without limitation, human and veterinary animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.) and experimental animal models. In a preferred embodiment, the subject is a human.
[0048] As described herein, the term “vaccinating” designates typically the sequential administration of one or more antigens to a subject, to produce and / or enhance an immune response against the antigen(s). The sequential administration includes a priming immunization followed by one or several boosting immunizations.
[0049] Within the context of the present invention, the term “pathogen” refers to any agent that can cause a pathological condition. Examples of “pathogens” include, without limitation, cells (e.g., bacteria cells, diseased mammal cells, cancer mammal cells), fungus, parasites, viruses, prions or toxins. Preferred pathogens are infectious pathogens. In a particular embodiment, the infectious pathogen is a virus, such as the coronaviruses.
[0050] An antigen, as used therein, designates any molecule which can cause a T- cell or B-cell immune response in a subject. An antigen specific for a pathogen is, typically, an element obtained or derived from said pathogen, which contains an epitope, and which can cause an immune response against the pathogen. Depending on the pathogenic agent, the antigen may be of various nature, such as a (poly)peptide, protein, nucleic acid, lipid, cell, etc. Live weakened forms of pathogens (e.g., bacteria, viruses), or killed or inactivated forms thereof may be used as well, or purified material therefrom such as proteins, peptides, lipids, etc. The antigen may be naturally-occurring or artificially created. It may be exogenous to the treated mammal, or endogenous (e.g., tumor antigens). The antigen may be produced by techniques known per se in the art, such as for instance synthetic or recombinant technologies, or enzymatic approaches.
[0051] In a particular embodiment, the antigen is a protein, polypeptide and / or peptide. The terms “polypeptide”, “peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. The terms also apply to amino acid polymers in which one or more amino acid residues may be modified or non-naturally occurring residues, such as an artificial chemical mimetic of a corresponding naturally occurring amino acid. It should be understood that the term “protein” also includes fragments or variants of different antigens, such as epitope-containing fragments, or proteins obtained from a pathogen and subsequently enzymatically, chemically, mechanically or thermally modified.
[0052] A “therapeutically effective amount” means the amount of a compound (e.g., a CVB-based composition as described herein) that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound or bacteria administered as well as the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
[0053] The phrase “pharmaceutically acceptable”, as used in connection with compositions of the disclosure, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., a human). Preferably, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
[0054] The term “pharmaceutically acceptable composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
[0055] The term “administration” refers to the introduction of an amount of a predetermined substance into a patient by a certain suitable method. The composition disclosed herein may be administered via any of the common routes, as long as it is able to reach a desired tissue, for example, but is not limited to, inhaling, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrapulmonary, or intrarectal administration. However, since peptides are digested uponoral administration, active ingredients of a composition for oral administration should be coated or formulated for protection against degradation in the stomach.
[0056] The term “dose” means a single amount of a compound or an agent that is being administered thereto; and / or “regimen: which means a plurality of pre-determined doses that can be different in amounts or similar, given at various time intervals, which can be different or similar in terms of duration. In some embodiments, a regimen also encompasses a time of a delivery period (e.g., agent administration period, or treatment period). Alternatively, a regimen is a plurality of predetermined plurality pre-determined vaporized amounts given at pre-determined time intervals.
[0057] The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Alternatively, the carrier can be a solid dosage form carrier, including but not limited to one or more of a binder (for compressed pills), a glidant, an encapsulating agent, a flavorant, and a colorant. Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.
[0058] The terms “treat” or “treatment” of a state, disorder or condition include: (1) preventing or delaying the appearance of at least one clinical or sub-clinical symptom of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or sub-clinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or sub-clinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
[0059] By “comprising” or “containing” or “including” is meant that at least the named compound, element, particle, or method step is present in the composition orarticle or method, but does not exclude the presence of other compounds, materials, particles, method steps, even if the other such compounds, material, particles, method steps have the same function as what is named.
[0060] As used herein, the term “parainfluenza virus 5” (PIV5) includes, for example and not limitation, strains KNU-11, CC-14, D277, 1168-1, and 08-1990. Nonlimiting examples of PIV5 genomes are listed in GenBank Accession Nos. NC_006430.1, AF052755.1, KC852177.1, KP893891.1, KC237065.1, KC237064.1 and KC237063.1, which are hereby incorporated by reference.
[0061] As used herein, the term “expression” refers to the process by which polynucleic acids are transcribed into mRNA and translated into peptides, polypeptides, or proteins. If the polynucleic acid is derived from genomic DNA, expression may, if an appropriate eukaryotic host cell or organism is selected, include splicing of the mRNA. In the context of the present invention, the term also encompasses the yield of the F gene mRNA and F proteins achieved following expression thereof.
[0062] As used herein, the term “F protein” or “Fusion protein” or “F protein polypeptide” or “Fusion protein polypeptide” refers to a polypeptide or protein having all or part of an amino acid sequence of an RSV Fusion protein polypeptide. Numerous RSV Fusion and Attachment proteins have been described and are known to those of skill in the art. WO / 2008 / 114149, which is herein incorporated by reference in its entirety, sets out exemplary F and G protein variants (for example, naturally occurring variants).
[0063] As used herein, the term “combination” of a CVB-based composition as described herein and at least a second pharmaceutically active ingredient means at least two, but any desired combination of compounds can be delivered simultaneously or sequentially (e.g., within a 24-hour period). It is contemplated that when used to treat various diseases, the compositions and methods of the present disclosure can be utilized with other therapeutic methods / agents suitable for the same or similar diseases. Such other therapeutic methods / agents can be co-administered (simultaneously or sequentially, in any order) to generate additive or synergistic effects. Suitable therapeutically effective dosages for each agent may be lowered due to the additive action or synergy. Also, two or more embodiments of the disclosure may be also co-administered to generate additive or synergistic effects.
[0064] The term “coronavirus” refers to a group of related RNA viruses that cause diseases in mammals and birds. In humans, these viruses cause respiratory tract infections that can range from mild to lethal. Mild illnesses include some cases of the common cold (which is caused also by certain other viruses, predominantly rhinoviruses), while more lethal varieties can cause SARS, MERS, and COVID-19. There are presently no vaccines or antiviral drugs to prevent or treat human coronavirus infections.
[0065] The term “SARS” or “severe acute respiratory syndrome” refers to a viral respiratory disease of zoonotic origin that surfaced in the early 2000s caused by severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-1), the first- identified strain of the SARS coronavirus species severe acute respiratory syndrome- related coronavirus (SARS-CoV). The syndrome caused the 2002-2004 SARS outbreak. In 2019, its successor, the related virus strain Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), was discovered. The term “Covid- 19” or “Coronavirus disease 2019” refers to a severe acute respiratory syndrome (SARS) caused by a virus known as SARS-Coronavirus 2 (SARS-CoV-2).
[0066] The mention of one or more method steps does not preclude the presence of additional method steps or intervening method steps between those steps expressly identified. Similarly, it is also to be understood that the mention of one or more components in a composition does not preclude the presence of additional components than those expressly identified.
[0067] The materials described as making up the various elements of the disclosure are intended to be illustrative and not restrictive. Many suitable materials that would perform the same or a similar function as the materials described herein are intended to be embraced within the scope of the disclosure. Such other materials not described herein can include, but are not limited to, for example, materials that are developed after the time of the development of the disclosure.II. CPI-RSV-F, W3AASH and CVB-RSV-F Compositions
[0068] Respiratory syncytial virus (RSV) is a member of the genus Pneumoviridae. Human RSV (HRSV) is the leading cause of severe lower respiratory tract disease in young children and is responsible for considerable morbidity and mortality in humans. RSV is also recognized as an important agent of disease in immunocompromisedadults and in the elderly. Due to incomplete resistance to RSV in the infected host after a natural infection, RSV may infect multiple times during childhood and adult life.
[0069] This virus has a genome comprised of a single strand negative-sense RNA, which is tightly associated with viral protein to form the nucleocapsid. The viral envelope is composed of a plasma membrane derived lipid bilayer that contains virally encoded structural proteins. A viral polymerase is packaged with the virion and transcribes genomic RNA into mRNA. The RSV genome encodes three transmembrane structural proteins, F, G, and SH, two matrix proteins, M and M2, three nucleocapsid proteins N, P, and L, and two nonstructural proteins, NS1 and NS2.
[0070] Fusion of HRS V and cell membranes is thought to occur at the cell surface and is a necessary step for the transfer of viral ribonucleoprotein into the cell cytoplasm during the early stages of infection. This process is mediated by the fusion (F) protein, which also promotes fusion of the membrane of infected cells with that of adjacent cells to form a characteristic syncytia, which is both a prominent cytopathic effect and an additional mechanism of viral spread. Accordingly, neutralization of fusion activity is important in host immunity. Indeed, monoclonal antibodies developed against the F protein have been shown to neutralize virus infectivity and inhibit membrane fusion (Calder et al., 2000, Virology 271 : 122-131).
[0071] The F protein of RSV shares structural features and limited, but significant amino acid sequence identity with F glycoproteins of other paramyxoviruses. It is synthesized as an inactive precursor of 574 amino acids (F0) that is cotranslationally glycosylated on asparagines in the endoplasmic reticulum, where it assembles into homooligomers. Before reaching the cell surface, the F0 precursor is cleaved by a protease into F2 from the N terminus and Fl from the C terminus. The F2 and Fl chains remain covalently linked by one or more disulfide bonds..
[0072] CPI-RSV-F is a parainfluenza virus (PIV5) based RSV vaccine expressing the RSV F protein, is provided herein as prophylactic intranasal vaccines to prevent RSV infection and serious complications associated with RSV infection. CPI-RSV-F was designed to induce immune responses to the F protein of RSV, which is the main antigenic protein that is highly conserved between the RSV subgroups A and B. Anti-F antibodies inhibit virus entry into host cells and RSV F is a proven vaccine target based on the efficacy data from the commercial product palivizumab (RSV F monoclonalantibody). W3AASH-RSV-F and CVB-RSV are modified RSV vaccine, their backbone difference from the CPLRSV-F is summarized in Figure. 1.
[0073] The disclosure provides CPLRSV-F, W3AASH-RSV-F and CVB-RSV compositions, systems and methods for their use in multiple applications including functional genomics, drug discovery, target validation, protein production (e.g., therapeutic proteins, vaccines, monoclonal antibodies), gene therapy, and therapeutic treatments such as cancer therapy.A. Pharmacology Summary of RSV studies
[0074] The disclosure provides CPLRSV-F, W3AASH-RSV-F and CVB-RSV compositions, systems and methods for their use in multiple applications including functional genomics, drug discovery, target validation, protein production (e.g., therapeutic proteins, vaccines, monoclonal antibodies), gene therapy, and therapeutic treatments such as cancer therapy.
[0075] Previously published studies based on W3A strain of PIV5 construct engineered to express RSV-F protein included immunogenicity and challenge studies in mice, cotton rats and African green monkeys (1,2,3). As part of these studies, permissiveness for PIV5 replication was confirmed in cotton rats and African monkeys (1, 2). In addition, the following studies were performed: 1) compared vector constructs based on CPI vs. W3 A PIV5 strain; 2) compared vaccine constructs expressing RSV prefusion versus wt F-protein in place of PIV5 SH gene (ASH) or inserted between PIV5 SH and NH (SH-NH) or between HN and L (HN-L). These studies led to the selection of CPLRSV-F (CPLRSV-F), containing the full length of RSV F-protein inserted between SH and HN gene for use in the initial human studies.
[0076] In addition, the protective efficacy of CPLRSV-F vaccine has been evaluated in RSV challenge studies conducted in mice and cotton rats. Immunization with a single intranasal dose protected animals from RSV infection based on significantly reduced RSV viral titers observed in lung and nasal washes of immunized animals compared to controls.
[0077] More recent preclinical proof of concept studies conducted with the vaccine vector construct CPLRSV-F included immunogenicity and challenge studies conducted by Blue Lake Biotechnology Inc. in mice and African green monkeys. In addition, preclinical data from a NIH sponsored study of the CPLRSV-F construct in a cotton ratchallenge study are summarized herein. The CPI-RSV-F vaccine used in these more recent non-clinical studies used a prior vaccine vector construct (rescued from BHK cells) that is the same as the vector construct used for clinical lot material (rescued from 293 / Vero cells), and similarly produced using serum-free Vero cells as the substrate and formulated with sucrose phosphate glutamate (SPG) buffer. These non-clinical studies included the control (PIV5 W3A strain with SH gene deleted, W3AASH-RSV-F, engineered to express RSV F protein) as an active comparator.
[0078] In summary, the non-clinical studies in various animal models have demonstrated the ability of CPI-RSV-F, W3 AASH-RSV-F and CVB-RSV to induce RSV F specific immune responses, as observed by F-specific antibody and cell mediated immune responses following a single intranasal dose. All of these vaccine candidates were well tolerated in these animal models and no indication of sensitization following vaccination.
[0079] Table 1 : Non-clinical study overview of prior vaccine constructs studies and recent studies with CPI-RSV-F construct.i. Studies in Mice and Cotton Rats, and Monkeys with related W3A PIV5 vector expressing RSV F proteinPIV5 (W3A -RSV-F and RSV-G protein study in Balb / c mice: In this study Balb / c mice received a single intranasal dose of W3A-RSV-F (106PFU dose in 50 pl) followed by RSV challenge. The PIV5 W3A vaccine vector construct in this study consisted of wild type RSV F protein inserted into the PIV5 HN and L intergenic regions. A single intranasal dose resulted in IgG2a / IgGl RSV responses similar to that observed after wild-type RSV A2 infection at Day 21 after immunization.
[0080] PIV5 (W3A) expressing wild-type or Prefusion RSV F protein challenge study in mice and cotton rats'. This study evaluated PIV5 vectored vaccines that were improved by changing location of F-protein insertion (inserted at SH-HN junction of PIV5 or replacing the SH with the RSV F protein gene). In addition, this study evaluated both the wild type (wt) F-protein or a prefusion conformation F-protein (pF).
[0081] Mice were immunized intranasally with single dose of W3AASH -RSV-F (RSV F protein gene inserted at deleted SH region of PIV5) expression wild type F protein or prefusion stabilized RSV F mutant (W3 AASH -RSV-pF) or improved vector W3 AASH -RSV-F or W3 A-RSV-pF SH-HN (the F-protein gene inserted at the SH-HN junction) at lx 106PFU. The study groups were as follows (Table 2).
[0082] Table 2: Study groups in mice challenge study
[0083] Following immunization, both humoral and cell mediated immune responses were observed. The highest neutralizing antibody responses were detected with vaccine construct using the wt F protein. Also, vaccine constructs containing the wt F inserted prior to the HN junction with ASH seemed to be most immunogenic. The level of cell- mediated immune responses (based on IFN-gamma using ELISPOT) was similar between the various vaccine constructs.
[0084] Mice were challenged 28 days after immunization with RSV A2 to determine protective efficacy. Challenge virus was only obtained from one of five mice at day 4 post challenge in the W3 AASH-RSV-F group with none of the mice in the other vaccination groups. In the PBS control group challenge virus was recovered from all mice.
[0085] A similar study was conducted in cotton rats which are more permissive to RSV infection. Rats were immunized with low dose of 103PFU of the modified vectors (W3 A-RSV-F (SH-HN), W3 A-RSV-pF, W3 AASH-RSV-F) containing wild type or perfusion stabilized F-protein (pF) or 102PFU of W3AASH-RSV-pF.
[0086] Immune responses were observed in all groups including neutralizing antibody responses against RSV A Tracy strain (97% identical to RSV A / A2 strain). Similar to the mouse study, the groups immunized with vaccine constructs containing thewt F protein had higher antibody levels compared to the pF groups, with F insertion prior to the HN gene junction with ASH having the highest values (approx, titer of 128). The neutralization antibody titers to RSV / B / 18537 were significantly lower than to RSV / A Tracy strain, only the W3A(SH-HN)-RSV-F and W3AASH-RSV-F groups had significant antibody levels (approx, titer of 8) detected. After RSV challenge on Day 28 with 1.21 xlO5PFU of RSV / A / Tracy, reduction in RSV viral load in nasal washes (1.4- 1.66 Logio reduction) and lung lavage fluid (2-3 Logio reduction) was observed for all vaccine dose groups. The RSV challenge virus was recovered from all mice in the PBS control group (approx. 105PFU per nasal wash, or 105PFU / g lung wash).
[0087] Overall, these initial studies in the mouse and cotton rat models did not show evidence of the prefusion F-protein being more immunogenic and protective then the wild type F protein. Also, no difference was observed in the vector performance between ASH and the SH-HN insertion vector construct for the intranasal route.
[0088] Sigmovir Protocol #XV-131 Study report (Phan et al. 2017) challenge studies in cotton rat using intranasal and subcutaneous route '. In a follow-on study (1, Phan et al. 2017) the efficacy, immunogenicity and safety of higher doses 105and 106PFU of W3A(SH-NH)-RSV-F and W3AASH-RSV-F were tested in a cotton rat challenge study evaluating two different routes intranasal (i.n.) and subcutaneous (s.c). This study also included a positive control for enhancement of disease (animals immunized with FI- RSV followed by RSV challenge and a positive control group consisting of animals that were pre-infected with RSV followed by RSV challenge. Animals in this study were challenged with RSV A2 on Day 49 followed by necropsy and histology 5 days later (Day 54). The study groups in this study were as follows (Table 3).
[0089] Table 3 : Study groups in Protocol #XV-131.
[0090] Immunogenicity: W3A(SH-HN)-RSV-F resulted in similar neutralizing antibody titer in 105and 106dose between i.n and s.c group. W3AASH-RSV-F vaccination induced slightly higher neutralizing antibody titers in i.n group compared to s.c group, with 106dose resulting in a slightly higher titer, although it was not statistically significant.
[0091] Efficacy: W3A(SH-HN)-RSV-F resulted in complete protection in the lower respiratory tract by either i.n or s.c administration. Animals also had significantly lower viral loads in the upper respiratory tract.
[0092] W3 A(SH-HN)-RSV-F vaccination resulted in complete protection in the lower respiratory tract by s.c administration and almost complete protection by i.n administration based on reduced titers (average titer of 103PFU) observed in lung and nasal washes compared to control animals sham immunized with PBS (average titer of 105PFU).
[0093] Safety: Lung sections from the different groups were examined for hallmarks of pulmonary inflammation: peribronchiolitis, perivasculitis, interstitial pneumonia, and alveolitis and scored for severity. The largest lesions were observed in the FI-RSV-immunized, RSV-challenged group (positive control group). Pulmonary changes were moderate in the groups immunized with W3 A-RSV-F (SH-HN) or W3 AASH-RSV-F (intranasally or subcutaneously), with levels below those observed inthe RSV-immunized, RSV-challenged positive control group and similar to those in the PBS sham-immunized, RSV-challenged group.
[0094] Cytokine levels measured in lung tissues at 5 days post-challenge by quantitative real-time PCR (qPCR) were not indicative of potential of enhanced infection. The IL-4 mRNA level was significantly elevated only in the FI-RSV-vaccinated group, consistent with the histopathology results and the enhanced disease phenotype. ZFNy- mRNA levels were the highest in the sham-immunized and FI-RSV-immunized groups. IFN-mRNA levels were similarly low between groups immunized with the PIV5-based candidates and the RSV-immunized group. IL-2 mRNA levels were similar in all groups, but the average IL-2 level in the FI-RSV immunized group was significantly higher than that in the other groups.
[0095] After intranasal challenge of immunized mice with RSV A2 (106PFU in 50 pl) at Day 28 after immunization, lung sections obtained at 4 days after challenge showed no exacerbation of lung lesions relative to RSV A2-immunized mice. Protective immunity was observed as assessed by viral load in lung tissues (n=5 mice per group).
[0096] PIV5 (W3A) expressing RSV F or G protein challenge study in cotton rats and African green monkeys'. This study evaluated PIV5 vectored RSV F protein in cotton rats and African green monkeys for replication, immunogenicity and efficacy of protection against RSV challenge. In this study, the F protein was inserted into the intergenic regions of PIV5 HN and L gene.
[0097] PIV5 replication permissiveness in cotton rats and African green monkeys: Cotton rats (n=4 per group) were inoculated intranasally with IxlO5PFU of PIV5 at volumes of 10 pl or 100 pl. Viral titers were observed in nose homogenates (up 1 xlO4PFU) at day 4 which cleared mostly by day 6. The larger inoculum volume (100 pl) resulted in observation of vaccine virus in the lungs of all the animals at day 6, which was only observed for one animal inoculated with the smaller volume of 10 pl.
[0098] To evaluate PIV5 permissiveness in African green monkeys, 60 animals were screened for anti-PIV5 antibodies and all were found to be negative. Animals (n=3 per group) were infected intranasally with IxlO2up to IxlO8PFU of PIV5 in 0.25mL dose volume. Nasal wash and bronchoalveolar washes were assessed for virus shedding on days 3, 5, 7, 10 and 14. Virus was shed from both nose and lungs for up to 10-dayperiod with peak replication at Day 5 for the dose as low as IxlO2PFU. This data demonstrates permissiveness of African green monkeys for PIV5.
[0099] Immunogenicity in cotton rats and African green monkeys after single dose W3A-RSV-F: Cotton rats were immunized intranasally with IxlO3, IxlO4, IxlO5and IxlO6PFU of W3A-RSV-F. At all dose levels, IgG antibody responses were noted at Day 28 with comparable responses per dose group. Neutralizing antibodies were observed in all dose group ranging from titer of 64 to 256. In addition, IgA responses in lung homogenates were observed in all dose groups at Day 21 post inoculation.
[0100] African green monkeys (PIV5 and RSV serum negative) received a single intranasal immunization with IxlO4or IxlO6PFU W3A-RSV-F. Sera obtained at Day 21 post inoculation showed high titers of F-specific antibody responses. In addition, neutralizing antibody responses were observed at Day 21 at low levels (52 in 1 xlO6PFU dose group). Nasal swabs obtained at 21 days post immunization showed significant levels of F-protein IgA responses. Cell mediated responses as assessed by gamma interferon showed low level responses in the IxlO6PFU dose group.
[0101] Protection in cotton rats (Study #131) and African green monkeys from RSV challenge: Cotton rats immunized intranasally with single dose ranging from IxlO3to IxlO6PFU W3A-RSV-F were challenged with RSV A2 strain at Day 28 after immunization. Protection was assessed by measuring viral loads in nose and lung tissues. Reduced viral loads were observed in a dose-dependent manner except for the IxlO6PFU group which showed higher levels relative to IxlO3PFU group but still reduced compared to control group. In the IxlO5dose group, no virus was detected in the lung and reduced titers (order of 3 logio) were observed in the nose.
[0102] African green monkeys immunized with IxlO4or IxlO6PFU W3A-RSV-F were challenged 28 days after immunization with RSV A2. Nasal and BAL samples were assessed for RSV viral load Days 3-14 after challenge. Immunization with W3A-RSV-F did not shorten virus shedding, however, peak viral RSV loads were reduced 10 to 100- fold in both dose groups, with the highest reduction observed in the IxlO6PFU dose group.
[0103] Responses to W3 A-RSV-F in RSV exposed African green monkeys: Prior exposure to RSV did not interfere with ability to boost RSV neutralization antibody titers(50-fold increase) in African green monkeys (seroconverted by intranasal infection with RSV A2).
[0104] Lung pathology in W3 A-RSV-F immunized cotton rats after RSV challenge: In animals immunized at Day 0 with dose IxlO6PFU PIV5-RSV-F and challenged at Day 49 with RSV A2, lungs obtained five days after challenge were blindly examined by histopathology for alveolitis, interstitial pneumonitis, perivasculitis, and peribroncholitis and compared to lungs obtained from control animals inoculated with Formalin- inactivated RSV. The scores of positive control animals inoculated with formalin- inactivated RSV were significantly higher than PBS control animals but not the scores of W3 A-RSV-F animals (ANOVA paired t-test).B. Parainfluenza Virus 5 (PIV5)
[0105] Parainfluenza virus 5 (PIV5), a negative-stranded RNA virus, is a member of the Rubulavirus genus of the family Paramyxoviridae which includes many important human and animal pathogens such as mumps virus, human parainfluenza virus type 2 and type 4, Newcastle disease virus, Sendai virus, HPIV3, measles virus, canine distemper virus, rinderpest virus and respiratory syncytial virus. PIV5 was previously known as Simian Virus-5 (SV5). Although PIV5 is a virus that infects many animals and humans, no known symptoms or diseases in humans have been associated with PIV5. Unlike most paramyxoviruses, PIV5 infect normal cells with little cytopathic effect. As a negative stranded RNA virus, the genome of PIV5 is very stable. As PIV5 does not have a DNA phase in its life cycle and it replicates solely in cytoplasm, PIV5 is unable to integrate into the host genome. Therefore, using PIV5 as a vector avoids possible unintended consequences from genetic modifications of host cell DNAs. PIV5 can grow to high titers in cells, including Vero cells which have been approved for vaccine production by WHO and FDA. Thus, PIV5 presents many advantages as a vaccine vector.
[0106] A PIV5-based vaccine vector of the present invention may be based on any of a variety of wild type, mutant, or recombinant (rPIV5) strains. Wild type strains include, but are not limited to, the PIV5 strains W3 A, WR (ATCC® Number VR- 288TM), canine parainfluenza virus strain 78-238 (ATCC number VR-1573) (Evermann et al., 1980, J Am Vet Med Assoc; 177: 1132-1134; and Evermann et al., 1981, Arch Virol; 68: 165-172), canine parainfluenza virus strain D008 (ATCC number VR-399) (Binn et al., 1967, Proc Soc Exp Biol Med; 126: 140-145), MIL, DEN, LN, MEL, cryptovirus, CPI+, CPI-, H221, 78524, T1 and SER. See, for example, Chatziandreou etal., 2004, J Gen Virol; 85(Pt 10):3007-16; Choppin, 1964, Virology: 23:224-233; and Baumgartner et al., 1987, Intervirology; 27:218-223. Additionally, PIV5 strains used in commercial kennel cough vaccines, such as, for example, BI, FD, Merck, and Merial vaccines, may be used.C. PIV5 CPI strain vector backbone
[0107] The PIV5 CPI strain vector backbone differs from that of PIV5 W3A strain vector as follows (Figure 1). The most notable difference is in the PIV5 F protein of the CPI strain that consists of an additional 22 amino acid extension as part of its cytoplasmic tail. The extension of the F protein is thought to result in inhibition of the fusogenic properties of the virus (5,6). CPI based viruses are more lytic and produce more progeny virus in infected cells compared to the W3 A based viruses that does not have the extended PIV5 F protein tail and possess additional amino acid difference compared with CPI (4). CVB backbone with S156N or S157F in PIV5 W3A improves virus yield in cell culture and is more immunogenic in vivo than CPI backbone.
[0108] Previously, recombinant PIV5 viruses expressing foreign genes from numerous pathogens, including Influenza, Rabies, Respiratory Syncytial Virus, Tuberculosis, Burkholderia, and MERS-CoV, SARS-CoV-2 have been generated and tested as vaccine candidates (Li, Z., et al., J Virol, 87(1):354 (2013); Chen, Z., et al., J Virol, 87(6): 2986 (2013); Wang, D., et al., J Virol, 91(11) (2017); Chen, Z., et al., Vaccine, 33(51):7217 (2015); Lafontaine, E.R., et al., Vaccine X., 1 : 100002 (2018); Li, K., et al., mBio, 11(2) (2020); An et al., Sci Adv, Jul 2;7, 2021). Because it actively replicates in the respiratory tract following intranasal immunization, PIV5-vectored vaccines can generate mucosal immunity that includes antigen-specific IgA antibodies and long-lived IgA plasma cells (Wang, D., et al., J Virol, 91(11) (2017). Xiao, P., et al., Front Immunol,. 12:623996 (2021)).D. PIV5 CVB Backbone
[0109] Provided herein is a modified PIV5 vector, CVB. The CVB backbone vector is immunogenic and can be used as an effective vaccine platform. The CVB backbone comprises mutations at amino acid residue SI 57 or SI 56 of the P / V gene, wherein a phosphorylation site is removed resulting in higher transcription activities thereby improving virus titer in cell culture.
[0110] In some embodiments, the mutation at amino acid residue SI 57 or SI 56 comprises the substitution of serine (S) with an amino acid residue selected from a group consisting of alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), selenocysteine (U), valine (V), tryptophan (W), and tyrosine (Y). In one embodiment, the amino acid substitution at amino acid residue SI 57 comprises a substitution of serine (S) to phenylalanine (F) or SI 56 comprises a substitution of serine (S) to asparagine (N). i. CVB Backbone
[0111] The CVB backbone nucleic acid sequence is provided herein: ACCAAGGGGAAAATGAAGTGGTGACTCAAATCATCGAAGACCCTCGAGATTA CATAGGTCCGGAACCTATGGCCTTCGTGACCGACCTCGAGTCAGAGTAGTTCA ATAAGGACCTATCAAGTTTGGGCAATTTTTCGTCCCCGACACAAAAATGTCAT CCGTGCTTAAAGCATATGAGCGATTCACGCTCACTCAAGAACTGCAAGATCA GAGTGAGGAAGGTACAATCCCACCTACAACACTAAAACCGGTAATCAGGGTA TTTATACTAACCTCTAATAACCCAGAGCTAAGATCCCGGCTTCTTCTATTCTGC CTACGGATTGTTCTCAGTAATGGTGCAAGGGATTCCCATCGCTTTGGAGCATT ACTCACAATGTTTTCGCTACCATCAGCCACAATGCTCAATCATGTCAAATTAG CTGACCAGTCACCAGAAGCTGATATCGAAAGGGTAGAGATCGATGGCTTTGA GGAGGGATCATTCCGCTTAATCCCCAATGCTCGTTCAGGTATGAGCCGTGGAG AGATCAATGCCTATGCTGCACTTGCAGAAGATCTACCTGACACACTAAACCAT GCAACACCTTTCGTTGATTCCGAAGTCGAGGGAACTGCATGGGATGAGATTG AGACTTTCTTAGATATGTGTTACAGTGTCCTAATGCAGGCATGGATAGTGACT TGCAAGTGCATGACTGCGCCAGACCAACCTGCTGCTTCTATTGAGAAACGCCT GCAAAAATATCGTCAGCAAGGCAGGATCAACCCGAGATATCTCCTGCAACCG GAGGCTCGACGAATAATCCAGAATGTAATCCGGAAGGGAATGGTGGTCAGAC ATTTCCTCACCTTTGAACTGCAGCTTGCCCGAGCACAAAGCCTTGTATCAAAT AGGTATTATGCTATGGTAGGGGATGTTGGAAAGTATATAGAGAATTGTGGAA TGGGAGGCTTCTTTTTGACACTAAAATATGCATTAGGAACTAGATGGCCCACA CTTGCTTTAGCTGCATTTTCAGGAGAGCTAACAAAGCTAAAGTCCCTCATGGC ATTATACCAGACCCTTGGTGAGCAGGCCCGATATTTGGCCCTATTGGAGTCAC CACATTTGATGGATTTTGCTGCAGCAAACTACCCACTGCTATATAGCTATGCT ATGGGAATAGGCTATGTGTTAGATGTCAACATGAGGAACTACGCTTTCTCCAGATCATACATGAACAAGACATATTTCCAATTGGGAATGGAAACTGCAAGAAAACAACAGGGTGCAGTTGACATGAGGATGGCAGAAGATCTCGGTCTAACTCAAGCCGAACGCACCGAGATGGCAAATACACTTGCCAAATTGACCACAGCAAATCGAGGGGCAGACACCAGGGGAGGAGTCAACCCGTTCTCATCTGTCACTGGGACAACTCAGGTGCCCGCTGCAGCAACAGGTGACACACTCGAGAGTTACATGGCAGCGGATCGACTGAGGCAGAGATATGCTGATGCAGGCACCCATGATGATGAGATGCCACCATTGGAAGAGGAGGAAGAGGACGACACATCTGCAGGTCCACGCACTGGACCAACTCTTGAACAAGTGGCCTTGGACATCCAGAACGCAGCAGTTGGAGCTCCCATCCATACAGATGACCTGAATGCCGCACTGGGTGATCTTGACATCTAGACAATTCAGATCCCAATCTAAAATTGACATACCTAATTGATTAGTTAGATGGAACTACAGTGGATTCCATAAGGTTCCTGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACAAGCGACTGCCGGTGCCAACAGCGCAATCCACAATCTACAATGGATCCCACTGATCTGAGCTTCTCCCCAGATGAGATCAATAAGCTCATAGAGACAGGCCTGAATACTGTAGAGTATTTTACTTCCCAACAAGTCACAGGAACATCCTCTCTTGGAAAGAATACAATACCACCAGGGGTCACAGGACTACTAACCAATGCTGCAGAGGCAAAGATCCAAGAGTCAACTAACCATCAGAAGGGCTCAGTTGGTGGGGGTGCAAAACCAAAGAAACCGCGACCAAAAATTGCCATTGTGCCAGCAGATGACAAAACAGTGCCCGGAAAGCCGATCCCAAACCCTCTATTAGGTCTGGACTCCACCCCGAGCACCCAAACTGTGCTTGATCTAAGTGGGAAAACATTACCATCAGGATCCTATAAGGGGGTTAAGCTTGCGAAATTTGGAAAAGAAAATCTGATGACACGGTTCATCGAGGAACCCAGAGAGAATCCTATCGCAACCAGTTtCCCCATCGATTTTAAGAGGGGCAGGGATACCGGCGGGTTCCATAGAAGGGAGTACTCAATCGGATGGGTGGGAGATGAAGTCAAGGTCACTGAGTGGTGCAATCCATCCTGTTCTCCAATCACCGCTGCAGCAAGGCGATTTGAATGCACTTGTCACCAGTGTCCAGTCACTTGCTCTGAATGTGAACGAGATACTTAATACAGTGAGAAATTTGGACTCTCGGATGAATCAACTGGAGACAAAAGTAGATCGCATTCTCTCATCTCAGTCTCTAATCCAGACCATCAAGAATGACATAGTTGGACTTAAAGCAGGGATGGCTACTTTAGAAGGAATGATTACAACTGTGAAAATCATGGACCCGGGAGTTCCCAGTAATGTTACTGTGGAAGATGTACGCAAGACACTAAGTAACCATGCTGTTGTTGTGCCAGAATCATTCAATGATAGTTTCTTGACTCAATCTGAAGATGTAATTTCACTTGATGAGTTGGCTCGACCAACTGCAACAAGTGTTAAGAAGATTGTCAGGAAGGTTCCTCCTCAGAAGGATCTGACTGGATTGAAGATTACACTAGAGCAATTGGCAAAGGATTGCATCAGCAAACCGAAGATGAGGGAAGAGTATCTCCTCAAAATCAACCAGGCTTCCAGTGAGGCTCAGCTAATTGACCTCAAGAAAGCAATCATCCGCAGTGCAATTTGATCAAGAAACACCCAATTACACTACACTGGTATGACACTGTACTAACCCTGAGGGTTTTAGAAAAAACGATTAACGATAAATAAGCCCGAACACTACACACTACCTGAGGCAGCCATGCCATCCATCAGCATTCCCGCAGACCCCACCAATCCACGTCAATCAATAAAAGCGTTCCCAATTGTGATCAACAGTGATGGGGGTGAGAAAGGCCGCTTGGTTAAACAACTACGCACAACCTACTTGAATGACCTAGATACTCATGAGCCACTGGTGACATTCATAAATACCTATGGATTCATCTACGAACAGGATCGGGGGAATACCATTGTCGGAGAGGATCAACTTGGGAAGAAAAGAGAGGCTGTGACCGCTGCAATGGTTACCCTTGGATGTGGGCCTAATCTACCATCATTAGGGAATGTCCTGGGACAACTGAGGGAATTCCAGGTCACTGTTAGGAAGACATCCAGCAAAGCGGAAGAGATGGTCTTTGAAATTGTTAAGTATCCGAGAATATTTCGGGGTCATACATTAATCCAGAAAGGACTAGTCTGTGTCTCCGCAGAAAAATTTGTTAAGTCACCAGGGAAAATACAATCTGGAATGGACTATCTCTTCATTCCGACATTTCTGTCAGTGACTTACTGTCCAGCTGCAATCAAATTTCAGGTACCTGGCCCCATGTTGAAAATGAGATCAAGATACACTCAGAGCTTACAACTTGAACTAATGATAAGAATCCTGTGTAAGCCCGATTCGCCACTTATGAAGGTCCATACCCCTGACAAGGAGGGAAGAGGATGTCTTGTATCAGTATGGCTGCATGTATGCAACATCTTCAAATCAGGAAACAAGAATGGCAGTGAGTGGCAGGAATACTGGATGAGAAAGTGTGCTAACATGCAACTTGAAGTGTCGATTGCAGATATGTGGGGACCAACTATCATAATTCATGCCAGAGGTCACATTCCCAAAAGTGCTAAGTTGTTTTTTGGAAAGGGTGGATGGAGCTGCCATCCACTTCACGAAGTTGTTCCAAGTGTCACTAAAACACTATGGTCCGTGGGCTGTGAGATTACAAAGGCGAAGGCAATAATACAAGAGAGTAGCATCTCTCTTCTCGTGGAGACTACTGACATCATAAGTCCAAAAGTCAAAATTTCATCTAAGCATCGCCGCTTTGGGAAATCAAATTGGGGTCTGTTCAAGAAAACTAAATCACTGCCTAACCTGACGGAGCTGGAATGACTGACCTCTAATCGAGACTACACCGCCGCAAACTATAGGTGGGTGGTACCTCAGTGATTAATCTTGTAAGCACTGATCGTAGGCTACAACACACTAATATTATCCAGATTAGAGAGCTTAATTAGCTCTGTATTAATAATAACACTACTATTCCAATAACTGGAATCACCAGCTTGATTTATCTCCAAAATGATTCAAAGAAAACAAATCATATTAAGACTATCCTAAGCACGAACCCATATCGTCCTTCAAATCATGGGTACTATAATTCAATTTCTGGTGGTCTCCTGTCTATTGGCAGGAGCAGGCAGCCTTGATCCAGCAGCCCTCATGCAAATCGGTGTCATTCCAACAAATGTCCGGCAACTTATGTATTATACTGAAGCTTCATCAGCATTCATTGTTGTGAAGTTAATGCCTACAATTGACTCGCCGATTAGTGGATGTAATATAACATCAATTTCAAGCTATAATGCAACAGTGACAAAACTCCTACAGCCGATCGGTGAGAATTTGGAGACGATTAGGAACCAGTTGATTCCAACTCGGAGGAGACGCCGGTTTGCAGGGGTGGTGATTGGATTAGCTGCATTAGGAGTAGCTACTGCCGCACAGGTCACTGCCGCAGTGGCACTAGTAAAGGCAAATGAAAATGCTGCGGCTATACTCAATCTCAAAAATGCAATCCAAAAAACAAATGCAGCAGTTGCAGATGTGGTCCAGGCCACACAATCACTAGGAACGGCAGTTCAAGCAGTTCAAGATCACATAAACAGTGTGGTAAGTCCAGCAATTACAGCAGCCAATTGTAAGGCCCAAGATGCTATCATTGGCTCAATCCTCAATCTCTATTTGACCGAGTTGACAACCATCTTCCACAATCAAATTACAAACCCTGCATTGAGTCCCATTACAATTCAAGCTTTAAGGATCCTACTGGGGAGTACCTTGCCGACTGTGGTCGAAAAATCTTTCAATACCCAGATAAGTGCAGCTGAGCTTCTCTCATCAGGGTTATTGACAGGCCAGATTGTGGGATTAGATTTGACCTATATGCAGATGGTCATAAAAATTGAGCTGCCAACTTTAACTGTACAACCTGCAACCCAGATCATAGATCTGGCCACCATTTCTGCATTCATTAACAATCAAGAAGTCATGGCCCAATTACCAACACGTGTTATGGTGACTGGCAGCTTGATCCAAGCCTATCCCGCATCGCAATGCACCATTACACCCAACACTGTGTACTGTAGGTATAATGATGCCCAAGTACTCTCAGATGATACTATGGCTTGCCTCCAAGGTAACTTGACAAGATGCACCTTCTCTCCAGTGGTTGGGAGCTTTCTCACTCGATTCGTGCTGTTCGATGGAATAGTTTATGCAAATTGCAGGTCGATGTTGTGCAAGTGCATGCAACCTGCTGCTGTGATCCTACAGCCGAGTTCATCCCCTGTAACTGTCATTGACATGTACAAATGTGTGAGTCTGCAGCTTGACAATCTCAGATTCACCATCACTCAATTGGCCAATGTAACCTACAATAGCACCATCAAGCTTGAATCATCCCAGATCTTGTCTATTGATCCGTTGGATATATCCCAGAATCTAGCTGCGGTGAATAAGAGTCTAAGTGATGCACTACAACACTTAGCACAAAGTGACACATATCTTTCTGCAATCACATCAGCTACGACTACAAGTGTATTATCCATAATAGCAATCTGTCTTGGATCGTTAGGTTTAATATTAATAATCTTGCTCAGTGTAGTTGTGTGGAAGTTATTGACCATTGTCGTTGCTAATCGAAATAGAATGGAGAATTTTGTTTATCATAAATAAGCATTCCACCACTCACGATCTGATCTCAGTGAGAAAAATCAACCTGCAACTCTTGGAACAAGATAAGACAGTCATCCATTAGTAATTTTTAAGAAAAAAACGATAGGACCGAACCTAGTATTGAAAGAACCGTCTCGGTCAATCTAGGTAATCGAGCTGATACCGTCTCGGAAAGCTCAAATCCTGCTATAGGCTATCCACTGCATCATCTCTCCTGCCATACTTCCTACTCACATCATATCTATTTTAAAGAAAAAATAGGCCCGAACACTAATCGTGCCGGCAGTGCCACTGCACACACAACACTACACATACAATACACTACAATGGTTGCAGAAGATGCCCCTGTTAGGGCCACTTGCCGAGTATTATTTCGAACAACAACTTTAATCTTTCTATGCACACTACTAGCATTAAGCATCTCTATCCTTTATGAGAGTTTAATAACCCAAAAGCAAATCATGAGCCAAGCAGGCTCAACTGGATCTAATTCTGGATTAGGAAGTATCACTGATCTTCTTAATAATATTCTCTCTGTCGCAAATCAGATTATATATAACTCTGCAGTCGCTCTACCTCTACAATTGGACACTCTTGAATCAACACTCCTTACAGCCATTAAGTCTCTTCAAACCAGTGACAAGCTAGAACAGAACTGCTCGTGGAGTGCTGCACTGATTAATGATAATAGATACATTAATGGCATCAATCAGTTCTATTTTTCAATTGCTGAGGGTCGCAATCTGACACTTGGCCCACTTCTTAATATGCCTAGTTTCATTCCAACTGCCACGACACCAGAGGGCTGCACCAGGATCCCATCATTCTCGCTCACTAAGACACACTGGTGTTATACACACAATGTTATCCTGAATGGATGCCAGGATCATGTATCCTCAAATCAATTTGTTTCTATGGGAATCATTGAACCCACTTCTGCCGGGTTTCCATTCTTTCGAACCCTAAAGACTCTATATCTCAGCGATGGGGTCAATCGTAAGAGCTGCTCTATCAGTACAGTTCCGGGGGGTTGTATGATGTACTGTTTTGTTTCTACTCAACCAGAGAGGGATGACTACTTTTCTGCCGCTCCTCCAGAACAACGAATTATTATAATGTACTATAATGATACAATCGTGGAGCGCATAATTAATCCACCCGGGGTACTAGATGTATGGGCAACATTGAACCCAGGAACAGGAAGCGGGGTATATTATTTAGGTTGGGTGCTCTTTCCAATATATGGCGGCGTGATTAAAGGTACGAGTTTATGGAATAATCAAGCAAATAAATACTTTATCCCCCAGATGGTTGCTGCTCTCTGCTCACAAAACCAGGCAACTCAAGTCCAAAATGCTAAGTCATCATACTATAGCAGCTGGTTTGGCAATCGAATGATTCAGTCTGGGATCCTGGCATGTCCTCTTCGACAGGATCTAACCAATGAGTGTTTAGTTCTGCCCTTTTCTAATGATCAGGTGCTTATGGGTGCTGAAGGGAGATTATACATGTATGGTGACTCGGTGTATTACTATCAAAGAAGCAATAGTTGGTGGCCTATGACCATGCTGTATAAGGTAACCATAACATTCACTAATGGTCAGCCATCTGCTATATCAGCTCAGAATGTGCCCACACAGCAGGTCCCTAGACCTGGGACAGGAGACTGCTCTGCAACCAATAGATGTCCCGGTTTTTGCTTGACAGGAGTGTATGCCGATGCCTGGTTACTGACCAACCCTTCGTCTACCAGTACATTTGGATCAGAAGCAACCTTCACTGGTTCTTATCTCAACACAGCAACTCAGCGTATCAATCCGACGATGTATATCGCGAACAACACACAGATCATAAGCTCACAGCAATTTGGATCAAGCGGTCAAGAAGCAGCATATGGCCACACAACTTGTTTTAGGGACACAGGCTCTGTTATGGTATACTGTATCTATATTATTGAATTGTCCTCATCTCTCTTAGGACAATTTCAGATTGTCCCATTTATCCGTCAGGTGACACTATCCTAAAGGCAGAAGCCTTCAGGTCTGACCCAGCCAATCAAAGCATTATACCAGACCATGGAATGCATACCAAACATTATTGACACTAATGACACACAAAATTGGTTTTAAGAAAAACCAAGAGAACAATAGGCCAGAATGGCTGGGTCTCGGGAGATATTACTCCCTGAAGTCCATCTCAATTCACCAATTGTAAAGCATAAGCTATACTATTACATTCTACTTGGAAACCTCCCAAATGAGATCGACCTTGACGATTTAGGTCCATTACATAATCAAAATTGGAATCAGATAGCACATGAAGAGTCTAACTTAGCTCAACGCTTGGTAAATGTAAGAAATTTTCTAATTACCCACATCCCTGATCTTAGAAAGGGCCATTGGCAAGAGTATGTCAATGTAATACTGTGGCCGCGAATTCTTCCCTTGATCCCGGATTTTAAAATCAATGACCAATTGCCTCTGCTCAAAAATTGGGACAAGTTAGTTAAAGAATCATGTTCAGTAATCAATGCAGGTACTTCCCAGTGCATTCAGAATCTCAGCTATGGACTGACAGGTCGTGGGAACCTCTTTACACGATCACGTGAACTCTCTGGTGACCGCAGGGATATTGATCTTAAGACAGTTGTGGCAGCATGGCATGACTCAGACTGGAAAAGAATAAGTGATTTTTGGATTATGATCAAATTCCAGATGAGACAATTAATTGTTAGGCAAACAGATCATAATGATTCTGATTTAATCACGTATATCGAAAATAGAGAAGGCATAATCATCATAACCCCTGAACTGGTAGCATTATTTAACACTGAGAATCATACACTAACATACATGACCTTTGAAATTGTACTGATGGTTTCAGATATGTACGAAGGTCGTCACAACATTTTATCACTATGCACAGTTAGCACTTACCTGAATCCTCTGAAGAAAAGAATAACATATTTATTGAGCCTTGTAGATAACTTAGCTTTTCAGATAGGTGATGCTGTATATAACATAATTGCTTTGCTAGAATCCTTTGTATATGCACAGTTGCAAATGTCAGATCCCATCCCAGAACTCAGAGGACAATTCCATGCATTCGTATGTTCTGAGATTCTTGATGCACTAAGAGGAACTAATAGTTTCACCCAGGATGAATTAAGAACTGTGACAACTAATTTGATATCCCCATTCCAAGATCTGACCCCAGATCTTACGGCTGAATTGCTCTGTATAATGAGGCTTTGGGGACACCCCATGCTCACTGCCAGTCAAGCTGCAGGAAAGGTACGCGAGTCTATGTGTGCTGGAAAAGTATTAGACTTTCCCACCATTATGAAAACACTAGCCTTTTTCCATACTATTCTGATCAATGGATACAGGAGGAAGCATCATGGAGTATGGCCACCCTTAAACTTACCGGGTAATGCTTCAAAGGGTCTCACGGAACTTATGAATGACAATACTGAAATAAGCTATGAATTCACACTTAAGCATTGGAAGGAAGTCTCTCTTATAAAATTCAAGAAATGTTTTGATGCAGACGCAGGTGAGGAACTCAGTATATTTATGAAAGATAAGGCAATTAGTGCCCCAAAACAAGACTGGATGAGTGTGTTTAGAAGAAGCCTAATCAAACAGCGCCATCAGCATCATCAGGTCCCCCTACCAAATCCATTCAATCGACGGCTGTTGCTAAACTTTCTCGGAGATGACAAATTCGACCCGAATGTGGAGCTACAGTATGTAACATCAGGTGAGTATCTACATGATGACACGTTTTGTGCATCATATTCACTAAAAGAGAAGGAAATTAAACCTGATGGTCGAATTTTTGCAAAGTTGACTAAGAGAATGAGATCATGTCAAGTTATAGCAGAATCTCTTTTAGCGAACCATGCTGGGAAGTTAATGAAAGAGAATGGTGTTGTGATGAATCAGCTATCATTAACAAAATCACTATTAACAATGAGTCAGATTGGAATAATATCCGAGAAAGCTAGAAAGTCAACTCGAGATAACATAAATCAACCTGGTTTCCAGAATATCCAGAGAAATAAATCACATCACTCCAAGCAAGTCAATCAGCGAGATCCAAGTGATGACTTTGAATTGGCAGCATCTTTTTTAACTACTGATCTCAAAAAATATTGTTTACAATGGAGGTACCAGACAATTATCCCATTTGCTCAATCATTAAACAGAATGTATGGTTATCCTCATCTCTTTGAGTGGATTCACTTACGGCTAATGCGTAGTACACTTTACGTGGGGGATCCCTTCAACCCACCAGCAGATACCAGTCAATTTGATCTAGATAAAGTAATTAATGGAGATATCTTCATTGTATCACCCAGAGGTGGAATTGAAGGGCTGTGTCAAAAGGCTTGGACAATGATATCTATCGCTGTGATAATTCTATCTGCCACAGAGTCTGGCACACGAGTAATGAGTATGGTGCAGGGAGATAATCAAGCAATTGCTGTCACCACACGAGTACCAAGGAGCCTGCCGACTCTTGAGAAAAAGACTATTGCTTTTAGATCTTGTAATCTATTCTTTGAGAGGTTAAAATGTAATAATTTTGGATTAGGTCACCATTTGAAAGAACAAGAGACTATCATTAGTTCTCACTTCTTTGTTTATAGCAAGAGAATATTCTATCAGGGGAGGATTCTAACGCAAGCCTTAAAAAATGCTAGTAAGCTCTGCTTGACAGCTGATGTCCTAGGAGAATGCACCCAATCATCATGTTCTAATCTTGCAACTACTGTCATGAGGTTAACTGAGAATGGTGTTGAAAAAGATATCTGTTTCTACTTGAATATCTATATGACCATCAAACAGCTCTCCTATGATATCATCTTCCCTCAAGTGTCAATTCCTGGAGATCAGATCACATTAGAATACATAAATAATCCACACCTGGTATCACGATTGGCTCTTTTGCCATCCCAGTTAGGAGGTCTAAACTACCTGTCATGCAGTAGGCTGTTCAATCGAAACATAGGCGACCCGGTGGTTTCCGCAGTTGCAGATCTTAAGAGATTAATTAAATCAGGATGTATGGATTACTGGATCCTTTATAACTTATTAGGGAGAAAACCGGGAAACGGCTCATGGGCTACTTTAGCAGCTGACCCGTACTCAATCAATATAGAGTATCAATACCCTCCAACTACAGCTCTTAAGAGGCACACCCAACAAGCTCTGATGGAACTCAGTACGAATCCAATGTTACGTGGCATATTCTCTGACAATGCACAGGCAGAAGAAAATAACCTTGCTAGGTTTCTCCTGGATAGGGAGGTGATCTTTCCGCGTGTAGCTCACATCATCATTGAGCAAACCAGTGTCGGGAGGAGAAAACAGATTCAAGGATATTTGGATTCAACTAGATCGATAATGAGGAAATCACTAGAAATTAAGCCCTTATCCAATAGGAAGCTTAATGAAATACTGGATTACAACATCAATTACCTAGCTTACAATTTGGCATTACTCAAGAATGCTATTGAACCTCCGACTTATTTGAAGGCAATGACACTTGAAACATGTAGCATCGACATTGCAAGGAACCTCCGGAAGCTCTCCTGGGCCCCACTCTTGGGTGGGAGAAATCTTGAAGGATTAGAGACGCCAGATCCCATTGAAATTACTGCAGGAGCATTAATTGTTGGATCGGGCTACTGTGAACAGTGTGCTGCAGGAGACAATCGATTCACATGGTTTTTCTTGCCATCTGGTATCGAGATAGGAGGGGATCCCCGTGATAATCCTCCTATCCGTGTACCGTACATTGGCTCCAGGACTGATGAGAGGAGGGTAGCCTCAATGGCATACATCAGGGGTGCCTCGAGTAGCTTAAAAGCAGTTCTTAGACTGGCGGGAGTGTACATCTGGGCATTCGGAGATACTCTGGAGAATTGGATAGATGCACTGGATTTGTCTCACACTAGAGTTAACATCACACTTGAACAGCTGCAATCCCTCACCCCACTTCCAACCTCTGCCAATCTAACCCATCGGTTGGATGATGGCACAACTACCCTAAAGTTTACTCCTGCGAGCTCTTACACCTTTTCAAGTTTCACTCATATATCAAATGATGAGCAATACCTGACAATTAATGACAAAACTGCAGATTCAAATATAATCTACCAACAGTTAATGATCACTGGACTCGGAATCTTAGAAACATGGAATAATCCCCCAATCAATAGAACATTCGAAGAATCTACCCTACATTTGCACACTGGTGCATCATGTTGTGTCCGACCTGTGGACTCCTGCATTCTCTCAGAAGCATTAACAGTCAAGCCACATATTACAGTACCGTACAGCAATAAATTTGTATTTGATGAGGACCCGCTATCTGAATATGAAACTGCAAAACTGGAATCGTTATCATTCCAAGCCCAATTAGGCAACATTGATGCTGTAGATATGACAGGTAAATTAACATTATTGTCCCAATTCACTGCAAGGCAGATTATCAATGCAATCACTGGACTCGATGAGTCTGTCTCTCTTACTAATGATGCCATTGTTGCATCAGACTATGTCTCCAATTGGATTAGTGAATGCATGTATACCAAATTAGATGAATTATTTATGTATTGTGGGTGGGAACTACTATTGGAACTATCCTATCAAATGTATTATCTGAGGGTAGTTGGGTGGAGTAATATAGTGGATTATTCTTACATGATCTTGAGAAGAATCCCGGGTGCAGCATTAAACAATCTGGCATCTACATTAAGTCATCCAAAACTTTTCCGACGAGCTATCAACCTAGATATAGTTGCCCCCTTAAATGCTCCTCATTTTGCATCTCTGGACTACATCAAGATGAGTGTGGATGCAATACTCTGGGGCTGTAAAAGAGTCATCAATGTGCTCTCCAATGGAGGGGACTTAGAATTAGTTGTGACATCTGAAGATAGCCTTATTCTCAGTGACCGATCCATGAATCTCATTGCAAGGAAATTAACTTTATTATCACTGATTCACCATAATGGTTTGGAACTACCAAAGATTAAGGGGTTCTCTCCTGATGAGAAGTGTTTCGCTTTGACAGAATTTTTGAGGAAAGTGGTGAACTCAGGGTTGAGTTCAATAGAGAACCTATCAAATTTTATGTACAATGTGGAGAACCCACGGCTTGCAGCATTCGCCAGCAACAATTACTACCTGACCAGAAAATTATTGAATTCAATACGAGATACTGAGTCGGGTCAAGTAGCAGTCACCTCATATTATGAATCATTAGAATATATTGATAGTCTTAAGCTAACCCCACATGTGCCTGGCACCTCATGCATTGAGGATGATAGTCTATGTACAAATGATTACATAATCTGGATCATAGAGTCTAATGCAAACTTGGAGAAGTATCCAATTCCAAATAGCCCTGAGGATGATTCCAATTTCCATAACTTTAAGTTGAATGCTCCATCGCACCATACCTTACGCCCATTAGGGTTGTCATCAACTGCTTGGTATAAGGGTATAAGCTGCTGCAGGTACCTTGAGCGATTAAAGCTACCACAAGGTGATCATTTATATATTGCAGAAGGTAGTGGTGCCAGTATGACAATCATAGAATACCTATTCCCAGGAAGAAAGATATATTACAATTCTTTATTTAGTAGTGGTGACAATCCCCCACAAAGAAATTATGCACCAATGCCTACTCAGTTCATTGAGAGTGTCCCATACAAGCTCTGGCAAGCACACACAGATCAATATCCCGAGATTTTTGAGGACTTCATCCCTCTATGGAACGGAAACGCCGCCATGACTGACATAGGAATGACAGCTTGTGTAGAATTCATCATCAATCGAGTCGGCCCAAGGACTTGCAGTTTAGTACATGTAGATTTGGAATCAAGTGCAAGCTTAAATCAACAATGCCTGTCAAAGCCGATAATTAATGCTATCATCACTGCTACAACTGTTTTGTGCCCTCATGGGGTGCTTATTCTGAAATATAGTTGGTTGCCATTTACTAGATTTAGTACTTTGATCACTTTCTTATGGTGCTACTTTGAGAGAATCACTGTTCTTAGGAGCACATATTCTGATCCAGCTAATCATGAGGTTTATTTAATTTGTATCCTTGCCAACAACTTTGCATTCCAGACTGTCTCGCAGGCAACAGGAATGGCGATGACTTTAACTGATCAAGGGTTTACTTTGATATCACCTGAAAGAATAAATCAGTATTGGGATGGTCACTTGAAGCAAGAACGTATCGTAGCAGAAGCAATTGATAAGGTGGTTCTAGGAGAAAATGCTCTATTTAATTCGAGTGATAATGAATTAATTCTCAAATGTGGAGGGACACCAAATGCACGGAATCTCATCGATATCGAGCCAGTCGCAACTTTCATAGAATTTGAACAATTGATCTGCACAATGTTGACAACCCACTTGAAGGAAATAATTGATATAACAAGGTCTGGAACCCAGGATTATGAAAGTTTATTACTCACTCCTTACAATTTAGGTCTTCTTGGTAAAATCAGTACGATAGTGAGATTATTAACAGAAAGGATTCTAAATCATACTATCAGGAATTGGTTGATCCTCCCACCTTCGCTCCGGATGATCGTGAAGCAGGACTTGGAATTCGGCATATTCAGGATTACTTCCATCCTCAATTCTGATCGGTTCCTGAAGCTTTCTCCAAATAGGAAATACTTGATTGCACAATTAACTGCAGGCTACATTAGGAAATTGATTGAGGGGGATTGCAATATCGATCTAACCAGACCTATCCAAAAGCAAATCTGGAAAGCATTAGGTTGTGTAGTCTATTGTCACGATCCAATGGATCAAAGGGAGTCAACAGAGTTTATTGATATAAATATTAATGAAGAAATAGACCGCGGGATCGATGGCGAGGAAATCTAAACAT ATCAAGAATCAGAATTAGTTTAAGAAAAAAGAAGAGGATTAATCTTGGTTTT CCCCTTGGT (SEQ ID NO: 1).III. CVB-based RSV Compositions
[0112] Provided herein are the CVB-RSV-F genomic sequences.A. CVB-RSV-F Sequence
[0113] The CVB-RSV-F nucleic acid sequence is provided herein:ACCAAGGGGAAAATGAAGTGGTGACTCAAATCATCGAAGACCCTCGAGATTACATAGGTCCGGAACCTATGGCCTTCGTGACCGACCTCGAGTCAGAGTAGTTCAATAAGGACCTATCAAGTTTGGGCAATTTTTCGTCCCCGACACAAAAATGTCATCCGTGCTTAAAGCATATGAGCGATTCACGCTCACTCAAGAACTGCAAGATCAGAGTGAGGAAGGTACAATCCCACCTACAACACTAAAACCGGTAATCAGGGTATTTATACTAACCTCTAATAACCCAGAGCTAAGATCCCGGCTTCTTCTATTCTGCCTACGGATTGTTCTCAGTAATGGTGCAAGGGATTCCCATCGCTTTGGAGCATTACTCACAATGTTTTCGCTACCATCAGCCACAATGCTCAATCATGTCAAATTAGCTGACCAGTCACCAGAAGCTGATATCGAAAGGGTAGAGATCGATGGCTTTGAGGAGGGATCATTCCGCTTAATCCCCAATGCTCGTTCAGGTATGAGCCGTGGAGAGATCAATGCCTATGCTGCACTTGCAGAAGATCTACCTGACACACTAAACCATGCAACACCTTTCGTTGATTCCGAAGTCGAGGGAACTGCATGGGATGAGATTGAGACTTTCTTAGATATGTGTTACAGTGTCCTAATGCAGGCATGGATAGTGACTTGCAAGTGCATGACTGCGCCAGACCAACCTGCTGCTTCTATTGAGAAACGCCTGCAAAAATATCGTCAGCAAGGCAGGATCAACCCGAGATATCTCCTGCAACCGGAGGCTCGACGAATAATCCAGAATGTAATCCGGAAGGGAATGGTGGTCAGACATTTCCTCACCTTTGAACTGCAGCTTGCCCGAGCACAAAGCCTTGTATCAAATAGGTATTATGCTATGGTAGGGGATGTTGGAAAGTATATAGAGAATTGTGGAATGGGAGGCTTCTTTTTGACACTAAAATATGCATTAGGAACTAGATGGCCCACACTTGCTTTAGCTGCATTTTCAGGAGAGCTAACAAAGCTAAAGTCCCTCATGGCATTATACCAGACCCTTGGTGAGCAGGCCCGATATTTGGCCCTATTGGAGTCACCACATTTGATGGATTTTGCTGCAGCAAACTACCCACTGCTATATAGCTATGCTATGGGAATAGGCTATGTGTTAGATGTCAACATGAGGAACTACGCTTTCTCCAGATCATACATGAACAAGACATATTTCCAATTGGGAATGGAAACTGCAAGAAAACAACAGGGTGCAGTTGACATGAGGATGGCAGAAGATCTCGGTCTAACTCAAGCCGAACGCACCGAGATGGCAAATACACTTGCCAAATTGACCACAGCAAATCGAGGGGCAGACACCAGGGGAGGAGTCAACCCGTTCTCATCTGTCACTGGGACAACTCAGGTGCCCGCTGCAGCAACAGGTGACACACTCGAGAGTTACATGGCAGCGGATCGACTGAGGCAGAGATATGCTGATGCAGGCACCCATGATGATGAGATGCCACCATTGGAAGAGGAGGAAGAGGACGACACATCTGCAGGTCCACGCACTGGACCAACTCTTGAACAAGTGGCCTTGGACATCCAGAACGCAGCAGTTGGAGCTCCCATCCATACAGATGACCTGAATGCCGCACTGGGTGATCTTGACATCTAGACAATTCAGATCCCAATCTAAAATTGACATACCTAATTGATTAGTTAGATGGAACTACAGTGGATTCCATAAGGTTCCTGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACAAGCGACTGCCGGTGCCAACAGCGCAATCCACAATCTACAATGGATCCCACTGATCTGAGCTTCTCCCCAGATGAGATCAATAAGCTCATAGAGACAGGCCTGAATACTGTAGAGTATTTTACTTCCCAACAAGTCACAGGAACATCCTCTCTTGGAAAGAATACAATACCACCAGGGGTCACAGGACTACTAACCAATGCTGCAGAGGCAAAGATCCAAGAGTCAACTAACCATCAGAAGGGCTCAGTTGGTGGGGGTGCAAAACCAAAGAAACCGCGACCAAAAATTGCCATTGTGCCAGCAGATGACAAAACAGTGCCCGGAAAGCCGATCCCAAACCCTCTATTAGGTCTGGACTCCACCCCGAGCACCCAAACTGTGCTTGATCTAAGTGGGAAAACATTACCATCAGGATCCTATAAGGGGGTTAAGCTTGCGAAATTTGGAAAAGAAAATCTGATGACACGGTTCATCGAGGAACCCAGAGAGAATCCTATCGCAACCAGTTTCCCCATCGATTTTAAGAGGGGCAGGGATACCGGCGGGTTCCATAGAAGGGAGTACTCAATCGGATGGGTGGGAGATGAAGTCAAGGTCACTGAGTGGTGCAATCCATCCTGTTCTCCAATCACCGCTGCAGCAAGGCGATTTGAATGCACTTGTCACCAGTGTCCAGTCACTTGCTCTGAATGTGAACGAGATACTTAATACAGTGAGAAATTTGGACTCTCGGATGAATCAACTGGAGACAAAAGTAGATCGCATTCTCTCATCTCAGTCTCTAATCCAGACCATCAAGAATGACATAGTTGGACTTAAAGCAGGGATGGCTACTTTAGAAGGAATGATTACAACTGTGAAAATCATGGACCCGGGAGTTCCCAGTAATGTTACTGTGGAAGATGTACGCAAGACACTAAGTAACCATGCTGTTGTTGTGCCAGAATCATTCAATGATagtTTCTTGACTCAATCTGAAGATGTAATTTCACTTGATGAGTTGGCTCGACCAACTGCAACAAGTGTTAAGAAGATTGTCAGGAAGGTTCCTCCTCAGAAGGATCTGACTGGATTGAAGATTACACTAGAGCAATTGGCAAAGGATTGCATCAGCAAACCGAAGATGAGGGAAGAGTATCTCCTCAAAATCAACCAGGCTTCCAGTGAGGCTCAGCTAATTGACCTCAAGAAAGCAATCATCCGCAGTGCAATTTGATCAAGAAACACCCAATTACACTACACTGGTATGACACTGTACTAACCCTGAGGGTTTTAGAAAAAACGATTAACGATAAATAAGCCCGAACACTACACACTACCTGAGGCAGCCATGCCATCCATCAGCATTCCCGCAGACCCCACCAATCCACGTCAATCAATAAAAGCGTTCCCAATTGTGATCAACAGTGATGGGGGTGAGAAAGGCCGCTTGGTTAAACAACTACGCACAACCTACTTGAATGACCTAGATACTCATGAGCCACTGGTGACATTCATAAATACCTATGGATTCATCTACGAACAGGATCGGGGGAATACCATTGTCGGAGAGGATCAACTTGGGAAGAAAAGAGAGGCTGTGACCGCTGCAATGGTTACCCTTGGATGTGGGCCTAATCTACCATCATTAGGGAATGTCCTGGGACAACTGAGGGAATTCCAGGTCACTGTTAGGAAGACATCCAGCAAAGCGGAAGAGATGGTCTTTGAAATTGTTAAGTATCCGAGAATATTTCGGGGTCATACATTAATCCAGAAAGGACTAGTCTGTGTCTCCGCAGAAAAATTTGTTAAGTCACCAGGGAAAATACAATCTGGAATGGACTATCTCTTCATTCCGACATTTCTGTCAGTGACTTACTGTCCAGCTGCAATCAAATTTCAGGTACCTGGCCCCATGTTGAAAATGAGATCAAGATACACTCAGAGCTTACAACTTGAACTAATGATAAGAATCCTGTGTAAGCCCGATTCGCCACTTATGAAGGTCCATACCCCTGACAAGGAGGGAAGAGGATGTCTTGTATCAGTATGGCTGCATGTATGCAACATCTTCAAATCAGGAAACAAGAATGGCAGTGAGTGGCAGGAATACTGGATGAGAAAGTGTGCTAACATGCAACTTGAAGTGTCGATTGCAGATATGTGGGGACCAACTATCATAATTCATGCCAGAGGTCACATTCCCAAAAGTGCTAAGTTGTTTTTTGGAAAGGGTGGATGGAGCTGCCATCCACTTCACGAAGTTGTTCCAAGTGTCACTAAAACACTATGGTCCGTGGGCTGTGAGATTACAAAGGCGAAGGCAATAATACAAGAGAGTAGCATCTCTCTTCTCGTGGAGACTACTGACATCATAAGTCCAAAAGTCAAAATTTCATCTAAGCATCGCCGCTTTGGGAAATCAAATTGGGGTCTGTTCAAGAAAACTAAATCACTGCCTAACCTGACGGAGCTGGAATGACTGACCTCTAATCGAGACTACACCGCCGCAAACTATAGGTGGGTGGTACCTCAGTGATTAATCTTGTAAGCACTGATCGTAGGCTACAACACACTAATATTATCCAGATTAGAGAGCTTAATTAGCTCTGTATTAATAATAACACTACTATTCCAATAACTGGAATCACCAGCTTGATTTATCTCCAAAATGATTCAAAGAAAACAAATCATATTAAGACTATCCTAAGCACGAACCCATATCGTCCTTCAAATCATGGGTACTATAATTCAATTTCTGGTGGTCTCCTGTCTATTGGCAGGAGCAGGCAGCCTTGATCCAGCAGCCCTCATGCAAATCGGTGTCATTCCAACAAATGTCCGGCAACTTATGTATTATACTGAAGCTTCATCAGCATTCATTGTTGTGAAGTTAATGCCTACAATTGACTCGCCGATTAGTGGATGTAATATAACATCAATTTCAAGCTATAATGCAACAGTGACAAAACTCCTACAGCCGATCGGTGAGAATTTGGAGACGATTAGGAACCAGTTGATTCCAACTCGGAGGAGACGCCGGTTTGCAGGGGTGGTGATTGGATTAGCTGCATTAGGAGTAGCTACTGCCGCACAGGTCACTGCCGCAGTGGCACTAGTAAAGGCAAATGAAAATGCTGCGGCTATACTCAATCTCAAAAATGCAATCCAAAAAACAAATGCAGCAGTTGCAGATGTGGTCCAGGCCACACAATCACTAGGAACGGCAGTTCAAGCAGTTCAAGATCACATAAACAGTGTGGTAAGTCCAGCAATTACAGCAGCCAATTGTAAGGCCCAAGATGCTATCATTGGCTCAATCCTCAATCTCTATTTGACCGAGTTGACAACCATCTTCCACAATCAAATTACAAACCCTGCATTGAGTCCCATTACAATTCAAGCTTTAAGGATCCTACTGGGGAGTACCTTGCCGACTGTGGTCGAAAAATCTTTCAATACCCAGATAAGTGCAGCTGAGCTTCTCTCATCAGGGTTATTGACAGGCCAGATTGTGGGATTAGATTTGACCTATATGCAGATGGTCATAAAAATTGAGCTGCCAACTTTAACTGTACAACCTGCAACCCAGATCATAGATCTGGCCACCATTTCTGCATTCATTAACAATCAAGAAGTCATGGCCCAAT TACCAACACGTGTTATGGTGACTGGCAGCTTGATCCAAGCCTATCCCGCATC GCAATGCACCATTACACCCAACACTGTGTACTGTAGGTATAATGATGCCCAA GTACTCTCAGATGATACTATGGCTTGCCTCCAAGGTAACTTGACAAGATGCA CCTTCTCTCCAGTGGTTGGGAGCTTTCTCACTCGATTCGTGCTGTTCGATGGA ATAGTTTATGCAAATTGCAGGTCGATGTTGTGCAAGTGCATGCAACCTGCTG CTGTGATCCTACAGCCGAGTTCATCCCCTGTAACTGTCATTGACATGTACAA ATGTGTGAGTCTGCAGCTTGACAATCTCAGATTCACCATCACTCAATTGGCC AATGTAACCTACAATAGCACCATCAAGCTTGAATCATCCCAGATCTTGTCTA TTGATCCGTTGGATATATCCCAGAATCTAGCTGCGGTGAATAAGAGTCTAAG TGATGCACTACAACACTTAGCACAAAGTGACACATATCTTTCTGCAATCACA TCAGCTACGACTACAAGTGTATTATCCATAATAGCAATCTGTCTTGGATCGTT AGGTTTAATATTAATAATCTTGCTCAGTGTAGTTGTGTGGAAGTTATTGACCA TTGTCGTTGCTAATCGAAATAGAATGGAGAATTTTGTTTATCATAAATAAGC ATTCCACCACTCACGATCTGATCTCAGTGAGAAAAATCAACCTGCAACTCTT GGAACAAGATAAGACAGTCATCCATTAGTAATTTTTAAGAAAAAAACGATA GGACCGAACCTAGTATTGAAAGAACCGTCTCGGTCAATCTAGGTAATCGAGC TGATACCGTCTCGGAAAGCTCAAATCGCCGCCACCatggagctgctgatcctgaaagccaac gctattaccacaatcctgaccgccgtgacattctgctttgcttccggacagaatatcaccgaggagttctaccagtcaacatgtag cgccgtgagcaaggggtacctgagtgcactgcgaaccggatggtatacatccgtgattactatcgagctgtctaacatcaagaa aaacaaatgcaatggcactgacgccaagatcaagctgatcaagcaggagctggataagtacaaaaatgctgtgaccgaactg cagctgctgatgcagagcactccagctaccaacaatcgcgcacggagagaactgccccggttcatgaactataccctgaacaa tgcaaagaaaacaaatgtgactctgtccaagaaacgcaagaggcgcttcctgggatttctgctgggcgtggggtctgcaatcgc cagtggagtggccgtctctaaagtcctgcacctggagggcgaagtgaacaagatcaaatcagcactgctgagcacaaacaag gccgtggtcagtctgtcaaatggcgtgtccgtcctgacttctaaggtgctggacctgaaaaattatattgataagcagctgctgcc tatcgtcaacaaacagagctgttccatttctaatatcgagaccgtgatcgagttccagcagaagaacaatagacttctagagatta caagggaattttctgtgaacgctggcgtcactacccccgtgagtacctacatgctgacaaatagtgagctgctgtcactgattaac gacatgcctatcaccaatgatcagaagaaactgatgagtaacaatgtgcagatcgtcagacagcagagttactcaatcatgtcaa tcattaaggaggaagtcctggcctacgtggtccagctgccactgtatggcgtgatcgacactccctgctggaaactgcatacctc acctctgtgcacaactaacaccaaggaggggagcaatatctgcctgacacgaactgaccggggatggtactgtgataacgcc ggcagcgtgtccttctttccccaggctgagacctgcaaggtccagtccaacagggtgttctgtgacactatgaatagcctgaccc tgccttccgaagtcaacctgtgcaatgtggacatctttaatccaaagtacgattgtaagatcatgaccagcaagacagatgtcagc tcgagtgtgattacatcactgggggctatcgtgagctgctacggaaagactaaatgtaccgcaagcaacaaaaatcgcggcatc attaagaccttcagtaacgggtgcgactatgtctcaaacaagggcgtggatacagtgagcgtcgggaacactctgtactatgtcaataagcaggagggaaaatccctgtacgtgaagggcgaaccaatcattaacttctatgaccccctggtgttcccttccgacgagtt tgatgcctctattagtcaggtgaacgaaaaaatcaatcagagcctggcttttattcggaagtccgatgagctgctgcacaacgtga atgcagtcaagtctaccacaaacattatgatcactaccatcattatcgtgattatcgtcattctgctgtccctgatcgcagtggggct gctgctgtactgtaaagccagatctacacccgtgactctgtctaaggatcagctgagtggaattaacaatatcgcctttagcaact gaTAGGTCGACCACCTGCTATAGGCTATCCACTGCATCATCTCTCCTGCCATA CTTCCTACTCACATCATATCTATTTTAAAGAAAAAATAGGCCCGAACACTAA TCGTGCCGGCAGTGCCACTGCACACACAACACTACACATACAATACACTACA ATGGTTGCAGAAGATGCCCCTGTTAGGGCCACTTGCCGAGTATTATTTCGAA CAACAACTTTAATCTTTCTATGCACACTACTAGCATTAAGCATCTCTATCCTT TATGAGAGTTTAATAACCCAAAAGCAAATCATGAGCCAAGCAGGCTCAACT GGATCTAATTCTGGATTAGGAAGTATCACTGATCTTCTTAATAATATTCTCTC TGTCGCAAATCAGATTATATATAACTCTGCAGTCGCTCTACCTCTACAATTGG ACACTCTTGAATCAACACTCCTTACAGCCATTAAGTCTCTTCAAACCAGTGA CAAGCTAGAACAGAACTGCTCGTGGAGTGCTGCACTGATTAATGATAATAGA TACATTAATGGCATCAATCAGTTCTATTTTTCAATTGCTGAGGGTCGCAATCT GACACTTGGCCCACTTCTTAATATGCCTAGTTTCATTCCAACTGCCACGACAC CAGAGGGCTGCACCAGGATCCCATCATTCTCGCTCACTAAGACACACTGGTG TTATACACACAATGTTATCCTGAATGGATGCCAGGATCATGTATCCTCAAAT CAATTTGTTTCTATGGGAATCATTGAACCCACTTCTGCCGGGTTTCCATTCTT TCGAACCCTAAAGACTCTATATCTCAGCGATGGGGTCAATCGTAAGAGCTGC TCTATCAGTACAGTTCCGGGGGGTTGTATGATGTACTGTTTTGTTTCTACTCA ACCAGAGAGGGATGACTACTTTTCTGCCGCTCCTCCAGAACAACGAATTATT ATAATGTACTATAATGATACAATCGTGGAGCGCATAATTAATCCACCCGGGG TACTAGATGTATGGGCAACATTGAACCCAGGAACAGGAAGCGGGGTATATT ATTTAGGTTGGGTGCTCTTTCCAATATATGGCGGCGTGATTAAAGGTACGAG TTTATGGAATAATCAAGCAAATAAATACTTTATCCCCCAGATGGTTGCTGCT CTCTGCTCACAAAACCAGGCAACTCAAGTCCAAAATGCTAAGTCATCATACT ATAGCAGCTGGTTTGGCAATCGAATGATTCAGTCTGGGATCCTGGCATGTCC TCTTCGACAGGATCTAACCAATGAGTGTTTAGTTCTGCCCTTTTCTAATGATC AGGTGCTTATGGGTGCTGAAGGGAGATTATACATGTATGGTGACTCGGTGTA TTACTATCAAAGAAGCAATAGTTGGTGGCCTATGACCATGCTGTATAAGGTA ACCATAACATTCACTAATGGTCAGCCATCTGCTATATCAGCTCAGAATGTGC CCACACAGCAGGTCCCTAGACCTGGGACAGGAGACTGCTCTGCAACCAATAGATGTCCCGGTTTTTGCTTGACAGGAGTGTATGCCGATGCCTGGTTACTGACCAACCCTTCGTCTACCAGTACATTTGGATCAGAAGCAACCTTCACTGGTTCTTATCTCAACACAGCAACTCAGCGTATCAATCCGACGATGTATATCGCGAACAACACACAGATCATAAGCTCACAGCAATTTGGATCAAGCGGTCAAGAAGCAGCATATGGCCACACAACTTGTTTTAGGGACACAGGCTCTGTTATGGTATACTGTATCTATATTATTGAATTGTCCTCATCTCTCTTAGGACAATTTCAGATTGTCCCATTTATCCGTCAGGTGACACTATCCTAAAGGCAGAAGCCTTCAGGTCTGACCCAGCCAATCAAAGCATTATACCAGACCATGGAATGCATACCAAACATTATTGACACTAATGACACACAAAATTGGTTTTAAGAAAAACCAAGAGAACAATAGGCCAGAATGGCTGGGTCTCGGGAGATATTACTCCCTGAAGTCCATCTCAATTCACCAATTGTAAAGCATAAGCTATACTATTACATTCTACTTGGAAACCTCCCAAATGAGATCGACCTTGACGATTTAGGTCCATTACATAATCAAAATTGGAATCAGATAGCACATGAAGAGTCTAACTTAGCTCAACGCTTGGTAAATGTAAGAAATTTTCTAATTACCCACATCCCTGATCTTAGAAAGGGCCATTGGCAAGAGTATGTCAATGTAATACTGTGGCCGCGAATTCTTCCCTTGATCCCGGATTTTAAAATCAATGACCAATTGCCTCTGCTCAAAAATTGGGACAAGTTAGTTAAAGAATCATGTTCAGTAATCAATGCAGGTACTTCCCAGTGCATTCAGAATCTCAGCTATGGACTGACAGGTCGTGGGAACCTCTTTACACGATCACGTGAACTCTCTGGTGACCGCAGGGATATTGATCTTAAGACAGTTGTGGCAGCATGGCATGACTCAGACTGGAAAAGAATAAGTGATTTTTGGATTATGATCAAATTCCAGATGAGACAATTAATTGTTAGGCAAACAGATCATAATGATTCTGATTTAATCACGTATATCGAAAATAGAGAAGGCATAATCATCATAACCCCTGAACTGGTAGCATTATTTAACACTGAGAATCATACACTAACATACATGACCTTTGAAATTGTACTGATGGTTTCAGATATGTACGAAGGTCGTCACAACATTTTATCACTATGCACAGTTAGCACTTACCTGAATCCTCTGAAGAAAAGAATAACATATTTATTGAGCCTTGTAGATAACTTAGCTTTTCAGATAGGTGATGCTGTATATAACATAATTGCTTTGCTAGAATCCTTTGTATATGCACAGTTGCAAATGTCAGATCCCATCCCAGAACTCAGAGGACAATTCCATGCATTCGTATGTTCTGAGATTCTTGATGCACTAAGAGGAACTAATAGTTTCACCCAGGATGAATTAAGAACTGTGACAACTAATTTGATATCCCCATTCCAAGATCTGACCCCAGATCTTACGGCTGAATTGCTCTGTATAATGAGGCTTTGGGGACACCCCATGCTCACTGCCAGTCAAGCTGCAGGAAAGGTACGCGAGTCTATGTGTGCTGGAAAAGTATTAGACTTTCCCACCATTATGAAAACACTAGCCTTTTTCCATACTATTCTGATCAATGGATACAGGAGGAAGCATCATGGAGTATGGCCACCCTTAAACTTACCGGGTAATGCTTCAAAGGGTCTCACGGAACTTATGAATGACAATACTGAAATAAGCTATGAATTCACACTTAAGCATTGGAAGGAAGTCTCTCTTATAAAATTCAAGAAATGTTTTGATGCAGACGCAGGTGAGGAACTCAGTATATTTATGAAAGATAAGGCAATTAGTGCCCCAAAACAAGACTGGATGAGTGTGTTTAGAAGAAGCCTAATCAAACAGCGCCATCAGCATCATCAGGTCCCCCTACCAAATCCATTCAATCGACGGCTGTTGCTAAACTTTCTCGGAGATGACAAATTCGACCCGAATGTGGAGCTACAGTATGTAACATCAGGTGAGTATCTACATGATGACACGTTTTGTGCATCATATTCACTAAAAGAGAAGGAAATTAAACCTGATGGTCGAATTTTTGCAAAGTTGACTAAGAGAATGAGATCATGTCAAGTTATAGCAGAATCTCTTTTAGCGAACCATGCTGGGAAGTTAATGAAAGAGAATGGTGTTGTGATGAATCAGCTATCATTAACAAAATCACTATTAACAATGAGTCAGATTGGAATAATATCCGAGAAAGCTAGAAAGTCAACTCGAGATAACATAAATCAACCTGGTTTCCAGAATATCCAGAGAAATAAATCACATCACTCCAAGCAAGTCAATCAGCGAGATCCAAGTGATGACTTTGAATTGGCAGCATCTTTTTTAACTACTGATCTCAAAAAATATTGTTTACAATGGAGGTACCAGACAATTATCCCATTTGCTCAATCATTAAACAGAATGTATGGTTATCCTCATCTCTTTGAGTGGATTCACTTACGGCTAATGCGTAGTACACTTTACGTGGGGGATCCCTTCAACCCACCAGCAGATACCAGTCAATTTGATCTAGATAAAGTAATTAATGGAGATATCTTCATTGTATCACCCAGAGGTGGAATTGAAGGGCTGTGTCAAAAGGCTTGGACAATGATATCTATCGCTGTGATAATTCTATCTGCCACAGAGTCTGGCACACGAGTAATGAGTATGGTGCAGGGAGATAATCAAGCAATTGCTGTCACCACACGAGTACCAAGGAGCCTGCCGACTCTTGAGAAAAAGACTATTGCTTTTAGATCTTGTAATCTATTCTTTGAGAGGTTAAAATGTAATAATTTTGGATTAGGTCACCATTTGAAAGAACAAGAGACTATCATTAGTTCTCACTTCTTTGTTTATAGCAAGAGAATATTCTATCAGGGGAGGATTCTAACGCAAGCCTTAAAAAATGCTAGTAAGCTCTGCTTGACAGCTGATGTCCTAGGAGAATGCACCCAATCATCATGTTCTAATCTTGCAACTACTGTCATGAGGTTAACTGAGAATGGTGTTGAAAAAGATATCTGTTTCTACTTGAATATCTATATGACCATCAAACAGCTCTCCTATGATATCATCTTCCCTCAAGTGTCAATTCCTGGAGATCAGATCACATTAGAATACATAAATAATCCACACCTGGTATCACGATTGGCTCTTTTGCCATCCCAGTTAGGAGGTCTAAACTACCTGTCATGCAGTAGGCTGTTCAATCGAAACATAGGCGACCCGGTGGTTTCCGCAGTTGCAGATCTTAAGAGATTAATTAAATCAGGATGTATGGATTACTGGATCCTTTATAACTTATTAGGGAGAAAACCGGGAAACGGCTCATGGGCTACTTTAGCAGCTGACCCGTACTCAATCAATATAGAGTATCAATACCCTCCAACTACAGCTCTTAAGAGGCACACCCAACAAGCTCTGATGGAACTCAGTACGAATCCAATGTTACGTGGCATATTCTCTGACAATGCACAGGCAGAAGAAAATAACCTTGCTAGGTTTCTCCTGGATAGGGAGGTGATCTTTCCGCGTGTAGCTCACATCATCATTGAGCAAACCAGTGTCGGGAGGAGAAAACAGATTCAAGGATATTTGGATTCAACTAGATCGATAATGAGGAAATCACTAGAAATTAAGCCCTTATCCAATAGGAAGCTTAATGAAATACTGGATTACAACATCAATTACCTAGCTTACAATTTGGCATTACTCAAGAATGCTATTGAACCTCCGACTTATTTGAAGGCAATGACACTTGAAACATGTAGCATCGACATTGCAAGGAACCTCCGGAAGCTCTCCTGGGCCCCACTCTTGGGTGGGAGAAATCTTGAAGGATTAGAGACGCCAGATCCCATTGAAATTACTGCAGGAGCATTAATTGTTGGATCGGGCTACTGTGAACAGTGTGCTGCAGGAGACAATCGATTCACATGGTTTTTCTTGCCATCTGGTATCGAGATAGGAGGGGATCCCCGTGATAATCCTCCTATCCGTGTACCGTACATTGGCTCCAGGACTGATGAGAGGAGGGTAGCCTCAATGGCATACATCAGGGGTGCCTCGAGTAGCTTAAAAGCAGTTCTTAGACTGGCGGGAGTGTACATCTGGGCATTCGGAGATACTCTGGAGAATTGGATAGATGCACTGGATTTGTCTCACACTAGAGTTAACATCACACTTGAACAGCTGCAATCCCTCACCCCACTTCCAACCTCTGCCAATCTAACCCATCGGTTGGATGATGGCACAACTACCCTAAAGTTTACTCCTGCGAGCTCTTACACCTTTTCAAGTTTCACTCATATATCAAATGATGAGCAATACCTGACAATTAATGACAAAACTGCAGATTCAAATATAATCTACCAACAGTTAATGATCACTGGACTCGGAATCTTAGAAACATGGAATAATCCCCCAATCAATAGAACATTCGAAGAATCTACCCTACATTTGCACACTGGTGCATCATGTTGTGTCCGACCTGTGGACTCCTGCATTCTCTCAGAAGCATTAACAGTCAAGCCACATATTACAGTACCGTACAGCAATAAATTTGTATTTGATGAGGACCCGCTATCTGAATATGAAACTGCAAAACTGGAATCGTTATCATTCCAAGCCCAATTAGGCAACATTGATGCTGTAGATATGACAGGTAAATTAACATTATTGTCCCAATTCACTGCAAGGCAGATTATCAATGCAATCACTGGACTCGATGAGTCTGTCTCTCTTACTAATGATGCCATTGTTGCATCAGACTATGTCTCCAATTGGATTAGTGAATGCATGTATACCAAATTAGATGAATTATTTATGTATTGTGGGTGGGAACTACTATTGGAACTATCCTATCAAATGTATTATCTGAGGGTAGTTGGGTGGAGTAATATAGTGGATTATTCTTACATGATCTTGAGAAGAATCCCGGGTGCAGCATTAAACAATCTGGCATCTACATTAAGTCATCCAAAACTTTTCCGACGAGCTATCAACCTAGATATAGTTGCCCCCTTAAATGCTCCTCATTTTGCATCTCTGGACTACATCAAGATGAGTGTGGATGCAATACTCTGGGGCTGTAAAAGAGTCATCAATGTGCTCTCCAATGGAGGGGACTTAGAATTAGTTGTGACATCTGAAGATAGCCTTATTCTCAGTGACCGATCCATGAATCTCATTGCAAGGAAATTAACTTTATTATCACTGATTCACCATAATGGTTTGGAACTACCAAAGATTAAGGGGTTCTCTCCTGATGAGAAGTGTTTCGCTTTGACAGAATTTTTGAGGAAAGTGGTGAACTCAGGGTTGAGTTCAATAGAGAACCTATCAAATTTTATGTACAATGTGGAGAACCCACGGCTTGCAGCATTCGCCAGCAACAATTACTACCTGACCAGAAAATTATTGAATTCAATACGAGATACTGAGTCGGGTCAAGTAGCAGTCACCTCATATTATGAATCATTAGAATATATTGATAGTCTTAAGCTAACCCCACATGTGCCTGGCACCTCATGCATTGAGGATGATAGTCTATGTACAAATGATTACATAATCTGGATCATAGAGTCTAATGCAAACTTGGAGAAGTATCCAATTCCAAATAGCCCTGAGGATGATTCCAATTTCCATAACTTTAAGTTGAATGCTCCATCGCACCATACCTTACGCCCATTAGGGTTGTCATCAACTGCTTGGTATAAGGGTATAAGCTGCTGCAGGTACCTTGAGCGATTAAAGCTACCACAAGGTGATCATTTATATATTGCAGAAGGTAGTGGTGCCAGTATGACAATCATAGAATACCTATTCCCAGGAAGAAAGATATATTACAATTCTTTATTTAGTAGTGGTGACAATCCCCCACAAAGAAATTATGCACCAATGCCTACTCAGTTCATTGAGAGTGTCCCATACAAGCTCTGGCAAGCACACACAGATCAATATCCCGAGATTTTTGAGGACTTCATCCCTCTATGGAACGGAAACGCCGCCATGACTGACATAGGAATGACAGCTTGTGTAGAATTCATCATCAATCGAGTCGGCCCAAGGACTTGCAGTTTAGTACATGTAGATTTGGAATCAAGTGCAAGCTTAAATCAACAATGCCTGTCAAAGCCGATAATTAATGCTATCATCACTGCTACAACTGTTTTGTGCCCTCATGGGGTGCTTATTCTGAAATATAGTTGGTTGCCATTTACTAGATTTAGTACTTTGATCACTTTCTTATGGTGCTACTTTGAGAGAATCACTGTTCTTAGGAGCACATATTCTGATCCAGCTAATCATGAGGTTTATTTAATTTGTATCCTTGCCAACAACTTTGCATTCCAGACTGTCTCGCAGGCAACAGGAATGGCGATGACTTTAACTGATCAAGGGTTTACTTTGATATCACCTGAAAGAATAAATCAGTATTGGGATGGTCACTTGAAGCAAGAACGTATCGTAGCAGAAGCAATTGATAAGGTGGTTCTAGGAGAAAATGCTCTATTTAATTCGAGTGATAATGAATTAATTCTCAAATGTGGAGGGACACCAAATGCACGGAATCTCATCGATATCGAGCCAGTCGCAACTTTCATAGAATTTGAACAATTGATCTGCACAATGTTGACAACCCACTTGAAGGAAATAATTGATATAACAAGGTCTGGAACCCAGGATTATGAAAGTTTATTACTCACTCCTTACAATTTAGGTCTTCTTGGTAAAATCAGTACGATAGTGAGATTATTAACAGAAAGGATTCTAAATCATACTATCAGGAATTGGTTGATCCTCCCACCTTCGCTCCGGATGATCGTGAAGCAGGACTTGGAATTCGGCATATTCAGGATTACTTCCATCCTCAATTCTGATCGGTTCCTGAAGCTTTCTCCAAATAGGAAATACTTGATTGCACAATTAACTGCAGGCTACATTAGGAAATTGATTGAGGGGGATTGCAATATCGATCTAACCAGACCTATCCAAAAGCAAATCTGGAAAGCATTAGGTTGTGTAGTCTATTGTCACGATCCAATGGATCAAAGGGAGTCAACAGAGTTTATTGATA TAAATATTAATGAAGAAATAGACCGCGGGATCGATGGCGAGGAAATCTAAA CATATCAAGAATCAGAATTAGTTTAAGAAAAAAGAAGAGGATTAATCTTGG TTTTCCCCTTGGT (SEQ ID NO: 2).
[0114] The inserted RSV-F sequence is in the lowercase and the CVB sequence is in the uppercase.IV. CVB-based SARS-CoV-2 Compositions
[0115] The disclosure provides CVB-based SARS-CoV-2 compositions, systems and methods for their use in multiple applications including functional genomics, drug discovery, target validation, protein production (e.g., therapeutic proteins, vaccines, monoclonal antibodies), gene therapy, and therapeutic treatments such as cancer therapy.A. SARS-CoV-2
[0116] With the present invention, constructs of the modified parainfluenza virus type-5 (PIV5) virus, CVB, expressing the SARS-CoV-2 envelope spike (S) and nucleocapsid (N) protein have been generated for use as vaccines against CO VID. These constructs demonstrate effectiveness as vaccines, with single dose intranasal immunization inducing protective immunity in ferrets and cats.
[0117] Coronavirus disease 2019 (COVID-19) is a newly emerging infectious disease currently spreading across the world. It is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Zhu et al., 2020, N Engl J Med; 382:727-733). SARS-CoV-2 was first identified in Wuhan, China in December 2019, and has subsequently spread globally to cause the COVID-19 pandemic. The virus has infected more than 221 million persons world-wide, caused more than 4,574,000 deaths as of September 8, 2021, and is poised to continue to spread in the absence of herd immunity. While vaccines and antibody therapies have been introduced worldwide, the emergence of multiple viral variants which are rapidly replacing the original virus identified in Wuhan has allowed for immune escape in vaccinated populations, presenting a need for improved vaccine efficacy.
[0118] SARS-CoV-2 is a single-stranded RNA-enveloped virus belonging to the 13 coronavirus family (Lu et al., 2020, Lancet; 395:565-74). An RNA-based metagenomic next-generation sequencing approach has been applied to characterize its entire genome, which is 29,881 nucleotides (nt) in length (GenBank Sequence Accession MN908947)encoding 9860 amino acids (Chen et al., 2020, Emerg Microbes Infect; 9:313-9). Fullgenome sequenced genomes available at GenBank include isolate 2019-nCoV WHU01 (GenBank accession number MN988668) and NC_045512 for SARS-CoV-2, both isolates from Wuhan, China, and at least seven additional sequences (MN938384.1, MN975262.1, MN985325.1, MN988713.1, MN994467.1, MN994468.1, and MN997409.1) which are >99.9% identical and are hereby incorporate by reference. i. SARS-CoV-2 Variants
[0119] Since SARS-CoV-2 was first identified in 2019, multiple genetic variants of SARS-CoV-2 have been emerging and circulating around the world. Viral mutations and variants in the United States are routinely monitored through sequence-based surveillance, laboratory studies, and epidemiological investigations. The US government SARS-CoV-2 Interagency Group (SIG) developed a Variant Classification scheme that defines three classes of SARS-CoV-2 variants: variant of interest, variant of concern and variant of high consequence. a. Variant of Interest
[0120] A SARS-CoV-2 variant of interest is a variant with specific genetic markers that have been associated with changes to receptor binding, reduced neutralization by antibodies generated against previous infection or vaccination, reduced efficacy of treatments, potential diagnostic impact, or predicted increase in transmissibility or disease severity.
[0121] A variant of interest might require one or more appropriate public health actions, including enhanced sequence surveillance, enhanced laboratory characterization, or epidemiological investigations to assess how easily the virus spreads to others, the severity of disease, the efficacy of therapeutics and whether currently approved or authorized vaccines offer protection. The growing list variants of interest that are being monitored and characterized include, but are not limited to, Eta, Iota, Kappa, Lambda and Mu. b. Variant of Concern
[0122] A SARS-CoV-2 variant of concern is a variant for which there is evidence of an increase in transmissibility, more severe disease (e.g., increased hospitalizations or deaths), significant reduction in neutralization by antibodies generated during previous infection or vaccination, reduced effectiveness of treatments or vaccines, or diagnosticdetection failures. Possible attributes of a variant of concern include evidence of impact on diagnostics, treatments, or vaccines, widespread interference with diagnostic test targets, evidence of substantially decreased susceptibility to one or more class of therapies, evidence of significant decreased neutralization by antibodies generated during previous infection or vaccination, evidence of reduced vaccine-induced protection from severe disease, evidence of increased transmissibility and evidence of increased disease severity.
[0123] Variants of concern might require one or more appropriate public health actions, such as notification to WHO under the International Health Regulations, reporting to CDC, local or regional efforts to control spread, increased testing, or research to determine the effectiveness of vaccines and treatments against the variant. Based on the characteristics of the variant, additional considerations may include the development of new diagnostics or the modification of vaccines or treatments. The growing list of variants of concern that are being closely monitored and characterized, includes, but is not limited to, Alpha, Beta, Delta, Gamma and Omicron. c. Variant of High Consequence
[0124] A SARS-CoV-2 variant of high consequence has clear evidence that prevention measures or medical countermeasures (MCMs) have significantly reduced effectiveness relative to previously circulating variants. Possible attributes of a variant of high consequence include a demonstrated failure of diagnostic test targets, evidence to suggest a significant reduction in vaccine effectiveness, a disproportionately high number of vaccine breakthrough cases, or very low vaccine-induced protection against severe disease, significantly reduced susceptibility to multiple Emergency Use Authorization (EUA) or approved therapeutics and more severe clinical disease and increased hospitalizations.
[0125] A variant of high consequence would require notification to WHO under the International Health Regulations, reporting to CDC, an announcement of strategies to prevent or contain transmission, and recommendations to update treatments and vaccines. Currently, there are no SARS-CoV-2 variants that rise to the level of high consequence.B. PIV5 CVB Vectored SARS-CoV-2 Constructs
[0126] A PIV5 vaccine vector of the present invention may be constructed using any of a variety of methods, including, but not limited to, the reverse genetics systemdescribed in more detail in He et al. (Virology; 237(2):249-60, 1997). PIV5 encodes eight viral proteins. Nucleocapsid protein (NP), phosphoprotein (P) and large RNA polymerase (L) protein are important for transcription and replication of the viral RNA genome. The V protein plays important roles in viral pathogenesis as well as viral RNA synthesis. The fusion (F) protein, a glycoprotein, mediates both cell-to-cell and virus-to- cell fusion in a pH-independent manner that is essential for virus entry into cells. The structures of the F protein have been determined and critical amino acid residues for efficient fusion have been identified. The hemagglutinin-neuraminidase (HN) glycoprotein is also involved in virus entry and release from the host cells. The matrix (M) protein plays an important role in virus assembly and budding. The hydrophobic (SH) protein is a 44-residue hydrophobic integral membrane protein and is oriented in membranes with its N terminus in the cytoplasm. For reviews of the molecular biology of paramyxoviruses see, for example, Whelan et al., 2004, Curr Top Microbiol Immunol; 283:61-119; and Lamb & Parks, (2006). Paramyxoviridae: the viruses and their replication. In Fields Virology, 5th edn, pp. 1449-1496. Edited by D. M. Knipe & P. M. Howley. Philadelphia, PA: Lippincott Williams & Wilkins.
[0127] Because PIV5 actively replicates in the respiratory tract following intranasal immunization, PIV5-vectored vaccines can generate mucosal immunity that includes antigen-specific IgA antibodies and long-lived IgA plasma cells (Wang, D., et al., J Virol, 91(11) (2017). Xiao, P., et al., Front Immunol,. 12:623996 (2021)). Recently a PIV5- vectored vaccine expressing the spike protein from SARS-CoV-2 Wuhan (WAI; CVXGA1) has been shown to be efficacious in mice and ferrets. A single, intranasal dose of CVXGA1 induced WAI -neutralizing antibodies and protected K18-hACE2 mice against lethal infection with SARS-CoV-2 WAI. Furthermore, a single, intranasal dose of CVXGA1 protected ferrets from infection with SARS-CoV-2 WAI and blocked transmission to cohoused naive ferrets (An, D., et al., Sci Adv, 7(27) (2021)). While these studies determined its efficacy against SARS-CoV-2 WAI, further studies were necessary to establish its efficacy against SARS-CoV-2 variants.
[0128] A PIV5 viral vaccine of the present invention may also have a mutation, alteration, or deletion in one or more of these eight proteins of the PIV5 genome. For example, a PIV5 viral expression vector may include one or more mutations, including, but not limited to any of those described herein. In some aspects, a combination of two ormore (two, three, four, five, six, seven, or more) mutations may be advantageous and may demonstrated enhanced activity.
[0129] In one embodiment, the PIV5 vector was further modified by introducing the mutations in the PIV5 V / P gene and by deletion of the PIV5 SH gene, further enhancing vaccine efficiency. S157F and S308A in the PIV5 V / P genes have been shown previously to increase viral polymerase activities and improve viral titer or yield (Timani KA, Sun D, Sun M, et al. J Virol., 82(18): 9123 -9133 (2008); Sun D, Luthra P, Li Z, He B., PLoS Pathog., 5(7):el000525 (2009)). PIV5 W3A strain-based RSV vaccine with a single S157F mutation was shown to induce higher levels of neutralizing antibodies than PIV5 CPI-vectored RSV vaccine in cotton rats (See table 19). PIV5 W3A strain lacking the SH gene and expressing influenza virus H5 HA protein induced higher levels of antibodies and provided better protection against influenza virus challenge (Li Z, Gabbard JD, Mooney A, et al., J Virol., 87(17): 9604-9609 (2013)). In one embodiment, a newly generated modified PIV5 viral vector backbone is presented herein and named as CVB through introducing S157F into the V / P gene, and deleting the SH gene from the PIV5 W3 A viral genome. In another embodiment, CVB -vectored SARS-CoV-2 vaccines for intranasal immunization were generated.
[0130] A mutation includes, but is not limited to, a mutation of the V / P gene, a mutation of the shared N-terminus of the V and P proteins, a mutation of residues 26, 32, 33, 50, 102, 156, and / or 157 of the shared N-terminus of the V and P proteins, a mutation lacking the C-terminus of the V protein, a mutation lacking the small hydrophobic (SH) protein, a mutation of the fusion (F) protein, a mutation of the phosphoprotein (P), a mutation of the large RNA polymerase (L) protein, a mutation incorporating residues from canine parainfluenza virus, and / or a mutation that enhances syncytial formation.
[0131] A mutation may include, but is not limited to, rPIV5-V / P-CPI-, rPIV5-CPL, rPIV5-CPI+, rPIV5V AC, rPIV-Rev, rPIV5-RL, rPIV5-P-S156N, rPIV5-P-S157A, rPIV5-P-S308A, rPIV5-L-A1981D and rPIV5-F-S443P, rPIV5-MDA7, rPIV5 ASH-CPL, rPIV5 ASH-Rev, and combinations thereof.
[0132] PIV5 can infect cells productively with little cytopathic effect (CPE) in many cell types. In some cell types, PIV5 infection causes formation of syncytia, i.e., fusion of many cells together, leading to cell death. A mutation may include one or moremutations that promote syncytia formation (see, for example Paterson et al., 2000, Virology; 270: 17-30).
[0133] The V protein of PIV5 plays a critical role in blocking apoptosis induced by virus. Recombinant PIV5 lacking the conserved cysteine-rich C-terminus (rPIV5V AC) of the V protein induces apoptosis in a variety of cells through an intrinsic apoptotic pathway, likely initiated through endoplasmic reticulum (ER)-stress (Sun et al., 2004, J Virol; 78:5068-5078). Mutant recombinant PIV5 with mutations in the N-terminus of the V / P gene products, such as rPIV5-CPI-, also induce apoptosis (Wansley and Parks, 2002, J Virol; 76: 10109-10121). A mutation includes, but is not limited to, rPIV5 ASH, rPIV5- CPI-, rPIV5VAC, and combinations thereof. i. CVB-based Vaccine Vectors Encoding the SARS-CoV-2 Spike (S) Protein
[0134] With the CVB-based vaccine vectors of the present invention, a heterologous nucleotide sequence encoding the spike (S) protein of a coronavirus, including, but not limited to, the S protein of SARS-CoV-2, is inserted in the CVB genome. Coronavirus entry into host cells is mediated by the transmembrane S glycoprotein (Tortorici and Veesler, 2019, Adv Virus Res; 105:93-116). As the coronavirus S glycoprotein is surface-exposed and mediates entry into host cells, it is the main target of neutralizing antibodies upon infection and the focus of therapeutic and vaccine design. The spike S protein of SARS-CoV-2 is composed of two subunits, SI and S2. The SI subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2, while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain. (Huang et al., 2020, Acta Pharmacol Sinica; 0: 1-9 (available on the worldwide web at doi.org / 10.1038 / s41401-020-0485-4).
[0135] The total length of SARS-CoV-2 S is 1273 amino acids (aa) and consists of a signal peptide (amino acids 1-13) located at the N-terminus, the SI subunit (14-685 residues), and the S2 subunit (686-1273 residues); the last two regions are responsible for receptor binding and membrane fusion, respectively. In the SI subunit, there is an N- terminal domain (14-305 residues) and a receptor-binding domain (RBD, 319-541 residues); the fusion peptide (FP) (788-806 residues), heptapeptide repeat sequence 1 (HR1) (912-984 residues), HR2 (1163-1213 residues), TM domain (1213-1237 residues),and cytoplasm domain (1237-1273 residues) comprise the S2 subunit (Xia et al., 2020, Cell Mol Immunol; 17:765-7).
[0136] In some CVB-based vaccine vectors of the present invention, the heterologous nucleotide sequence encoding the spike (S) protein of a coronavirus, including, but not limited to, the S protein of SARS-CoV-2, has been modified so that the cytoplasmic tail of the coronavirus S protein has been replaced with the cytoplasmic tail of the fusion (F) protein of PIV5.
[0137] In some CVB-based vaccine vectors of the present invention, the heterologous nucleotide sequence encoding the coronavirus S protein, including but not limited to, the S protein of SARS-CoV-2, has been modified so that the S protein includes an amino acid substitution at amino acid residue W886 and / or F888. In some aspects, the amino acid substitution at amino acid residue W886 includes a substitution of tryptophan (W) to arginine (R) and / or the amino acid substitution at amino acid residue W888 includes a substitution of phenylalanine (F) to arginine (R).
[0138] In some CVB-based vaccine vectors of the present invention, the heterologous nucleotide sequence encoding the spike (S) protein of a coronavirus, including, but not limited to, the S protein of SARS-CoV-2, includes both a modification so that the cytoplasmic tail of the coronavirus S protein has been replaced with the cytoplasmic tail of the fusion (F) protein of PIV5 and includes an amino acid substitution at amino acid residue W886 and / or F888. In some aspects, the amino acid substitution at amino acid residue W886 includes a substitution of tryptophan (W) to arginine (R) and / or the amino acid substitution at amino acid residue W888 includes a substitution of phenylalanine (F) to arginine (R).
[0139] The heterologous nucleotide sequence encoding the coronavirus S protein, including but not limited to the S protein of SARS-CoV-2, may be inserted in any of a variety of locations in the CVB genome.
[0140] CVB vaccine vectors encoding SARS-COV-2 variants of concern or variants of interest are disclosed herein. The CVB-based vaccine vectors may comprise inserting the SARS-CoV-2 spike (S) or the nucleocapsid (N) gene from different variants into CVB vector.
[0141] The CVB-based vaccine vectors of the present invention, have a CVB viral expression vector comprising mutations at amino acid residue SI 56 or SI 57 and a deletion of the small hydrophobic (SH) gene of the PIV5 W3 A viral genome.
[0142] In some CVB-based vaccine vectors of the present invention, the mutation at amino acid residue SI 57 comprises the substitution of serine (S) with an amino acid residue selected from a group consisting of alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), selenocysteine (U), valine (V), tryptophan (W), tyrosine (Y).
[0143] In some CVB-based vaccine vectors of the present invention, the amino acid substitution at amino acid residue SI 57 comprises a substitution of serine (S) to phenylalanine (F) or S156N comprises a substitution of serine (S) to asparagine (N).
[0144] In some CVB-based vaccine vectors of the present invention, the SH gene has a deletion of the SH open reading frame or a deletion of an entire SH gene transcript unit.
[0145] In some CVB-based vaccine vectors of the present invention, the PIV5 genome has a heterologous nucleic acid sequence with at least 98%sequence identity to SEQ ID NOs: 27, 28, 29, 30, 31, 32, or 33 and wherein the viral expression vector expresses a heterologous polypeptide comprising a coronavirus spike (S) and / or nucleocapsid (N) proteins.
[0146] In some CVB-based vaccine vectors of the present invention, the coronavirus S protein is a coronavirus S protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a variant of interest or a variant of concern of SARS-CoV-2 and the coronavirus N protein is the coronavirus N protein of SARS-CoV-2, a variant of interest or a variant of concern of SARS-CoV-2.
[0147] In another embodiment, the coronavirus S protein is the coronavirus S protein of a SARS-CoV-2 Wuhan strain, a SARS-CoV-2 beta variant, a SARS-CoV-2 gamma variant, a SARS-CoV-2 delta variant, or a SARS-CoV-2 omicron variant and the coronavirus N protein is the coronavirus N protein of a SARS-CoV-2 Wuhan strain, a SARS-CoV-2 beta variant, a SARS-CoV-2 gamma variant, a SARS-CoV-2 delta variant, or a SARS-CoV-2 omicron variant.
[0148] In some CVB-based vaccine vectors of the present invention, the coronavirus S protein comprises the coronavirus S protein of SARS-CoV-2 and wherein the cytoplasmic tail of the coronavirus S protein has been replaced with the cytoplasmic tail of the fusion (F) protein of CVB.
[0149] In some CVB-based vaccine vectors of the present invention, the PIV5 W3A viral genome comprises open reading frame deletion mutations of the SH gene and the S gene of SARS-CoV-2 Wuhan strain is inserted between the PIV5 hemagglutinin (HN) and polymerase (L) genes of PIV5.
[0150] In some CVB-based vaccine vectors of the present invention, the entire SH gene transcript unit of PIV5 W3A viral genome is deleted and the S gene of the SARS- CoV-2 Wuhan strain is placed between the HN and L genes of PIV5.
[0151] In some CVB-based vaccine vectors of the present invention, the N gene of SARS-CoV-2 Wuhan strain is inserted to replace the SH gene of PIV5, and the S gene of SARS-CoV-2 Wuhan strain is inserted between the HN and L genes of PIV5.
[0152] In some CVB-based vaccine vectors of the present invention, the S gene of SARS-CoV-2 Omicron BA.1 variant is inserted to replace the S gene of SARS-CoV-2 Wuhan strain and the N gene of SARS-CoV-2 Wuhan strain is inserted in the place of SH gene of PIV5.
[0153] In some CVB-based vaccine vectors of the present invention, the S gene of SARS-CoV-2 Omicron BA.5 variant is inserted between the HN and L genes of PIV5 to replace the S gene of Wuhan strain.
[0154] In some CVB-based vaccine vectors of the present invention, the S gene of SARS-CoV-2 Omicron BA.5 variant is inserted to replace the S gene of Wuhan strain and the N gene of SARS-CoV-2 Wuhan strain is inserted to replace the SH gene of PIV5.
[0155] In some CVB-based vaccine vectors of the present invention, the PIV5 F and HN genes are deleted and wherein the S gene of SARS-CoV-2 Wuhan strain is between HN and L genes of PIV5.
[0156] Also included in the present invention are virions and infectious viral particles that include a PIV5 genome including a heterologous nucleotide sequence encoding a coronavirus S protein, including but not limited to the S protein of SARS- CoV-2.
[0157] Also included in the present invention are compositions including one or more of the PIV5 viral constructs or virions, as described herein. Such a composition may include a pharmaceutically acceptable carrier. As used, a pharmaceutically acceptable carrier refers to one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. Such a carrier may be pyrogen free. The present invention also includes methods of making and using the viral vectors and compositions described herein.
[0158] The compositions of the present disclosure may be formulated in pharmaceutical preparations in a variety of forms adapted to the chosen route of administration. One of skill will understand that the composition will vary depending on mode of administration and dosage unit.
[0159] The agents of this invention can be administered in a variety of ways, including, but not limited to, intravenous, topical, oral, intranasal, subcutaneous, intraperitoneal, intramuscular, and intratumor deliver. In some aspects, the agents of the present invention may be formulated for controlled or sustained release. One advantage of intranasal immunization is the potential to induce a mucosal immune response.C. CVB-S backbone Vaccine Virus Sequences
[0160] The CVB -vectored SARS-CoV-2 vaccine virus sequences from the constructs in Table 1 are listed below. The inserted N of SARS-CoV-2 sequences are in the underlined lowercase, M sequences are italicized lowercase, E sequences are bolded lowercase and S is in the lowercase: i. CVL104
[0161] The nucleic acid sequence for CVL104 is:GCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATA GGCGTATCACGAGGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAAC CTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATG CCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCG GGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCAT ATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAG GCTAATACGACTCACTATAGGGACCAAGGGGAAAATGAAGTGGTGACTCAAA TCATCGAAGACCCTCGAGATTACATAGGTCCGGAACCTATGGCCTTCGTGACCGACCTCGAGTCAGAGTAGTTCAATAAGGACCTATCAAGTTTGGGCAATTTTTCGTCCCCGACACAAAAATGTCATCCGTGCTTAAAGCATATGAGCGATTCACGCTCACTCAAGAACTGCAAGATCAGAGTGAGGAAGGTACAATCCCACCTACAACACTAAAACCGGTAATCAGGGTATTTATACTAACCTCTAATAACCCAGAGCTAAGATCCCGGCTTCTTCTATTCTGCCTACGGATTGTTCTCAGTAATGGTGCAAGGGATTCCCATCGCTTTGGAGCATTACTCACAATGTTTTCGCTACCATCAGCCACAATGCTCAATCATGTCAAATTAGCTGACCAGTCACCAGAAGCTGATATCGAAAGGGTAGAGATCGATGGCTTTGAGGAGGGATCATTCCGCTTAATCCCCAATGCTCGTTCAGGTATGAGCCGTGGAGAGATCAATGCCTATGCTGCACTTGCAGAAGATCTACCTGACACACTAAACCATGCAACACCTTTCGTTGATTCCGAAGTCGAGGGAACTGCATGGGATGAGATTGAGACTTTCTTAGATATGTGTTACAGTGTCCTAATGCAGGCATGGATAGTGACTTGCAAGTGCATGACTGCGCCAGACCAACCTGCTGCTTCTATTGAGAAACGCCTGCAAAAATATCGTCAGCAAGGCAGGATCAACCCGAGATATCTCCTGCAACCGGAGGCTCGACGAATAATCCAGAATGTAATCCGGAAGGGAATGGTGGTCAGACATTTCCTCACCTTTGAACTGCAGCTTGCCCGAGCACAAAGCCTTGTATCAAATAGGTATTATGCTATGGTAGGGGATGTTGGAAAGTATATAGAGAATTGTGGAATGGGAGGCTTCTTTTTGACACTAAAATATGCATTAGGAACTAGATGGCCCACACTTGCTTTAGCTGCATTTTCAGGAGAGCTAACAAAGCTAAAGTCCCTCATGGCATTATACCAGACCCTTGGTGAGCAGGCCCGATATTTGGCCCTATTGGAGTCACCACATTTGATGGATTTTGCTGCAGCAAACTACCCACTGCTATATAGCTATGCTATGGGAATAGGCTATGTGTTAGATGTCAACATGAGGAACTACGCTTTCTCCAGATCATACATGAACAAGACATATTTCCAATTGGGAATGGAAACTGCAAGAAAACAACAGGGTGCAGTTGACATGAGGATGGCAGAAGATCTCGGTCTAACTCAAGCCGAACGCACCGAGATGGCAAATACACTTGCCAAATTGACCACAGCAAATCGAGGGGCAGACACCAGGGGAGGAGTCAACCCGTTCTCATCTGTCACTGGGACAACTCAGGTGCCCGCTGCAGCAACAGGTGACACACTCGAGAGTTACATGGCAGCGGATCGACTGAGGCAGAGATATGCTGATGCAGGCACCCATGATGATGAGATGCCACCATTGGAAGAGGAGGAAGAGGACGACACATCTGCAGGTCCACGCACTGGACCAACTCTTGAACAAGTGGCCTTGGACATCCAGAACGCAGCAGTTGGAGCTCCCATCCATACAGATGACCTGAATGCCGCACTGGGTGATCTTGACATCTAGACAATTCAGATCCCAATCTAAAATTGACATACCTAATTGATTAGTTAGATGGAACTACAGTGGATTCCATAAGGTTCCTGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACAAGCGACTGCCGGTGCCAACAGCGCAATCCACAATCTACAATGGATCCCACTGATCTGAGCTTCTCCCCAGATGAGATCAATAAGCTCATAGAGACAGGCCTGAATACTGTAGAGTATTTTACTTCCCAACAAGTCACAGGAACATCCTCTCTTGGAAAGAATACAATACCACCAGGGGTCACAGGACTACTAACCAATGCTGCAGAGGCAAAGATCCAAGAGTCAACTAACCATCAGAAGGGCTCAGTTGGTGGGGGTGCAAAACCAAAGAAACCGCGACCAAAAATTGCCATTGTGCCAGCAGATGACAAAACAGTGCCCGGAAAGCCGATCCCAAACCCTCTATTAGGTCTGGACTCCACCCCGAGCACCCAAACTGTGCTTGATCTAAGTGGGAAAACATTACCATCAGGATCCTATAAGGGGGTTAAGCTTGCGAAATTTGGAAAAGAAAATCTGATGACACGGTTCATCGAGGAACCCAGAGAGAATCCTATCGCAACCAGTTtCCCCATCGATTTTAAGAGGGGCAGGGATACCGGCGGGTTCCATAGAAGGGAGTACTCAATCGGATGGGTGGGAGATGAAGTCAAGGTCACTGAGTGGTGCAATCCATCCTGTTCTCCAATCACCGCTGCAGCAAGGCGATTTGAATGCACTTGTCACCAGTGTCCAGTCACTTGCTCTGAATGTGAACGAGATACTTAATACAGTGAGAAATTTGGACTCTCGGATGAATCAACTGGAGACAAAAGTAGATCGCATTCTCTCATCTCAGTCTCTAATCCAGACCATCAAGAATGACATAGTTGGACTTAAAGCAGGGATGGCTACTTTAGAAGGAATGATTACAACTGTGAAAATCATGGACCCGGGAGTTCCCAGTAATGTTACTGTGGAAGATGTACGCAAGACACTAAGTAACCATGCTGTTGTTGTGCCAGAATCATTCAATGATAGTTTCTTGACTCAATCTGAAGATGTAATTTCACTTGATGAGTTGGCTCGACCAACTGCAACAAGTGTTAAGAAGATTGTCAGGAAGGTTCCTCCTCAGAAGGATCTGACTGGATTGAAGATTACACTAGAGCAATTGGCAAAGGATTGCATCAGCAAACCGAAGATGAGGGAAGAGTATCTCCTCAAAATCAACCAGGCTTCCAGTGAGGCTCAGCTAATTGACCTCAAGAAAGCAATCATCCGCAGTGCAATTTGATCAAGAAACACCCAATTACACTACACTGGTATGACACTGTACTAACCCTGAGGGTTTTAGAAAAAACGATTAACGATAAATAAGCCCGAACACTACACACTACCTGAGGCAGCCATGCCATCCATCAGCATTCCCGCAGACCCCACCAATCCACGTCAATCAATAAAAGCGTTCCCAATTGTGATCAACAGTGATGGGGGTGAGAAAGGCCGCTTGGTTAAACAACTACGCACAACCTACTTGAATGACCTAGATACTCATGAGCCACTGGTGACATTCATAAATACCTATGGATTCATCTACGAACAGGATCGGGGGAATACCATTGTCGGAGAGGATCAACTTGGGAAGAAAAGAGAGGCTGTGACCGCTGCAATGGTTACCCTTGGATGTGGGCCTAATCTACCATCATTAGGGAATGTCCTGGGACAACTGAGGGAATTCCAGGTCACTGTTAGGAAGACATCCAGCAAAGCGGAAGAGATGGTCTTTGAAATTGTTAAGTATCCGAGAATATTTCGGGGTCATACATTAATCCAGAAAGGACTAGTCTGTGTCTCCGCAGAAAAATTTGTTAAGTCACCAGGGAAAATACAATCTGGAATGGACTATCTCTTCATTCCGACATTTCTGTCAGTGACTTACTGTCCAGCTGCAATCAAATTTCAGGTACCTGGCCCCATGTTGAAAATGAGATCAAGATACACTCAGAGCTTACAACTTGAACTAATGATAAGAATCCTGTGTAAGCCCGATTCGCCACTTATGAAGGTCCATACCCCTGACAAGGAGGGAAGAGGATGTCTTGTATCAGTATGGCTGCATGTATGCAACATCTTCAAATCAGGAAACAAGAATGGCAGTGAGTGGCAGGAATACTGGATGAGAAAGTGTGCTAACATGCAACTTGAAGTGTCGATTGCAGATATGTGGGGACCAACTATCATAATTCATGCCAGAGGTCACATTCCCAAAAGTGCTAAGTTGTTTTTTGGAAAGGGTGGATGGAGCTGCCATCCACTTCACGAAGTTGTTCCAAGTGTCACTAAAACACTATGGTCCGTGGGCTGTGAGATTACAAAGGCGAAGGCAATAATACAAGAGAGTAGCATCTCTCTTCTCGTGGAGACTACTGACATCATAAGTCCAAAAGTCAAAATTTCATCTAAGCATCGCCGCTTTGGGAAATCAAATTGGGGTCTGTTCAAGAAAACTAAATCACTGCCTAACCTGACGGAGCTGGAATGACTGACCTCTAATCGAGACTACACCGCCGCAAACTATAGGTGGGTGGTACCTCAGTGATTAATCTTGTAAGCACTGATCGTAGGCTACAACACACTAATATTATCCAGATTAGAGAGCTTAATTAGCTCTGTATTAATAATAACACTACTATTCCAATAACTGGAATCACCAGCTTGATTTATCTCCAAAATGATTCAAAGAAAACAAATCATATTAAGACTATCCTAAGCACGAACCCATATCGTCCTTCAAATCATGGGTACTATAATTCAATTTCTGGTGGTCTCCTGTCTATTGGCAGGAGCAGGCAGCCTTGATCCAGCAGCCCTCATGCAAATCGGTGTCATTCCAACAAATGTCCGGCAACTTATGTATTATACTGAAGCTTCATCAGCATTCATTGTTGTGAAGTTAATGCCTACAATTGACTCGCCGATTAGTGGATGTAATATAACATCAATTTCAAGCTATAATGCAACAGTGACAAAACTCCTACAGCCGATCGGTGAGAATTTGGAGACGATTAGGAACCAGTTGATTCCAACTCGGAGGAGACGCCGGTTTGCAGGGGTGGTGATTGGATTAGCTGCATTAGGAGTAGCTACTGCCGCACAGGTCACTGCCGCAGTGGCACTAGTAAAGGCAAATGAAAATGCTGCGGCTATACTCAATCTCAAAAATGCAATCCAAAAAACAAATGCAGCAGTTGCAGATGTGGTCCAGGCCACACAATCACTAGGAACGGCAGTTCAAGCAGTTCAAGATCACATAAACAGTGTGGTAAGTCCAGCAATTACAGCAGCCAATTGTAAGGCCCAAGATGCTATCATTGGCTCAATCCTCAATCTCTATTTGACCGAGTTGACAACCATCTTCCACAATCAAATTACAAACCCTGCATTGAGTCCCATTACAATTCAAGCTTTAAGGATCCTACTGGGGAGTACCTTGCCGACTGTGGTCGAAAAATCTTTCAATACCCAGATAAGTGCAGCTGAGCTTCTCTCATCAGGGTTATTGACAGGCCAGATTGTGGGATTAGATTTGACCTATATGCAGATGGTCATAAAAATTGAGCTGCCAACTTTAACTGTACAACCTGCAACCCAGATCATAGATCTGGCCACCATTTCTGCATTCATTAACAATCAAGAAGTCATGGCCCAATTACCAACACGTGTTATGGTGACTGGCAGCTTGATCCAAGCCTATCCCGCATCGCAATGCACCATTACACCCAACACTGTGTACTGTAGGTATAATGATGCCCAAGTACTCTCAGATGATACTATGGCTTGCCTCCAAGGTAACTTGACAAGATGCACCTTCTCTCCAGTGGTTGGGAGCTTTCTCACTCGATTCGTGCTGTTCGATGGAATAGTTTATGCAAATTGCAGGTCGATGTTGTGCAAGTGCATGCAACCTGCTGCTGTGATCCTACAGCCGAGTTCATCCCCTGTAACTGTCATTGACATGTACAAATGTGTGAGTCTGCAGCTTGACAATCTCAGATTCACCATCACTCAATTGGCCAATGTAACCTACAATAGCACCATCAAGCTTGAATCATCCCAGATCTTGTCTATTGATCCGTTGGATATATCCCAGAATCTAGCTGCGGTGAATAAGAGTCTAAGTGATGCACTACAACACTTAGCACAAAGTGACACATATCTTTCTGCAATCACATCAGCTACGACTACAAGTGTATTATCCATAATAGCAATCTGTCTTGGATCGTTAGGTTTAATATTAATAATCTTGCTCAGTGTAGTTGTGTGGAAGTTATTGACCATTGTCGTTGCTAATCGAAATAGAATGGAGAATTTTGTTTATCATAAATAAGCATTCCACCACTCACGATCTGATCTCAGTGAGAAAAATCAACCTGCAACTCTTGGAACAAGATAAGACAGTCATCCATTAGTAATTTTTAAGAAAAAAACGATAGGACCGAACCTAGTATTGAAAGAACCGTCTCGGTCAATCTAGGTAATCGAGCTGATACCGTCTCGGAAAGCTCAAATCCTGCTATAGGCTATCCACTGCATCATCTCTCCTGCCATACTTCCTACTCACATCATATCTATTTTAAAGAAAAAATAGGCCCGAACACTAATCGTGCCGGCAGTGCCACTGCACACACAACACTACACATACAATACACTACAATGGTTGCAGAAGATGCCCCTGTTAGGGCCACTTGCCGAGTATTATTTCGAACAACAACTTTAATCTTTCTATGCACACTACTAGCATTAAGCATCTCTATCCTTTATGAGAGTTTAATAACCCAAAAGCAAATCATGAGCCAAGCAGGCTCAACTGGATCTAATTCTGGATTAGGAAGTATCACTGATCTTCTTAATAATATTCTCTCTGTCGCAAATCAGATTATATATAACTCTGCAGTCGCTCTACCTCTACAATTGGACACTCTTGAATCAACACTCCTTACAGCCATTAAGTCTCTTCAAACCAGTGACAAGCTAGAACAGAACTGCTCGTGGAGTGCTGCACTGATTAATGATAATAGATACATTAATGGCATCAATCAGTTCTATTTTTCAATTGCTGAGGGTCGCAATCTGACACTTGGCCCACTTCTTAATATGCCTAGTTTCATTCCAACTGCCACGACACCAGAGGGCTGCACCAGGATCCCATCATTCTCGCTCACTAAGACACACTGGTGTTATACACACAATGTTATCCTGAATGGATGCCAGGATCATGTATCCTCAAATCAATTTGTTTCTATGGGAATCATTGAACCCACTTCTGCCGGGTTTCCATTCTTTCGAACCCTAAAGACTCTATATCTCAGCGATGGGGTCAATCGTAAGAGCTGCTCTATCAGTACAGTTCCGGGGGGTTGTATGATGTACTGTTTTGTTTCTACTCAACCAGAGAGGGATGACTACTTTTCTGCCGCTCCTCCAGAACAACGAATTATTATAATGTACTATAATGATACAATCGTGGAGCGCATAATTAATCC ACCCGGGGTACTAGATGTATGGGCAACATTGAACCCAGGAACAGGAAGCGG GGTATATTATTTAGGTTGGGTGCTCTTTCCAATATATGGCGGCGTGATTAAAG GTACGAGTTTATGGAATAATCAAGCAAATAAATACTTTATCCCCCAGATGGTT GCTGCTCTCTGCTCACAAAACCAGGCAACTCAAGTCCAAAATGCTAAGTCATC ATACTATAGCAGCTGGTTTGGCAATCGAATGATTCAGTCTGGGATCCTGGCAT GTCCTCTTCGACAGGATCTAACCAATGAGTGTTTAGTTCTGCCCTTTTCTAATG ATCAGGTGCTTATGGGTGCTGAAGGGAGATTATACATGTATGGTGACTCGGT GTATTACTATCAAAGAAGCAATAGTTGGTGGCCTATGACCATGCTGTATAAG GTAACCATAACATTCACTAATGGTCAGCCATCTGCTATATCAGCTCAGAATGT GCCCACACAGCAGGTCCCTAGACCTGGGACAGGAGACTGCTCTGCAACCAAT AGATGTCCCGGTTTTTGCTTGACAGGAGTGTATGCCGATGCCTGGTTACTGAC CAACCCTTCGTCTACCAGTACATTTGGATCAGAAGCAACCTTCACTGGTTCTT ATCTCAACACAGCAACTCAGCGTATCAATCCGACGATGTATATCGCGAACAA CACACAGATCATAAGCTCACAGCAATTTGGATCAAGCGGTCAAGAAGCAGCA TATGGCCACACAACTTGTTTTAGGGACACAGGCTCTGTTATGGTATACTGTAT CTATATTATTGAATTGTCCTCATCTCTCTTAGGACAATTTCAGATTGTCCCATTTATCCGTCAGGTGACACTATCCTAAAGGCAGAAGCCTTCAGGTCTGACCCAG CCAATCAAAGCATTATACCAGACCATGGCCTACCATCGGCTTTAAAGAAAAA AATAGGCCCGGACGGGTTAGCAACAAGCGGCGGCCGCCatgttcgtcttcctggtcctgctg cctctggtctcctcacagtgcgtcaatctgacaactcggactcagctgccacctgcttatactaatagcttcaccagaggcgtgtac tatcctgacaaggtgtttagaagctccgtgctgcactctacacaggatctgtttctgccattctttagcaacgtgacctggttccacgc catccacgtgagcggcaccaatggcacaaagcggttcgacaatcccgtgctgccttttaacgatggcgtgtacttcgcctctacc gagaagagcaacatcatcagaggctggatctttggcaccacactggactccaagacacagtctctgctgatcgtgaacaatgcc accaacgtggtcatcaaggtgtgcgagttccagttttgtaatgatcccttcctgggcgtgtactatcacaagaacaataagagctgg atggagtccgagtttagagtgtattctagcgccaacaactgcacatttgagtacgtgagccagcctttcctgatggacctggaggg caagcagggcaatttcaagaacctgagggagttcgtgtttaagaatatcgacggctacttcaaaatctactctaagcacaccccca tcaacctggtgcgcgacctgcctcagggcttcagcgccctggagcccctggtggatctgcctatcggcatcaacatcacccggtt tcagacactgctggccctgcacagaagctacctgacacccggcgactcctctagcggatggaccgccggcgctgccgcctact atgtgggctacctccagccccggaccttcctgctgaagtacaacgagaatggcaccatcacagacgcagtggattgcgccctgg accccctgagcgagacaaagtgtacactgaagtcctttaccgtggagaagggcatctatcagacatccaatttcagggtgcagcc aaccgagtctatcgtgcgctttcctaatatcacaaacctgtgcccatttggcgaggtgttcaacgcaacccgcttcgccagcgtgta cgcctggaataggaagcggatcagcaactgcgtggccgactatagcgtgctgtacaactccgcctctttcagcacctttaagtgct atggcgtgtcccccacaaagctgaatgacctgtgctttaccaacgtctacgccgattctttcgtgatcaggggcgacgaggtgcgccagatcgcccccggccagacaggcaagatcgcagactacaattataagctgccagacgatttcaccggctgcgtgatcgcct ggaacagcaacaatctggattccaaagtgggcggcaactacaattatctgtaccggctgtttagaaagagcaatctgaagccctt cgagagggacatctctacagaaatctaccaggccggcagcaccccttgcaatggcgtggagggctttaactgttatttcccactc cagtcctacggcttccagcccacaaacggcgtgggctatcagccttaccgcgtggtggtgctgagctttgagctgctgcacgcc ccagcaacagtgtgcggccccaagaagtccaccaatctggtgaagaacaagtgcgtgaacttcaacttcaacggcctgaccgg cacaggcgtgctgaccgagtccaacaagaagttcctgccatttcagcagttcggcagggacatcgcagataccacagacgccg tgcgcgacccacagaccctggagatcctggacatcacaccctgctctttcggcggcgtgagcgtgatcacacccggcaccaat acaagcaaccaggtggccgtgctgtatcaggacgtgaattgtaccgaggtgcccgtggctatccacgccgatcagctgacccc aacatggcgggtgtacagcaccggctccaacgtcttccagacaagagccggatgcctgatcggagcagagcacgtgaacaatt cctatgagtgcgacatcccaatcggcgccggcatctgtgcctcttaccagacccagacaaactctcccagaagagcccggagc gtggcctcccagtctatcatcgcctataccatgtccctgggcgccgagaacagcgtggcctactctaacaatagcatcgccatcc caaccaacttcacaatctctgtgaccacagagatcctgcccgtgtccatgaccaagacatctgtggactgcacaatgtatatctgtg gcgattctaccgagtgcagcaacctgctgctccagtacggcagcttttgtacccagctgaatagagccctgacaggcatcgccgt ggagcaggataagaacacacaggaggtgttcgcccaggtgaagcaaatctacaagaccccccctatcaaggactttggcggct tcaatttttcccagatcctgcctgatccatccaagccttctaagcggagctttatcgaggacctgctgttcaacaaggtgaccctggc cgatgccggcttcatcaagcagtatggcgattgcctgggcgacatcgcagccagggacctgatctgcgcccagaagtttaatgg cctgaccgtgctgccacccctgctgacagatgagatgatcgcacagtacacaagcgccctgctggccggcaccatcacatccg gatggaccttcggcgcaggagccgccctccagatcccctttgccatgcagatggcctataggttcaacggcatcggcgtgaccc agaatgtgctgtacgagaaccagaagctgatcgccaatcagtttaactccgccatcggcaagatccaggacagcctgtcctctac agccagcgccctgggcaagctccaggatgtggtgaatcagaacgcccaggccctgaataccctggtgaagcagctgagcagc aacttcggcgccatctctagcgtgctgaatgacatcctgagccggctggacaaggtggaggcagaggtgcagatcgaccggct gatcaccggccggctccagagcctccagacctatgtgacacagcagctgatcagggccgccgagatcagggccagcgccaat ctggcagcaaccaagatgtccgagtgcgtgctgggccagtctaagagagtggacttttgtggcaagggctatcacctgatgtcct tccctcagtctgccccacacggcgtggtgtttctgcacgtgacctacgtgcccgcccaggagaagaacttcaccacagcccctg ccatctgccacgatggcaaggcccactttccaagggagggcgtgttcgtgtccaacggcacccactggtttgtgacacagcgca atttctacgagccccagatcatcaccacagacaacaccttcgtgagcggcaactgtgacgtggtcatcggcatcgtgaacaatac cgtgtatgatccactccagcccgagctggacagctttaaggaggagctggataagtatttcaagaatcacacctcccctgacgtg gatctgggcgacatcagcggcatcaatgcctccgtggtgaacatccagaaggagatcgaccgcctgaacgaggtggctaaga atctgaacgagagcctgatcgacctccaggagctgggcaagtatgagcagtacatcaagtggccctggtacatctggctgggct tcatcgccggcctgatcgccatcgtgatggtgaccatcatgctgtgctgtatgacatcctgctgttcttgcctgaagggctgctgta gctgtggctcctgctgtaagttattgaccattgtcgttgctaatcgaaatagaatggagaattttgtttatcataaatgaAGTCGACTCATGGAATGCATACCAAACATTATTGACACTAATGACACACAAAATTGGTT TTAAGAAAAACCAAGAGAACAATAGGCCAGAATGGCTGGGTCTCGGGAGAT ATTACTCCCTGAAGTCCATCTCAATTCACCAATTGTAAAGCATAAGCTATACTATTACATTCTACTTGGAAACCTCCCAAATGAGATCGACCTTGACGATTTAGGTCCATTACATAATCAAAATTGGAATCAGATAGCACATGAAGAGTCTAACTTAGCTCAACGCTTGGTAAATGTAAGAAATTTTCTAATTACCCACATCCCTGATCTTAGAAAGGGCCATTGGCAAGAGTATGTCAATGTAATACTGTGGCCGCGAATTCTTCCCTTGATCCCGGATTTTAAAATCAATGACCAATTGCCTCTGCTCAAAAATTGGGACAAGTTAGTTAAAGAATCATGTTCAGTAATCAATGCAGGTACTTCCCAGTGCATTCAGAATCTCAGCTATGGACTGACAGGTCGTGGGAACCTCTTTACACGATCACGTGAACTCTCTGGTGACCGCAGGGATATTGATCTTAAGACAGTTGTGGCAGCATGGCATGACTCAGACTGGAAAAGAATAAGTGATTTTTGGATTATGATCAAATTCCAGATGAGACAATTAATTGTTAGGCAAACAGATCATAATGATTCTGATTTAATCACGTATATCGAAAATAGAGAAGGCATAATCATCATAACCCCTGAACTGGTAGCATTATTTAACACTGAGAATCATACACTAACATACATGACCTTTGAAATTGTACTGATGGTTTCAGATATGTACGAAGGTCGTCACAACATTTTATCACTATGCACAGTTAGCACTTACCTGAATCCTCTGAAGAAAAGAATAACATATTTATTGAGCCTTGTAGATAACTTAGCTTTTCAGATAGGTGATGCTGTATATAACATAATTGCTTTGCTAGAATCCTTTGTATATGCACAGTTGCAAATGTCAGATCCCATCCCAGAACTCAGAGGACAATTCCATGCATTCGTATGTTCTGAGATTCTTGATGCACTAAGAGGAACTAATAGTTTCACCCAGGATGAATTAAGAACTGTGACAACTAATTTGATATCCCCATTCCAAGATCTGACCCCAGATCTTACGGCTGAATTGCTCTGTATAATGAGGCTTTGGGGACACCCCATGCTCACTGCCAGTCAAGCTGCAGGAAAGGTACGCGAGTCTATGTGTGCTGGAAAAGTATTAGACTTTCCCACCATTATGAAAACACTAGCCTTTTTCCATACTATTCTGATCAATGGATACAGGAGGAAGCATCATGGAGTATGGCCACCCTTAAACTTACCGGGTAATGCTTCAAAGGGTCTCACGGAACTTATGAATGACAATACTGAAATAAGCTATGAATTCACACTTAAGCATTGGAAGGAAGTCTCTCTTATAAAATTCAAGAAATGTTTTGATGCAGACGCAGGTGAGGAACTCAGTATATTTATGAAAGATAAGGCAATTAGTGCCCCAAAACAAGACTGGATGAGTGTGTTTAGAAGAAGCCTAATCAAACAGCGCCATCAGCATCATCAGGTCCCCCTACCAAATCCATTCAATCGACGGCTGTTGCTAAACTTTCTCGGAGATGACAAATTCGACCCGAATGTGGAGCTACAGTATGTAACATCAGGTGAGTATCTACATGATGACACGTTTTGTGCATCATATTCACTAAAAGAGAAGGAAATTAAACCTGATGGTCGAATTTTTGCAAAGTTGACTAAGAGAATGAGATCATGTCAAGTTATAGCAGAATCTCTTTTAGCGAACCATGCTGGGAAGTTAATGAAAGAGAATGGTGTTGTGATGAATCAGCTATCATTAACAAAATCACTATTAACAATGAGTCAGATTGGAATAATATCCGAGAAAGCTAGAAAGTCAACTCGAGATAACATAAATCAACCTGGTTTCCAGAATATCCAGAGAAATAAATCACATCACTCCAAGCAAGTCAATCAGCGAGATCCAAGTGATGACTTTGAATTGGCAGCATCTTTTTTAACTACTGATCTCAAAAAATATTGTTTACAATGGAGGTACCAGACAATTATCCCATTTGCTCAATCATTAAACAGAATGTATGGTTATCCTCATCTCTTTGAGTGGATTCACTTACGGCTAATGCGTAGTACACTTTACGTGGGGGATCCCTTCAACCCACCAGCAGATACCAGTCAATTTGATCTAGATAAAGTAATTAATGGAGATATCTTCATTGTATCACCCAGAGGTGGAATTGAAGGGCTGTGTCAAAAGGCTTGGACAATGATATCTATCGCTGTGATAATTCTATCTGCCACAGAGTCTGGCACACGAGTAATGAGTATGGTGCAGGGAGATAATCAAGCAATTGCTGTCACCACACGAGTACCAAGGAGCCTGCCGACTCTTGAGAAAAAGACTATTGCTTTTAGATCTTGTAATCTATTCTTTGAGAGGTTAAAATGTAATAATTTTGGATTAGGTCACCATTTGAAAGAACAAGAGACTATCATTAGTTCTCACTTCTTTGTTTATAGCAAGAGAATATTCTATCAGGGGAGGATTCTAACGCAAGCCTTAAAAAATGCTAGTAAGCTCTGCTTGACAGCTGATGTCCTAGGAGAATGCACCCAATCATCATGTTCTAATCTTGCAACTACTGTCATGAGGTTAACTGAGAATGGTGTTGAAAAAGATATCTGTTTCTACTTGAATATCTATATGACCATCAAACAGCTCTCCTATGATATCATCTTCCCTCAAGTGTCAATTCCTGGAGATCAGATCACATTAGAATACATAAATAATCCACACCTGGTATCACGATTGGCTCTTTTGCCATCCCAGTTAGGAGGTCTAAACTACCTGTCATGCAGTAGGCTGTTCAATCGAAACATAGGCGACCCGGTGGTTTCCGCAGTTGCAGATCTTAAGAGATTAATTAAATCAGGATGTATGGATTACTGGATCCTTTATAACTTATTAGGGAGAAAACCGGGAAACGGCTCATGGGCTACTTTAGCAGCTGACCCGTACTCAATCAATATAGAGTATCAATACCCTCCAACTACAGCTCTTAAGAGGCACACCCAACAAGCTCTGATGGAACTCAGTACGAATCCAATGTTACGTGGCATATTCTCTGACAATGCACAGGCAGAAGAAAATAACCTTGCTAGGTTTCTCCTGGATAGGGAGGTGATCTTTCCGCGTGTAGCTCACATCATCATTGAGCAAACCAGTGTCGGGAGGAGAAAACAGATTCAAGGATATTTGGATTCAACTAGATCGATAATGAGGAAATCACTAGAAATTAAGCCCTTATCCAATAGGAAGCTTAATGAAATACTGGATTACAACATCAATTACCTAGCTTACAATTTGGCATTACTCAAGAATGCTATTGAACCTCCGACTTATTTGAAGGCAATGACACTTGAAACATGTAGCATCGACATTGCAAGGAACCTCCGGAAGCTCTCCTGGGCCCCACTCTTGGGTGGGAGAAATCTTGAAGGATTAGAGACGCCAGATCCCATTGAAATTACTGCAGGAGCATTAATTGTTGGATCGGGCTACTGTGAACAGTGTGCTGCAGGAGACAATCGATTCACATGGTTTTTCTTGCCATCTGGTATCGAGATAGGAGGGGATCCCCGTGATAATCCTCCTATCCGTGTACCGTACATTGGCTCCAGGACTGATGAGAGGAGGGTAGCCTCAATGGCATACATCAGGGGTGCCTCGAGTAGCTTAAAAGCAGTTCTTAGACTGGCGGGAGTGTACATCTGGGCATTCGGAGATACTCTGGAGAATTGGATAGATGCACTGGATTTGTCTCACACTAGAGTTAACATCACACTTGAACAGCTGCAATCCCTCACCCCACTTCCAACCTCTGCCAATCTAACCCATCGGTTGGATGATGGCACAACTACCCTAAAGTTTACTCCTGCGAGCTCTTACACCTTTTCAAGTTTCACTCATATATCAAATGATGAGCAATACCTGACAATTAATGACAAAACTGCAGATTCAAATATAATCTACCAACAGTTAATGATCACTGGACTCGGAATCTTAGAAACATGGAATAATCCCCCAATCAATAGAACATTCGAAGAATCTACCCTACATTTGCACACTGGTGCATCATGTTGTGTCCGACCTGTGGACTCCTGCATTCTCTCAGAAGCATTAACAGTCAAGCCACATATTACAGTACCGTACAGCAATAAATTTGTATTTGATGAGGACCCGCTATCTGAATATGAAACTGCAAAACTGGAATCGTTATCATTCCAAGCCCAATTAGGCAACATTGATGCTGTAGATATGACAGGTAAATTAACATTATTGTCCCAATTCACTGCAAGGCAGATTATCAATGCAATCACTGGACTCGATGAGTCTGTCTCTCTTACTAATGATGCCATTGTTGCATCAGACTATGTCTCCAATTGGATTAGTGAATGCATGTATACCAAATTAGATGAATTATTTATGTATTGTGGGTGGGAACTACTATTGGAACTATCCTATCAAATGTATTATCTGAGGGTAGTTGGGTGGAGTAATATAGTGGATTATTCTTACATGATCTTGAGAAGAATCCCGGGTGCAGCATTAAACAATCTGGCATCTACATTAAGTCATCCAAAACTTTTCCGACGAGCTATCAACCTAGATATAGTTGCCCCCTTAAATGCTCCTCATTTTGCATCTCTGGACTACATCAAGATGAGTGTGGATGCAATACTCTGGGGCTGTAAAAGAGTCATCAATGTGCTCTCCAATGGAGGGGACTTAGAATTAGTTGTGACATCTGAAGATAGCCTTATTCTCAGTGACCGATCCATGAATCTCATTGCAAGGAAATTAACTTTATTATCACTGATTCACCATAATGGTTTGGAACTACCAAAGATTAAGGGGTTCTCTCCTGATGAGAAGTGTTTCGCTTTGACAGAATTTTTGAGGAAAGTGGTGAACTCAGGGTTGAGTTCAATAGAGAACCTATCAAATTTTATGTACAATGTGGAGAACCCACGGCTTGCAGCATTCGCCAGCAACAATTACTACCTGACCAGAAAATTATTGAATTCAATACGAGATACTGAGTCGGGTCAAGTAGCAGTCACCTCATATTATGAATCATTAGAATATATTGATAGTCTTAAGCTAACCCCACATGTGCCTGGCACCTCATGCATTGAGGATGATAGTCTATGTACAAATGATTACATAATCTGGATCATAGAGTCTAATGCAAACTTGGAGAAGTATCCAATTCCAAATAGCCCTGAGGATGATTCCAATTTCCATAACTTTAAGTTGAATGCTCCATCGCACCATACCTTACGCCCATTAGGGTTGTCATCAACTGCTTGGTATAAGGGTATAAGCTGCTGCAGGTACCTTGAGCGATTAAAGCTACCACAAGGTGATCATTTATATATTGCAGAAGGTAGTGGTGCCAGTATGACAATCATAGAATACCTATTCCCAGGAAGAAAGATATATTACAATTCTTTATTTAGTAGTGGTGACAATCCCCCACAAAGAAATTATGCACCAATGCCTACTCAGTTCATTGAGAGTGTCCCATACAAGCTCTGGCAAGCACACACAGATCAATATCCCGAGATTTTTGAGGACTTCATCCCTCTATGGAACGGAAACGCCGCCATGACTGACATAGGAATGACAGCTTGTGTAGAATTCATCATCAATCGAGTCGGCCCAAGGACTTGCAGTTTAGTACATGTAGATTTGGAATCAAGTGCAAGCTTAAATCAACAATGCCTGTCAAAGCCGATAATTAATGCTATCATCACTGCTACAACTGTTTTGTGCCCTCATGGGGTGCTTATTCTGAAATATAGTTGGTTGCCATTTACTAGATTTAGTACTTTGATCACTTTCTTATGGTGCTACTTTGAGAGAATCACTGTTCTTAGGAGCACATATTCTGATCCAGCTAATCATGAGGTTTATTTAATTTGTATCCTTGCCAACAACTTTGCATTCCAGACTGTCTCGCAGGCAACAGGAATGGCGATGACTTTAACTGATCAAGGGTTTACTTTGATATCACCTGAAAGAATAAATCAGTATTGGGATGGTCACTTGAAGCAAGAACGTATCGTAGCAGAAGCAATTGATAAGGTGGTTCTAGGAGAAAATGCTCTATTTAATTCGAGTGATAATGAATTAATTCTCAAATGTGGAGGGACACCAAATGCACGGAATCTCATCGATATCGAGCCAGTCGCAACTTTCATAGAATTTGAACAATTGATCTGCACAATGTTGACAACCCACTTGAAGGAAATAATTGATATAACAAGGTCTGGAACCCAGGATTATGAAAGTTTATTACTCACTCCTTACAATTTAGGTCTTCTTGGTAAAATCAGTACGATAGTGAGATTATTAACAGAAAGGATTCTAAATCATACTATCAGGAATTGGTTGATCCTCCCACCTTCGCTCCGGATGATCGTGAAGCAGGACTTGGAATTCGGCATATTCAGGATTACTTCCATCCTCAATTCTGATCGGTTCCTGAAGCTTTCTCCAAATAGGAAATACTTGATTGCACAATTAACTGCAGGCTACATTAGGAAATTGATTGAGGGGGATTGCAATATCGATCTAACCAGACCTATCCAAAAGCAAATCTGGAAAGCATTAGGTTGTGTAGTCTATTGTCACGATCCAATGGATCAAAGGGAGTCAACAGAGTTTATTGATATAAATATTAATGAAGAAATAGACCGCGGGATCGATGGCGAGGAAATCTAAACATATCAAGAATCAGAATTAGTTTAAGAAAAAAGAAGAGGATTAATCTTGGTTTTCCCCTTGGTGGGTCGGCATGGCATCTCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCACTCGGATGGCTAAGGGAGCGGCCGGGGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAGTTGGCTGCTGCCACCGCTGAGCAATAACTAGCATAACCCCTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTGCTGAAAGGAGGAACTATATCCGGATCATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGT (SEQ ID NO: 3).ii. CVL87
[0162] The nucleic acid sequence for CVL87 is:GCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCTAATACGACTCACTATAGGGACCAAGGGGAAAATGAAGTGGTGACTCAAATCATCGAAGACCCTCGAGATTACATAGGTCCGGAACCTATGGCCTTCGTGACCGACCTCGAGTCAGAGTAGTTCAATAAGGACCTATCAAGTTTGGGCAATTTTTCGTCCCCGACACAAAAATGTCATCCGTGCTTAAAGCATATGAGCGATTCACGCTCACTCAAGAACTGCAAGATCAGAGTGAGGAAGGTACAATCCCACCTACAACACTAAAACCGGTAATCAGGGTATTTATACTAACCTCTAATAACCCAGAGCTAAGATCCCGGCTTCTTCTATTCTGCCTACGGATTGTTCTCAGTAATGGTGCAAGGGATTCCCATCGCTTTGGAGCATTACTCACAATGTTTTCGCTACCATCAGCCACAATGCTCAATCATGTCAAATTAGCTGACCAGTCACCAGAAGCTGATATCGAAAGGGTAGAGATCGATGGCTTTGAGGAGGGATCATTCCGCTTAATCCCCAATGCTCGTTCAGGTATGAGCCGTGGAGAGATCAATGCCTATGCTGCACTTGCAGAAGATCTACCTGACACACTAAACCATGCAACACCTTTCGTTGATTCCGAAGTCGAGGGAACTGCATGGGATGAGATTGAGACTTTCTTAGATATGTGTTACAGTGTCCTAATGCAGGCATGGATAGTGACTTGCAAGTGCATGACTGCGCCAGACCAACCTGCTGCTTCTATTGAGAAACGCCTGCAAAAATATCGTCAGCAAGGCAGGATCAACCCGAGATATCTCCTGCAACCGGAGGCTCGACGAATAATCCAGAATGTAATCCGGAAGGGAATGGTGGTCAGACATTTCCTCACCTTTGAACTGCAGCTTGCCCGAGCACAAAGCCTTGTATCAAATAGGTATTATGCTATGGTAGGGGATGTTGGAAAGTATATAGAGAATTGTGGAATGGGAGGCTTCTTTTTGACACTAAAATATGCATTAGGAACTAGATGGCCCACACTTGCTTTAGCTGCATTTTCAGGAGAGCTAACAAAGCTAAAGTCCCTCATGGCATTATACCAGACCCTTGGTGAGCAGGCCCGATATTTGGCCCTATTGGAGTCACCACATTTGATGGATTTTGCTGCAGCAAACTACCCACTGCTATATAGCTATGCTATGGGAATAGGCTATGTGTTAGATGTCAACATGAGGAACTACGCTTTCTCCAGATCATACATGAACAAGACATATTTCCAATTGGGAATGGAAACTGCAAGAAAACAACAGGGTGCAGTTGACATGAGGATGGCAGAAGATCTCGGTCTAACTCAAGCCGAACGCACCGAGATGGCAAATACACTTGCCAAATTGACCACAGCAAATCGAGGGGCAGACACCAGGGGAGGAGTCAACCCGTTCTCATCTGTCACTGGGACAACTCAGGTGCCCGCTGCAGCAACAGGTGACACACTCGAGAGTTACATGGCAGCGGATCGACTGAGGCAGAGATATGCTGATGCAGGCACCCATGATGATGAGATGCCACCATTGGAAGAGGAGGAAGAGGACGACACATCTGCAGGTCCACGCACTGGACCAACTCTTGAACAAGTGGCCTTGGACATCCAGAACGCAGCAGTTGGAGCTCCCATCCATACAGATGACCTGAATGCCGCACTGGGTGATCTTGACATCTAGACAATTCAGATCCCAATCTAAAATTGACATACCTAATTGATTAGTTAGATGGAACTACAGTGGATTCCATAAGGTTCCTGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACAAGCGACTGCCGGTGCCAACAGCGCAATCCACAATCTACAATGGATCCCACTGATCTGAGCTTCTCCCCAGATGAGATCAATAAGCTCATAGAGACAGGCCTGAATACTGTAGAGTATTTTACTTCCCAACAAGTCACAGGAACATCCTCTCTTGGAAAGAATACAATACCACCAGGGGTCACAGGACTACTAACCAATGCTGCAGAGGCAAAGATCCAAGAGTCAACTAACCATCAGAAGGGCTCAGTTGGTGGGGGTGCAAAACCAAAGAAACCGCGACCAAAAATTGCCATTGTGCCAGCAGATGACAAAACAGTGCCCGGAAAGCCGATCCCAAACCCTCTATTAGGTCTGGACTCCACCCCGAGCACCCAAACTGTGCTTGATCTAAGTGGGAAAACATTACCATCAGGATCCTATAAGGGGGTTAAGCTTGCGAAATTTGGAAAAGAAAATCTGATGACACGGTTCATCGAGGAACCCAGAGAGAATCCTATCGCAACCAGTTtCCCCATCGATTTTAAGAGGGGCAGGGATACCGGCGGGTTCCATAGAAGGGAGTACTCAATCGGATGGGTGGGAGATGAAGTCAAGGTCACTGAGTGGTGCAATCCATCCTGTTCTCCAATCACCGCTGCAGCAAGGCGATTTGAATGCACTTGTCACCAGTGTCCAGTCACTTGCTCTGAATGTGAACGAGATACTTAATACAGTGAGAAATTTGGACTCTCGGATGAATCAACTGGAGACAAAAGTAGATCGCATTCTCTCATCTCAGTCTCTAATCCAGACCATCAAGAATGACATAGTTGGACTTAAAGCAGGGATGGCTACTTTAGAAGGAATGATTACAACTGTGAAAATCATGGACCCGGGAGTTCCCAGTAATGTTACTGTGGAAGATGTACGCAAGACACTAAGTAACCATGCTGTTGTTGTGCCAGAATCATTCAATGATAGTTTCTTGACTCAATCTGAAGATGTAATTTCACTTGATGAGTTGGCTCGACCAACTGCAACAAGTGTTAAGAAGATTGTCAGGAAGGTTCCTCCTCAGAAGGATCTGACTGGATTGAAGATTACACTAGAGCAATTGGCAAAGGATTGCATCAGCAAACCGAAGATGAGGGAAGAGTATCTCCTCAAAATCAACCAGGCTTCCAGTGAGGCTCAGCTAATTGACCTCAAGAAAGCAATCATCCGCAGTGCAATTTGATCAAGAAACACCCAATTACACTACACTGGTATGACACTGTACTAACCCTGAGGGTTTTAGAAAAAACGATTAACGATAAATAAGCCCGAACACTACACACTACCTGAGGCAGCCATGCCATCCATCAGCATTCCCGCAGACCCCACCAATCCACGTCAATCAATAAAAGCGTTCCCAATTGTGATCAACAGTGATGGGGGTGAGAAAGGCCGCTTGGTTAAACAACTACGCACAACCTACTTGAATGACCTAGATACTCATGAGCCACTGGTGACATTCATAAATACCTATGGATTCATCTACGAACAGGATCGGGGGAATACCATTGTCGGAGAGGATCAACTTGGGAAGAAAAGAGAGGCTGTGACCGCTGCAATGGTTACCCTTGGATGTGGGCCTAATCTACCATCATTAGGGAATGTCCTGGGACAACTGAGGGAATTCCAGGTCACTGTTAGGAAGACATCCAGCAAAGCGGAAGAGATGGTCTTTGAAATTGTTAAGTATCCGAGAATATTTCGGGGTCATACATTAATCCAGAAAGGACTAGTCTGTGTCTCCGCAGAAAAATTTGTTAAGTCACCAGGGAAAATACAATCTGGAATGGACTATCTCTTCATTCCGACATTTCTGTCAGTGACTTACTGTCCAGCTGCAATCAAATTTCAGGTACCTGGCCCCATGTTGAAAATGAGATCAAGATACACTCAGAGCTTACAACTTGAACTAATGATAAGAATCCTGTGTAAGCCCGATTCGCCACTTATGAAGGTCCATACCCCTGACAAGGAGGGAAGAGGATGTCTTGTATCAGTATGGCTGCATGTATGCAACATCTTCAAATCAGGAAACAAGAATGGCAGTGAGTGGCAGGAATACTGGATGAGAAAGTGTGCTAACATGCAACTTGAAGTGTCGATTGCAGATATGTGGGGACCAACTATCATAATTCATGCCAGAGGTCACATTCCCAAAAGTGCTAAGTTGTTTTTTGGAAAGGGTGGATGGAGCTGCCATCCACTTCACGAAGTTGTTCCAAGTGTCACTAAAACACTATGGTCCGTGGGCTGTGAGATTACAAAGGCGAAGGCAATAATACAAGAGAGTAGCATCTCTCTTCTCGTGGAGACTACTGACATCATAAGTCCAAAAGTCAAAATTTCATCTAAGCATCGCCGCTTTGGGAAATCAAATTGGGGTCTGTTCAAGAAAACTAAATCACTGCCTAACCTGACGGAGCTGGAATGACTGACCTCTAATCGAGACTACACCGCCGCAAACTATAGGTGGGTGGTACCTCAGTGATTAATCTTGTAAGCACTGATCGTAGGCTACAACACACTAATATTATCCAGATTAGAGAGCTTAATTAGCTCTGTATTAATAATAACACTACTATTCCAATAACTGGAATCACCAGCTTGATTTATCTCCAAAATGATTCAAAGAAAACAAATCATATTAAGACTATCCTAAGCACGAACCCATATCGTCCTTCAAATCATGGGTACTATAATTCAATTTCTGGTGGTCTCCTGTCTATTGGCAGGAGCAGGCAGCCTTGATCCAGCAGCCCTCATGCAAATCGGTGTCATTCCAACAAATGTCCGGCAACTTATGTATTATACTGAAGCTTCATCAGCATTCATTGTTGTGAAGTTAATGCCTACAATTGACTCGCCGATTAGTGGATGTAATATAACATCAATTTCAAGCTATAATGCAACAGTGACAAAACTCCTACAGCCGATCGGTGAGAATTTGGAGACGATTAGGAACCAGTTGATTCCAACTCGGAGGAGACGCCGGTTTGCAGGGGTGGTGATTGGATTAGCTGCATTAGGAGTAGCTACTGCCGCACAGGTCACTGCCGCAGTGGCACTAGTAAAGGCAAATGAAAATGCTGCGGCTATACTCAATCTCAAAAATGCAATCCAAAAAACAAATGCAGCAGTTGCAGATGTGGTCCAGGCCACACAATCACTAGGAACGGCAGTTCAAGCAGTTCAAGATCACATAAACAGTGTGGTAAGTCCAGCAATTACAGCAGCCAATTGTAAGGCCCAAGATGCTATCATTGGCTCAATCCTCAATCTCTATTTGACCGAGTTGACAACCATCTTCCACAATCAAATTACAAACCCTGCATTGAGTCCCATTACAATTCAAGCTTTAAGGATCCTACTGGGGAGTACCTTGCCGACTGTGGTCGAAAAATCTTTCAATACCCAGATAAGTGCAGCTGAGCTTCTCTCATCAGGGTTATTGACAGGCCAGATTGTGGGATTAGATTTGACCTATATGCAGATGGTCATAAAAATTGAGCTGCCAACTTTAACTGTACAACCTGCAACCCAGATCATAGATCTGGCCACCATTTCTGCATTCATTAACAATCAAGAAGTCATGGCCCAATTACCAACACGTGTTATGGTGACTGGCAGCTTGATCCAAGCCTATCCCGCATCGCAATGCACCATTACACCCAACACTGTGTACTGTAGGTATAATGATGCCCAAGTACTCTCAGATGATACTATGGCTTGCCTCCAAGGTAACTTGACAAGATGCACCTTCTCTCCAGTGGTTGGGAGCTTTCTCACTCGATTCGTGCTGTTCGATGGAATAGTTTATGCAAATTGCAGGTCGATGTTGTGCAAGTGCATGCAACCTGCTGCTGTGATCCTACAGCCGAGTTCATCCCCTGTAACTGTCATTGACATGTACAAATGTGTGAGTCTGCAGCTTGACAATCTCAGATTCACCATCACTCAATTGGCCAATGTAACCTACAATAGCACCATCAAGCTTGAATCATCCCAGATCTTGTCTATTGATCCGTTGGATATATCCCAGAATCTAGCTGCGGTGAATAAGAGTCTAAGTGATGCACTACAACACTTAGCACAAAGTGACACATATCTTTCTGCAATCACATCAGCTACGACTACAAGTGTATTATCCATAATAGCAATCTGTCTTGGATCGTTAGGTTTAATATTAATAATCTTGCTCAGTGTAGTTGTGTGGAAGTTATTGACCATTGTCGTTGCTAATCGAAATAGAATGGAGAATTTTGTTTATCATAAATAAGCATTCCACCACTCACGATCTGATCTCAGTGAGAAAAATCAACCTGCAACTCTTGGAACAAGATAAGACAGTCATCCATTAGTAATTTTTAAGAAAAAAACGATAGGACCGAACCTAGTATTGAAAGAACCGTCTCGGTCAATCTAGGTAATCGAGCTGATACCGTCTCGGAAAGCTCAAATATGGTTGCAGAAGATGCCCCTGTTAGGGCCACTTGCCGAGTATTATTTCGAACAACAACTTTAATCTTTCTATGCACACTACTAGCATTAAGCATCTCTATCCTTTATGAGAGTTTAATAACCCAAAAGCAAATCATGAGCCAAGCAGGCTCAACTGGATCTAATTCTGGATTAGGAAGTATCACTGATCTTCTTAATAATATTCTCTCTGTCGCAAATCAGATTATATATAACTCTGCAGTCGCTCTACCTCTACAATTGGACACTCTTGAATCAACACTCCTTACAGCCATTAAGTCTCTTCAAACCAGTGACAAGCTAGAACAGAACTGCTCGTGGAGTGCTGCACTGATTAATGATAATAGATACATTAATGGCATCAATCAGTTCTA TTTTTCAATTGCTGAGGGTCGCAATCTGACACTTGGCCCACTTCTTAATATGCC TAGTTTCATTCCAACTGCCACGACACCAGAGGGCTGCACCAGGATCCCATCAT TCTCGCTCACTAAGACACACTGGTGTTATACACACAATGTTATCCTGAATGGA TGCCAGGATCATGTATCCTCAAATCAATTTGTTTCTATGGGAATCATTGAACC CACTTCTGCCGGGTTTCCATTCTTTCGAACCCTAAAGACTCTATATCTCAGCG ATGGGGTCAATCGTAAGAGCTGCTCTATCAGTACAGTTCCGGGGGGTTGTATGATGTACTGTTTTGTTTCTACTCAACCAGAGAGGGATGACTACTTTTCTGCCGCT CCTCCAGAACAACGAATTATTATAATGTACTATAATGATACAATCGTGGAGC GCATAATTAATCCACCCGGGGTACTAGATGTATGGGCAACATTGAACCCAGG AACAGGAAGCGGGGTATATTATTTAGGTTGGGTGCTCTTTCCAATATATGGCG GCGTGATTAAAGGTACGAGTTTATGGAATAATCAAGCAAATAAATACTTTATCCCCCAGATGGTTGCTGCTCTCTGCTCACAAAACCAGGCAACTCAAGTCCAAAATGCTAAGTCATCATACTATAGCAGCTGGTTTGGCAATCGAATGATTCAGTCT GGGATCCTGGCATGTCCTCTTCGACAGGATCTAACCAATGAGTGTTTAGTTCTGCCCTTTTCTAATGATCAGGTGCTTATGGGTGCTGAAGGGAGATTATACATGT ATGGTGACTCGGTGTATTACTATCAAAGAAGCAATAGTTGGTGGCCTATGACCATGCTGTATAAGGTAACCATAACATTCACTAATGGTCAGCCATCTGCTATATC AGCTCAGAATGTGCCCACACAGCAGGTCCCTAGACCTGGGACAGGAGACTGCTCTGCAACCAATAGATGTCCCGGTTTTTGCTTGACAGGAGTGTATGCCGATGCCTGGTTACTGACCAACCCTTCGTCTACCAGTACATTTGGATCAGAAGCAACCTTCACTGGTTCTTATCTCAACACAGCAACTCAGCGTATCAATCCGACGATGTATATCGCGAACAACACACAGATCATAAGCTCACAGCAATTTGGATCAAGCGGTC AAGAAGCAGCATATGGCCACACAACTTGTTTTAGGGACACAGGCTCTGTTATGGTATACTGTATCTATATTATTGAATTGTCCTCATCTCTCTTAGGACAATTTCA GATTGTCCCATTTATCCGTCAGGTGACACTATCCTAAAGGCAGAAGCCTTCAG GTCTGACCCAGCCAATCAAAGCATTATACCAGACCATGGCCTACCATCGGCTT TAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACAAGCGGCGGCCGCCatgttc gtcttcctggtcctgctgcctctggtctcctcacagtgcgtcaatctgacaactcggactcagctgccacctgcttatactaatagctt caccagaggcgtgtactatcctgacaaggtgtttagaagctccgtgctgcactctacacaggatctgtttctgccattctttagcaac gtgacctggttccacgccatccacgtgagcggcaccaatggcacaaagcggttcgacaatcccgtgctgccttttaacgatggc gtgtacttcgcctctaccgagaagagcaacatcatcagaggctggatctttggcaccacactggactccaagacacagtctctgct gatcgtgaacaatgccaccaacgtggtcatcaaggtgtgcgagttccagttttgtaatgatcccttcctgggcgtgtactatcacaa gaacaataagagctggatggagtccgagtttagagtgtattctagcgccaacaactgcacatttgagtacgtgagccagcctttcctgatggacctggagggcaagcagggcaatttcaagaacctgagggagttcgtgtttaagaatatcgacggctacttcaaaatcta ctctaagcacacccccatcaacctggtgcgcgacctgcctcagggcttcagcgccctggagcccctggtggatctgcctatcgg catcaacatcacccggtttcagacactgctggccctgcacagaagctacctgacacccggcgactcctctagcggatggaccgc cggcgctgccgcctactatgtgggctacctccagccccggaccttcctgctgaagtacaacgagaatggcaccatcacagacg cagtggattgcgccctggaccccctgagcgagacaaagtgtacactgaagtcctttaccgtggagaagggcatctatcagacat ccaatttcagggtgcagccaaccgagtctatcgtgcgctttcctaatatcacaaacctgtgcccatttggcgaggtgttcaacgcaa cccgcttcgccagcgtgtacgcctggaataggaagcggatcagcaactgcgtggccgactatagcgtgctgtacaactccgcct ctttcagcacctttaagtgctatggcgtgtcccccacaaagctgaatgacctgtgctttaccaacgtctacgccgattctttcgtgatc aggggcgacgaggtgcgccagatcgcccccggccagacaggcaagatcgcagactacaattataagctgccagacgatttca ccggctgcgtgatcgcctggaacagcaacaatctggattccaaagtgggcggcaactacaattatctgtaccggctgtttagaaa gagcaatctgaagcccttcgagagggacatctctacagaaatctaccaggccggcagcaccccttgcaatggcgtggagggct ttaactgttatttcccactccagtcctacggcttccagcccacaaacggcgtgggctatcagccttaccgcgtggtggtgctgagct ttgagctgctgcacgccccagcaacagtgtgcggccccaagaagtccaccaatctggtgaagaacaagtgcgtgaacttcaact tcaacggcctgaccggcacaggcgtgctgaccgagtccaacaagaagttcctgccatttcagcagttcggcagggacatcgca gataccacagacgccgtgcgcgacccacagaccctggagatcctggacatcacaccctgctctttcggcggcgtgagcgtgat cacacccggcaccaatacaagcaaccaggtggccgtgctgtatcaggacgtgaattgtaccgaggtgcccgtggctatccacg ccgatcagctgaccccaacatggcgggtgtacagcaccggctccaacgtcttccagacaagagccggatgcctgatcggagc agagcacgtgaacaattcctatgagtgcgacatcccaatcggcgccggcatctgtgcctcttaccagacccagacaaactctccc agaagagcccggagcgtggcctcccagtctatcatcgcctataccatgtccctgggcgccgagaacagcgtggcctactctaac aatagcatcgccatcccaaccaacttcacaatctctgtgaccacagagatcctgcccgtgtccatgaccaagacatctgtggactg cacaatgtatatctgtggcgattctaccgagtgcagcaacctgctgctccagtacggcagcttttgtacccagctgaatagagccct gacaggcatcgccgtggagcaggataagaacacacaggaggtgttcgcccaggtgaagcaaatctacaagaccccccctatc aaggactttggcggcttcaatttttcccagatcctgcctgatccatccaagccttctaagcggagctttatcgaggacctgctgttca acaaggtgaccctggccgatgccggcttcatcaagcagtatggcgattgcctgggcgacatcgcagccagggacctgatctgc gcccagaagtttaatggcctgaccgtgctgccacccctgctgacagatgagatgatcgcacagtacacaagcgccctgctggcc ggcaccatcacatccggatggaccttcggcgcaggagccgccctccagatcccctttgccatgcagatggcctataggttcaac ggcatcggcgtgacccagaatgtgctgtacgagaaccagaagctgatcgccaatcagtttaactccgccatcggcaagatccag gacagcctgtcctctacagccagcgccctgggcaagctccaggatgtggtgaatcagaacgcccaggccctgaataccctggt gaagcagctgagcagcaacttcggcgccatctctagcgtgctgaatgacatcctgagccggctggacaaggtggaggcagag gtgcagatcgaccggctgatcaccggccggctccagagcctccagacctatgtgacacagcagctgatcagggccgccgaga tcagggccagcgccaatctggcagcaaccaagatgtccgagtgcgtgctgggccagtctaagagagtggacttttgtggcaag ggctatcacctgatgtccttccctcagtctgccccacacggcgtggtgtttctgcacgtgacctacgtgcccgcccaggagaaga acttcaccacagcccctgccatctgccacgatggcaaggcccactttccaagggagggcgtgttcgtgtccaacggcacccact ggtttgtgacacagcgcaatttctacgagccccagatcatcaccacagacaacaccttcgtgagcggcaactgtgacgtggtcatcggcatcgtgaacaataccgtgtatgatccactccagcccgagctggacagctttaaggaggagctggataagtatttcaagaat cacacctcccctgacgtggatctgggcgacatcagcggcatcaatgcctccgtggtgaacatccagaaggagatcgaccgcct gaacgaggtggctaagaatctgaacgagagcctgatcgacctccaggagctgggcaagtatgagcagtacatcaagtggccct ggtacatctggctgggcttcatcgccggcctgatcgccatcgtgatggtgaccatcatgctgtgctgtatgacatcctgctgttcttg cctgaagggctgctgtagctgtggctcctgctgtaagttattgaccattgtcgttgctaatcgaaatagaatggagaattttgtttatca taaatgaAGTCGACTCATGGAATGCATACCAAACATTATTGACACTAATGACACA CAAAATTGGTTTTAAGAAAAACCAAGAGAACAATAGGCCAGAATGGCTGGGT CTCGGGAGATATTACTCCCTGAAGTCCATCTCAATTCACCAATTGTAAAGCAT AAGCTATACTATTACATTCTACTTGGAAACCTCCCAAATGAGATCGACCTTGA CGATTTAGGTCCATTACATAATCAAAATTGGAATCAGATAGCACATGAAGAG TCTAACTTAGCTCAACGCTTGGTAAATGTAAGAAATTTTCTAATTACCCACAT CCCTGATCTTAGAAAGGGCCATTGGCAAGAGTATGTCAATGTAATACTGTGG CCGCGAATTCTTCCCTTGATCCCGGATTTTAAAATCAATGACCAATTGCCTCT GCTCAAAAATTGGGACAAGTTAGTTAAAGAATCATGTTCAGTAATCAATGCA GGTACTTCCCAGTGCATTCAGAATCTCAGCTATGGACTGACAGGTCGTGGGA ACCTCTTTACACGATCACGTGAACTCTCTGGTGACCGCAGGGATATTGATCTT AAGACAGTTGTGGCAGCATGGCATGACTCAGACTGGAAAAGAATAAGTGATT TTTGGATTATGATCAAATTCCAGATGAGACAATTAATTGTTAGGCAAACAGAT CATAATGATTCTGATTTAATCACGTATATCGAAAATAGAGAAGGCATAATCAT CATAACCCCTGAACTGGTAGCATTATTTAACACTGAGAATCATACACTAACAT ACATGACCTTTGAAATTGTACTGATGGTTTCAGATATGTACGAAGGTCGTCAC AACATTTTATCACTATGCACAGTTAGCACTTACCTGAATCCTCTGAAGAAAAG AATAACATATTTATTGAGCCTTGTAGATAACTTAGCTTTTCAGATAGGTGATG CTGTATATAACATAATTGCTTTGCTAGAATCCTTTGTATATGCACAGTTGCAA ATGTCAGATCCCATCCCAGAACTCAGAGGACAATTCCATGCATTCGTATGTTC TGAGATTCTTGATGCACTAAGAGGAACTAATAGTTTCACCCAGGATGAATTA AGAACTGTGACAACTAATTTGATATCCCCATTCCAAGATCTGACCCCAGATCT TACGGCTGAATTGCTCTGTATAATGAGGCTTTGGGGACACCCCATGCTCACTG CCAGTCAAGCTGCAGGAAAGGTACGCGAGTCTATGTGTGCTGGAAAAGTATT AGACTTTCCCACCATTATGAAAACACTAGCCTTTTTCCATACTATTCTGATCA ATGGATACAGGAGGAAGCATCATGGAGTATGGCCACCCTTAAACTTACCGGG TAATGCTTCAAAGGGTCTCACGGAACTTATGAATGACAATACTGAAATAAGCTATGAATTCACACTTAAGCATTGGAAGGAAGTCTCTCTTATAAAATTCAAGAA ATGTTTTGATGCAGACGCAGGTGAGGAACTCAGTATATTTATGAAAGATAAGGCAATTAGTGCCCCAAAACAAGACTGGATGAGTGTGTTTAGAAGAAGCCTAATCAAACAGCGCCATCAGCATCATCAGGTCCCCCTACCAAATCCATTCAATCGACGGCTGTTGCTAAACTTTCTCGGAGATGACAAATTCGACCCGAATGTGGAGCTACAGTATGTAACATCAGGTGAGTATCTACATGATGACACGTTTTGTGCATCATATTCACTAAAAGAGAAGGAAATTAAACCTGATGGTCGAATTTTTGCAAAGTTGACTAAGAGAATGAGATCATGTCAAGTTATAGCAGAATCTCTTTTAGCGAACCATGCTGGGAAGTTAATGAAAGAGAATGGTGTTGTGATGAATCAGCTATCATTAACAAAATCACTATTAACAATGAGTCAGATTGGAATAATATCCGAGAAAGCTAGAAAGTCAACTCGAGATAACATAAATCAACCTGGTTTCCAGAATATCCAGAGAAATAAATCACATCACTCCAAGCAAGTCAATCAGCGAGATCCAAGTGATGACTTTGAATTGGCAGCATCTTTTTTAACTACTGATCTCAAAAAATATTGTTTACAATGGAGGTACCAGACAATTATCCCATTTGCTCAATCATTAAACAGAATGTATGGTTATCCTCATCTCTTTGAGTGGATTCACTTACGGCTAATGCGTAGTACACTTTACGTGGGGGATCCCTTCAACCCACCAGCAGATACCAGTCAATTTGATCTAGATAAAGTAATTAATGGAGATATCTTCATTGTATCACCCAGAGGTGGAATTGAAGGGCTGTGTCAAAAGGCTTGGACAATGATATCTATCGCTGTGATAATTCTATCTGCCACAGAGTCTGGCACACGAGTAATGAGTATGGTGCAGGGAGATAATCAAGCAATTGCTGTCACCACACGAGTACCAAGGAGCCTGCCGACTCTTGAGAAAAAGACTATTGCTTTTAGATCTTGTAATCTATTCTTTGAGAGGTTAAAATGTAATAATTTTGGATTAGGTCACCATTTGAAAGAACAAGAGACTATCATTAGTTCTCACTTCTTTGTTTATAGCAAGAGAATATTCTATCAGGGGAGGATTCTAACGCAAGCCTTAAAAAATGCTAGTAAGCTCTGCTTGACAGCTGATGTCCTAGGAGAATGCACCCAATCATCATGTTCTAATCTTGCAACTACTGTCATGAGGTTAACTGAGAATGGTGTTGAAAAAGATATCTGTTTCTACTTGAATATCTATATGACCATCAAACAGCTCTCCTATGATATCATCTTCCCTCAAGTGTCAATTCCTGGAGATCAGATCACATTAGAATACATAAATAATCCACACCTGGTATCACGATTGGCTCTTTTGCCATCCCAGTTAGGAGGTCTAAACTACCTGTCATGCAGTAGGCTGTTCAATCGAAACATAGGCGACCCGGTGGTTTCCGCAGTTGCAGATCTTAAGAGATTAATTAAATCAGGATGTATGGATTACTGGATCCTTTATAACTTATTAGGGAGAAAACCGGGAAACGGCTCATGGGCTACTTTAGCAGCTGACCCGTACTCAATCAATATAGAGTATCAATACCCTCCAACTACAGCTCTTAAGAGGCACACCCAACAAGCTCTGATGGAACTCAGTACGAATCCAATGTTACGTGGCATATTCTCTGACAATGCACAGGCAGAAGAAAATAACCTTGCTAGGTTTCTCCTGGATAGGGAGGTGATCTTTCCGCGTGTAGCTCACATCATCATTGAGCAAACCAGTGTCGGGAGGAGAAAACAGATTCAAGGATATTTGGATTCAACTAGATCGATAATGAGGAAATCACTAGAAATTAAGCCCTTATCCAATAGGAAGCTTAATGAAATACTGGATTACAACATCAATTACCTAGCTTACAATTTGGCATTACTCAAGAATGCTATTGAACCTCCGACTTATTTGAAGGCAATGACACTTGAAACATGTAGCATCGACATTGCAAGGAACCTCCGGAAGCTCTCCTGGGCCCCACTCTTGGGTGGGAGAAATCTTGAAGGATTAGAGACGCCAGATCCCATTGAAATTACTGCAGGAGCATTAATTGTTGGATCGGGCTACTGTGAACAGTGTGCTGCAGGAGACAATCGATTCACATGGTTTTTCTTGCCATCTGGTATCGAGATAGGAGGGGATCCCCGTGATAATCCTCCTATCCGTGTACCGTACATTGGCTCCAGGACTGATGAGAGGAGGGTAGCCTCAATGGCATACATCAGGGGTGCCTCGAGTAGCTTAAAAGCAGTTCTTAGACTGGCGGGAGTGTACATCTGGGCATTCGGAGATACTCTGGAGAATTGGATAGATGCACTGGATTTGTCTCACACTAGAGTTAACATCACACTTGAACAGCTGCAATCCCTCACCCCACTTCCAACCTCTGCCAATCTAACCCATCGGTTGGATGATGGCACAACTACCCTAAAGTTTACTCCTGCGAGCTCTTACACCTTTTCAAGTTTCACTCATATATCAAATGATGAGCAATACCTGACAATTAATGACAAAACTGCAGATTCAAATATAATCTACCAACAGTTAATGATCACTGGACTCGGAATCTTAGAAACATGGAATAATCCCCCAATCAATAGAACATTCGAAGAATCTACCCTACATTTGCACACTGGTGCATCATGTTGTGTCCGACCTGTGGACTCCTGCATTCTCTCAGAAGCATTAACAGTCAAGCCACATATTACAGTACCGTACAGCAATAAATTTGTATTTGATGAGGACCCGCTATCTGAATATGAAACTGCAAAACTGGAATCGTTATCATTCCAAGCCCAATTAGGCAACATTGATGCTGTAGATATGACAGGTAAATTAACATTATTGTCCCAATTCACTGCAAGGCAGATTATCAATGCAATCACTGGACTCGATGAGTCTGTCTCTCTTACTAATGATGCCATTGTTGCATCAGACTATGTCTCCAATTGGATTAGTGAATGCATGTATACCAAATTAGATGAATTATTTATGTATTGTGGGTGGGAACTACTATTGGAACTATCCTATCAAATGTATTATCTGAGGGTAGTTGGGTGGAGTAATATAGTGGATTATTCTTACATGATCTTGAGAAGAATCCCGGGTGCAGCATTAAACAATCTGGCATCTACATTAAGTCATCCAAAACTTTTCCGACGAGCTATCAACCTAGATATAGTTGCCCCCTTAAATGCTCCTCATTTTGCATCTCTGGACTACATCAAGATGAGTGTGGATGCAATACTCTGGGGCTGTAAAAGAGTCATCAATGTGCTCTCCAATGGAGGGGACTTAGAATTAGTTGTGACATCTGAAGATAGCCTTATTCTCAGTGACCGATCCATGAATCTCATTGCAAGGAAATTAACTTTATTATCACTGATTCACCATAATGGTTTGGAACTACCAAAGATTAAGGGGTTCTCTCCTGATGAGAAGTGTTTCGCTTTGACAGAATTTTTGAGGAAAGTGGTGAACTCAGGGTTGAGTTCAATAGAGAACCTATCAAATTTTATGTACAATGTGGAGAACCCACGGCTTGCAGCATTCGCCAGCAACAATTACTACCTGACCAGAAAATTATTGAATTCAATACGAGATACTGAGTCGGGTCAAGTAGCAGTCACCTCATATTATGAATCATTAGAATATATTGATAGTCTTAAGCTAACCCCACATGTGCCTGGCACCTCATGCATTGAGGATGATAGTCTATGTACAAATGATTACATAATCTGGATCATAGAGTCTAATGCAAACTTGGAGAAGTATCCAATTCCAAATAGCCCTGAGGATGATTCCAATTTCCATAACTTTAAGTTGAATGCTCCATCGCACCATACCTTACGCCCATTAGGGTTGTCATCAACTGCTTGGTATAAGGGTATAAGCTGCTGCAGGTACCTTGAGCGATTAAAGCTACCACAAGGTGATCATTTATATATTGCAGAAGGTAGTGGTGCCAGTATGACAATCATAGAATACCTATTCCCAGGAAGAAAGATATATTACAATTCTTTATTTAGTAGTGGTGACAATCCCCCACAAAGAAATTATGCACCAATGCCTACTCAGTTCATTGAGAGTGTCCCATACAAGCTCTGGCAAGCACACACAGATCAATATCCCGAGATTTTTGAGGACTTCATCCCTCTATGGAACGGAAACGCCGCCATGACTGACATAGGAATGACAGCTTGTGTAGAATTCATCATCAATCGAGTCGGCCCAAGGACTTGCAGTTTAGTACATGTAGATTTGGAATCAAGTGCAAGCTTAAATCAACAATGCCTGTCAAAGCCGATAATTAATGCTATCATCACTGCTACAACTGTTTTGTGCCCTCATGGGGTGCTTATTCTGAAATATAGTTGGTTGCCATTTACTAGATTTAGTACTTTGATCACTTTCTTATGGTGCTACTTTGAGAGAATCACTGTTCTTAGGAGCACATATTCTGATCCAGCTAATCATGAGGTTTATTTAATTTGTATCCTTGCCAACAACTTTGCATTCCAGACTGTCTCGCAGGCAACAGGAATGGCGATGACTTTAACTGATCAAGGGTTTACTTTGATATCACCTGAAAGAATAAATCAGTATTGGGATGGTCACTTGAAGCAAGAACGTATCGTAGCAGAAGCAATTGATAAGGTGGTTCTAGGAGAAAATGCTCTATTTAATTCGAGTGATAATGAATTAATTCTCAAATGTGGAGGGACACCAAATGCACGGAATCTCATCGATATCGAGCCAGTCGCAACTTTCATAGAATTTGAACAATTGATCTGCACAATGTTGACAACCCACTTGAAGGAAATAATTGATATAACAAGGTCTGGAACCCAGGATTATGAAAGTTTATTACTCACTCCTTACAATTTAGGTCTTCTTGGTAAAATCAGTACGATAGTGAGATTATTAACAGAAAGGATTCTAAATCATACTATCAGGAATTGGTTGATCCTCCCACCTTCGCTCCGGATGATCGTGAAGCAGGACTTGGAATTCGGCATATTCAGGATTACTTCCATCCTCAATTCTGATCGGTTCCTGAAGCTTTCTCCAAATAGGAAATACTTGATTGCACAATTAACTGCAGGCTACATTAGGAAATTGATTGAGGGGGATTGCAATATCGATCTAACCAGACCTATCCAAAAGCAAATCTGGAAAGCATTAGGTTGTGTAGTCTATTGTCACGATCCAATGGATCAAAGGGAGTCAACAGAGTTTATTGATATAAATATTAATGAAGAAATAGACCGCGGGATCGATGGCGAGGAAATCTAAACATATCAAGAATCAGAATTAGTTTAAGAAAAAAGAAGAGGATTAATCTTGGTTTTCCCCTTGGTGGGTCGGCATGGCATCTCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCACTCGGATGGCTAAGGGAGCGGCCGGGGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAGTTGGCTGCTGCCACCGCTGAGCAATAACTAGCATAACCCCTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTGCTGAAAGGAGGAACTATATCCGGATCATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATA TTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCG AAAAGT (SEQ ID NO: 4). iii. CVL85
[0163] The nucleic acid sequence for CVL85 is:GCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCTAATACGACTCACTATAGGGACCAAGGGGAAAATGAAGTGGTGACTCAAATCATCGAAGACCCTCGAGATTACATAGGTCCGGAACCTATGGCCTTCGTGACCGACCTCGAGTCAGAGTAGTTCAATAAGGACCTATCAAGTTTGGGCAATTTTTCGTCCCCGACACAAAAATGTCATCCGTGCTTAAAGCATATGAGCGATTCACGCTCACTCAAGAACTGCAAGATCAGAGTGAGGAAGGTACAATCCCACCTACAACACTAAAACCGGTAATCAGGGTATTTATACTAACCTCTAATAACCCAGAGCTAAGATCCCGGCTTCTTCTATTCTGCCTACGGATTGTTCTCAGTAATGGTGCAAGGGATTCCCATCGCTTTGGAGCATTACTCACAATGTTTTCGCTACCATCAGCCACAATGCTCAATCATGTCAAATTAGCTGACCAGTCACCAGAAGCTGATATCGAAAGGGTAGAGATCGATGGCTTTGAGGAGGGATCATTCCGCTTAATCCCCAATGCTCGTTCAGGTATGAGCCGTGGAGAGATCAATGCCTATGCTGCACTTGCAGAAGATCTACCTGACACACTAAACCATGCAACACCTTTCGTTGATTCCGAAGTCGAGGGAACTGCATGGGATGAGATTGAGACTTTCTTAGATATGTGTTACAGTGTCCTAATGCAGGCATGGATAGTGACTTGCAAGTGCATGACTGCGCCAGACCAACCTGCTGCTTCTATTGAGAAACGCCTGCAAAAATATCGTCAGCAAGGCAGGATCAACCCGAGATATCTCCTGCAACCGGAGGCTCGACGAATAATCCAGAATGTAATCCGGAAGGGAATGGTGGTCAGACATTTCCTCACCTTTGAACTGCAGCTTGCCCGAGCACAAAGCCTTGTATCAAATAGGTATTATGCTATGGTAGGGGATGTTGGAAAGTATATAGAGAATTGTGGAATGGGAGGCTTCTTTTTGACACTAAAATATGCATTAGGAACTAGATGGCCCACACTTGCTTTAGCTGCATTTTCAGGAGAGCTAACAAAGCTAAAGTCCCTCATGGCATTATACCAGACCCTTGGTGAGCAGGCCCGATATTTGGCCCTATTGGAGTCACCACATTTGATGGATTTTGCTGCAGCAAACTACCCACTGCTATATAGCTATGCTATGGGAATAGGCTATGTGTTAGATGTCAACATGAGGAACTACGCTTTCTCCAGATCATACATGAACAAGACATATTTCCAATTGGGAATGGAAACTGCAAGAAAACAACAGGGTGCAGTTGACATGAGGATGGCAGAAGATCTCGGTCTAACTCAAGCCGAACGCACCGAGATGGCAAATACACTTGCCAAATTGACCACAGCAAATCGAGGGGCAGACACCAGGGGAGGAGTCAACCCGTTCTCATCTGTCACTGGGACAACTCAGGTGCCCGCTGCAGCAACAGGTGACACACTCGAGAGTTACATGGCAGCGGATCGACTGAGGCAGAGATATGCTGATGCAGGCACCCATGATGATGAGATGCCACCATTGGAAGAGGAGGAAGAGGACGACACATCTGCAGGTCCACGCACTGGACCAACTCTTGAACAAGTGGCCTTGGACATCCAGAACGCAGCAGTTGGAGCTCCCATCCATACAGATGACCTGAATGCCGCACTGGGTGATCTTGACATCTAGACAATTCAGATCCCAATCTAAAATTGACATACCTAATTGATTAGTTAGATGGAACTACAGTGGATTCCATAAGGTTCCTGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACAAGCGACTGCCGGTGCCAACAGCGCAATCCACAATCTACAATGGATCCCACTGATCTGAGCTTCTCCCCAGATGAGATCAATAAGCTCATAGAGACAGGCCTGAATACTGTAGAGTATTTTACTTCCCAACAAGTCACAGGAACATCCTCTCTTGGAAAGAATACAATACCACCAGGGGTCACAGGACTACTAACCAATGCTGCAGAGGCAAAGATCCAAGAGTCAACTAACCATCAGAAGGGCTCAGTTGGTGGGGGTGCAAAACCAAAGAAACCGCGACCAAAAATTGCCATTGTGCCAGCAGATGACAAAACAGTGCCCGGAAAGCCGATCCCAAACCCTCTATTAGGTCTGGACTCCACCCCGAGCACCCAAACTGTGCTTGATCTAAGTGGGAAAACATTACCATCAGGATCCTATAAGGGGGTTAAGCTTGCGAAATTTGGAAAAGAAAATCTGATGACACGGTTCATCGAGGAACCCAGAGAGAATCCTATCGCAACCAGTTtCCCCATCGATTTTAAGAGGGGCAGGGATACCGGCGGGTTCCATAGAAGGGAGTACTCAATCGGATGGGTGGGAGATGAAGTCAAGGTCACTGAGTGGTGCAATCCATCCTGTTCTCCAATCACCGCTGCAGCAAGGCGATTTGAATGCACTTGTCACCAGTGTCCAGTCACTTGCTCTGAATGTGAACGAGATACTTAATACAGTGAGAAATTTGGACTCTCGGATGAATCAACTGGAGACAAAAGTAGATCGCATTCTCTCATCTCAGTCTCTAATCCAGACCATCAAGAATGACATAGTTGGACTTAAAGCAGGGATGGCTACTTTAGAAGGAATGATTACAACTGTGAAAATCATGGACCCGGGAGTTCCCAGTAATGTTACTGTGGAAGATGTACGCAAGACACTAAGTAACCATGCTGTTGTTGTGCCAGAATCATTCAATGATAGTTTCTTGACTCAATCTGAAGATGTAATTTCACTTGATGAGTTGGCTCGACCAACTGCAACAAGTGTTAAGAAGATTGTCAGGAAGGTTCCTCCTCAGAAGGATCTGACTGGATTGAAGATTACACTAGAGCAATTGGCAAAGGATTGCATCAGCAAACCGAAGATGAGGGAAGAGTATCTCCTCAAAATCAACCAGGCTTCCAGTGAGGCTCAGCTAATTGACCTCAAGAAAGCAATCATCCGCAGTGCAATTTGATCAAGAAACACCCAATTACACTACACTGGTATGACACTGTACTAACCCTGAGGGTTTTAGAAAAAACGATTAACGATAAATAAGCCCGAACACTACACACTACCTGAGGCAGCCATGCCATCCATCAGCATTCCCGCAGACCCCACCAATCCACGTCAATCAATAAAAGCGTTCCCAATTGTGATCAACAGTGATGGGGGTGAGAAAGGCCGCTTGGTTAAACAACTACGCACAACCTACTTGAATGACCTAGATACTCATGAGCCACTGGTGACATTCATAAATACCTATGGATTCATCTACGAACAGGATCGGGGGAATACCATTGTCGGAGAGGATCAACTTGGGAAGAAAAGAGAGGCTGTGACCGCTGCAATGGTTACCCTTGGATGTGGGCCTAATCTACCATCATTAGGGAATGTCCTGGGACAACTGAGGGAATTCCAGGTCACTGTTAGGAAGACATCCAGCAAAGCGGAAGAGATGGTCTTTGAAATTGTTAAGTATCCGAGAATATTTCGGGGTCATACATTAATCCAGAAAGGACTAGTCTGTGTCTCCGCAGAAAAATTTGTTAAGTCACCAGGGAAAATACAATCTGGAATGGACTATCTCTTCATTCCGACATTTCTGTCAGTGACTTACTGTCCAGCTGCAATCAAATTTCAGGTACCTGGCCCCATGTTGAAAATGAGATCAAGATACACTCAGAGCTTACAACTTGAACTAATGATAAGAATCCTGTGTAAGCCCGATTCGCCACTTATGAAGGTCCATACCCCTGACAAGGAGGGAAGAGGATGTCTTGTATCAGTATGGCTGCATGTATGCAACATCTTCAAATCAGGAAACAAGAATGGCAGTGAGTGGCAGGAATACTGGATGAGAAAGTGTGCTAACATGCAACTTGAAGTGTCGATTGCAGATATGTGGGGACCAACTATCATAATTCATGCCAGAGGTCACATTCCCAAAAGTGCTAAGTTGTTTTTTGGAAAGGGTGGATGGAGCTGCCATCCACTTCACGAAGTTGTTCCAAGTGTCACTAAAACACTATGGTCCGTGGGCTGTGAGATTACAAAGGCGAAGGCAATAATACAAGAGAGTAGCATCTCTCTTCTCGTGGAGACTACTGACATCATAAGTCCAAAAGTCAAAATTTCATCTAAGCATCGCCGCTTTGGGAAATCAAATTGGGGTCTGTTCAAGAAAACTAAATCACTGCCTAACCTGACGGAGCTGGAATGACTGACCTCTAATCGAGACTACACCGCCGCAAACTATAGGTGGGTGGTACCTCAGTGATTAATCTTGTAAGCACTGATCGTAGGCTACAACACACTAATATTATCCAGATTAGAGAGCTTAATTAGCTCTGTATTAATAATAACACTACTATTCCAATAACTGGAATCACCAGCTTGATTTATCTCCAAAATGATTCAAAGAAAACAAATCATATTAAGACTATCCTAAGCACGAACCCATATCGTCCTTCAAATCATGGGTACTATAATTCAATTTCTGGTGGTCTCCTGTCTATTGGCAGGAGCAGGCAGCCTTGATCCAGCAGCCCTCATGCAAATCGGTGTCATTCCAACAAATGTCCGGCAACTTATGTATTATACTGAAGCTTCATCAGCATTCATTGTTGTGAAGTTAATGCCTACAATTGACTCGCCGATTAGTGGATGTAATATAACATCAATTTCAAGCTATAATGCAACAGTGACAAAACTCCTACAGCCGATCGGTGAGAATTTGGAGACGATTAGGAACCAGTTGATTCCAACTCGGAGGAGACGCCGGTTTGCAGGGGTGGTGATTGGATTAGCTGCATTAGGAGTAGCTACTGCCGCACAGGTCACTGCCGCAGTGGCACTAGTAAAGGCAAATGAAAATGCTGCGGCTATACTCAATCTCAAAAATGCAATCCAAAAAACAAATGCAGCAGTTGCAGATGTGGTCCAGGCCACACAATCACTAGGAACGGCAGTTCAAGCAGTTCAAGATCACATAAACAGTGTGGTAAGTCCAGCAATTACAGCAGCCAATTGTAAGGCCCAAGATGCTATCATTGGCTCAATCCTCAATCTCTATTTGACCGAGTTGACAACCATCTTCCACAATCAAATTACAAACCCTGCATTGAGTCCCATTACAATTCAAGCTTTAAGGATCCTACTGGGGAGTACCTTGCCGACTGTGGTCGAAAAATCTTTCAATACCCAGATAAGTGCAGCTGAGCTTCTCTCATCAGGGTTATTGACAGGCCAGATTGTGGGATTAGATTTGACCTATATGCAGATGGTCATAAAAATTGAGCTGCCAACTTTAACTGTACAACCTGCAACCCAGATCATAGATCTGGCCACCATTTCTGCATTCATTAACAATCAAGAAGTCATGGCCCAATTACCAACACGTGTTATGGTGACTGGCAGCTTGATCCAAGCCTATCCCGCATCGCAATGCACCATTACACCCAACACTGTGTACTGTAGGTATAATGATGCCCAAGTACTCTCAGATGATACTATGGCTTGCCTCCAAGGTAACTTGACAAGATGCACCTTCTCTCCAGTGGTTGGGAGCTTTCTCACTCGATTCGTGCTGTTCGATGGAATAGTTTATGCAAATTGCAGGTCGATGTTGTGCAAGTGCATGCAACCTGCTGCTGTGATCCTACAGCCGAGTTCATCCCCTGTAACTGTCATTGACATGTACAAATGTGTGAGTCTGCAGCTTGACAATCTCAGATTCACCATCACTCAATTGGCCAATGTAACCTACAATAGCACCATCAAGCTTGAATCATCCCAGATCTTGTCTATTGATCCGTTGGATATATCCCAGAATCTAGCTGCGGTGAATAAGAGTCTAAGTGATGCACTACAACACTTAGCACAAAGTGACACATATCTTTCTGCAATCACATCAGCTACGACTACAAGTGTATTATCCATAATAGCAATCTGTCTTGGATCGTTAGGTTTAATATTAATAATCTTGCTCAGTGTAGTTGTGTGGAAGTTATTGACCATTGTCGTTGCTAATCGAAATAGAATGGAGAATTTTGTTTATCATAAATAAGCATTCCACCACTCACGATCTGATCTCAGTGAGAAAAATCAACCTGCAACTCTTGGAACAAGATAAGACAGTCATCCATTAGTAATTTTTAAGAAAAAAACGATAGGACCGAACCTAGTATTGAAAGAACCGTCTCGGTCAATCTAGGTAATCGAGCTGATACCGTCTCGGAAAGCTCAAATCGCGCGCCACCatgtcagataacggacca-cagaaccagaggaacgcacccaggattactttcggaggaccaagcgatagcaccgggagcaaccagaatggagagcggag cggagcaagatccaagcagagacggccccagggcctgccaaacaataccgcatcctggttcaccgccctgacacagcacgg caaggaggacctgaagtttccaaggggacagggagtgcctatcaacaccaatagctcccctgacgatcagatcggctactatag gagggcaacaaggagaatcaggggaggcgacggcaagatgaaggatctgagcccacgctggtactctactatctgggaacc ggacctgaggcaggcctgccatatggcgccaacaaggacggaatcatctgggtggcaaccgagggcgccctgaacacacca aaggatcacatcggcacaagaaatcccgccaacaatgcagcaatcgtgctgcagctgccacagggaaccacactgcccaagg gcttttacgcagagggctctcggggaggcagccaggcatctagcagatcctctagccggagcagaaactcctctaggaattcca ccccaggaagctccaggggcacatcccctgcccgcatggcaggaaacggaggcgacgccgccctggccctgctgctgctgg atcgcctgaatcagctggagtccaagatgtctggcaagggacagcagcagcagggacagaccgtgacaaagaagtccgccg ccgaggcctctaagaagccaaggcagaagcgcaccgccacaaaggcctacaacgtgacccaggccttcggcaggcgcgga ccagagcagacacagggcaattttggcgaccaggagctgatcaggcagggaaccgattataagcactggcctcagatcgccc agttcgccccatctgccagcgccttctttggcatgtctagaatcggcatggaggtgacccccagcggcacatggctgacctacac aggcgccatcaagctggacgataaggaccctaacttcaaggatcaggtcatcctgctgaacaagcacatcgacgcctataagac ctttccccctacagagcccaagaaggacaagaagaagaaggccgatgagacacaggccctgcctcagaggcagaagaagca gcagaccgtgacactgctgccagccgccgatctggacgatttctccaaacagctgcagcagagcatgtccagtgccgactcca cccaggcttgaCGTACGACCTGCTATAGGCTATCCACTGCATCATCTCTCCTGCCATACTTCCTACTCACATCATATCTATTTTAAAGAAAAAATAGGCCCGAACACTAATCGTGCCGGCAGTGCCACTGCACACACAACACTACACATACAATACACTACAATGGTTGCAGAAGATGCCCCTGTTAGGGCCACTTGCCGAGTATTATTTCGAACAACAACTTTAATCTTTCTATGCACACTACTAGCATTAAGCATCTCTATCCTTTATGAGAGTTTAATAACCCAAAAGCAAATCATGAGCCAAGCAGGCTCAACTGGATCTAATTCTGGATTAGGAAGTATCACTGATCTTCTTAATAATATTCTCTCTGTCGCAAATCAGATTATATATAACTCTGCAGTCGCTCTACCTCTACAATTGGACACTCTTGAATCAACACTCCTTACAGCCATTAAGTCTCTTCAAACCAGTGACAAGCTAGAACAGAACTGCTCGTGGAGTGCTGCACTGATTAATGATAATAGATACATTAATGGCATCAATCAGTTCTATTTTTCAATTGCTGAGGGTCGCAATCTGACACTTGGCCCACTTCTTAATATGCCTAGTTTCATTCCAACTGCCACGACACCAGAGGGCTGCACCAGGATCCCATCATTCTCGCTCACTAAGACACACTGGTGTTATACACACAATGTTATCCTGAATGGATGCCAGGATCATGTATCCTCAAATCAATTTGTTTCTATGGGAATCATTGAACCCACTTCTGCCGGGTTTCCATTCTTTCGAACCCTAAAGACTCTATATCTCAGCGATGGGGTCAATCGTAAGAGCTGCTCTATCAGTACAGTTCCGGGGGGTTGTATGATGTACTGTTTTGTTTCTACTCAACCAGAGAGGGATGACTACTTTTCTGCCGCTCCTCCAGAACAACGAATTATTATAATGTACTATAATGATACAATCGTGGAGCGCATAATTAATCCACCCGGGGTACTAGATGTATGGGCAACATTGAACCCAGGAACAGGAAGCGGGGTATATTATTTAGGTTGG GTGCTCTTTCCAATATATGGCGGCGTGATTAAAGGTACGAGTTTATGGAATAA TCAAGCAAATAAATACTTTATCCCCCAGATGGTTGCTGCTCTCTGCTCACAAA ACCAGGCAACTCAAGTCCAAAATGCTAAGTCATCATACTATAGCAGCTGGTTT GGCAATCGAATGATTCAGTCTGGGATCCTGGCATGTCCTCTTCGACAGGATCT AACCAATGAGTGTTTAGTTCTGCCCTTTTCTAATGATCAGGTGCTTATGGGTG CTGAAGGGAGATTATACATGTATGGTGACTCGGTGTATTACTATCAAAGAAG CAATAGTTGGTGGCCTATGACCATGCTGTATAAGGTAACCATAACATTCACTA ATGGTCAGCCATCTGCTATATCAGCTCAGAATGTGCCCACACAGCAGGTCCCT AGACCTGGGACAGGAGACTGCTCTGCAACCAATAGATGTCCCGGTTTTTGCTT GACAGGAGTGTATGCCGATGCCTGGTTACTGACCAACCCTTCGTCTACCAGTA CATTTGGATCAGAAGCAACCTTCACTGGTTCTTATCTCAACACAGCAACTCAG CGTATCAATCCGACGATGTATATCGCGAACAACACACAGATCATAAGCTCAC AGCAATTTGGATCAAGCGGTCAAGAAGCAGCATATGGCCACACAACTTGTTT TAGGGACACAGGCTCTGTTATGGTATACTGTATCTATATTATTGAATTGTCCTCATCTCTCTTAGGACAATTTCAGATTGTCCCATTTATCCGTCAGGTGACACTAT CCTAAAGGCAGAAGCCTTCAGGTCTGACCCAGCCAATCAAAGCATTATACCAGACCATGGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAG CAACAAGCGGCGGCCGCCatgttcgtcttcctggtcctgctgcctctggtctcctcacagtgcgtcaatctgacaa ctcggactcagctgccacctgcttatactaatagcttcaccagaggcgtgtactatcctgacaaggtgtttagaagctccgtgctgc actctacacaggatctgtttctgccattctttagcaacgtgacctggttccacgccatccacgtgagcggcaccaatggcacaaag cggttcgacaatcccgtgctgccttttaacgatggcgtgtacttcgcctctaccgagaagagcaacatcatcagaggctggatcttt ggcaccacactggactccaagacacagtctctgctgatcgtgaacaatgccaccaacgtggtcatcaaggtgtgcgagttccagt tttgtaatgatcccttcctgggcgtgtactatcacaagaacaataagagctggatggagtccgagtttagagtgtattctagcgcca acaactgcacatttgagtacgtgagccagcctttcctgatggacctggagggcaagcagggcaatttcaagaacctgagggagt tcgtgtttaagaatatcgacggctacttcaaaatctactctaagcacacccccatcaacctggtgcgcgacctgcctcagggcttca gcgccctggagcccctggtggatctgcctatcggcatcaacatcacccggtttcagacactgctggccctgcacagaagctacct gacacccggcgactcctctagcggatggaccgccggcgctgccgcctactatgtgggctacctccagccccggaccttcctgct gaagtacaacgagaatggcaccatcacagacgcagtggattgcgccctggaccccctgagcgagacaaagtgtacactgaag tcctttaccgtggagaagggcatctatcagacatccaatttcagggtgcagccaaccgagtctatcgtgcgctttcctaatatcaca aacctgtgcccatttggcgaggtgttcaacgcaacccgcttcgccagcgtgtacgcctggaataggaagcggatcagcaactgc gtggccgactatagcgtgctgtacaactccgcctctttcagcacctttaagtgctatggcgtgtcccccacaaagctgaatgacctg tgctttaccaacgtctacgccgattctttcgtgatcaggggcgacgaggtgcgccagatcgcccccggccagacaggcaagatc gcagactacaattataagctgccagacgatttcaccggctgcgtgatcgcctggaacagcaacaatctggattccaaagtgggcggcaactacaattatctgtaccggctgtttagaaagagcaatctgaagcccttcgagagggacatctctacagaaatctaccaggc cggcagcaccccttgcaatggcgtggagggctttaactgttatttcccactccagtcctacggcttccagcccacaaacggcgtg ggctatcagccttaccgcgtggtggtgctgagctttgagctgctgcacgccccagcaacagtgtgcggccccaagaagtccacc aatctggtgaagaacaagtgcgtgaacttcaacttcaacggcctgaccggcacaggcgtgctgaccgagtccaacaagaagttc ctgccatttcagcagttcggcagggacatcgcagataccacagacgccgtgcgcgacccacagaccctggagatcctggacat cacaccctgctctttcggcggcgtgagcgtgatcacacccggcaccaatacaagcaaccaggtggccgtgctgtatcaggacgt gaattgtaccgaggtgcccgtggctatccacgccgatcagctgaccccaacatggcgggtgtacagcaccggctccaacgtctt ccagacaagagccggatgcctgatcggagcagagcacgtgaacaattcctatgagtgcgacatcccaatcggcgccggcatct gtgcctcttaccagacccagacaaactctcccagaagagcccggagcgtggcctcccagtctatcatcgcctataccatgtccct gggcgccgagaacagcgtggcctactctaacaatagcatcgccatcccaaccaacttcacaatctctgtgaccacagagatcct gcccgtgtccatgaccaagacatctgtggactgcacaatgtatatctgtggcgattctaccgagtgcagcaacctgctgctccagt acggcagcttttgtacccagctgaatagagccctgacaggcatcgccgtggagcaggataagaacacacaggaggtgttcgcc caggtgaagcaaatctacaagaccccccctatcaaggactttggcggcttcaatttttcccagatcctgcctgatccatccaagcct tctaagcggagctttatcgaggacctgctgttcaacaaggtgaccctggccgatgccggcttcatcaagcagtatggcgattgcct gggcgacatcgcagccagggacctgatctgcgcccagaagtttaatggcctgaccgtgctgccacccctgctgacagatgaga tgatcgcacagtacacaagcgccctgctggccggcaccatcacatccggatggaccttcggcgcaggagccgccctccagatc ccctttgccatgcagatggcctataggttcaacggcatcggcgtgacccagaatgtgctgtacgagaaccagaagctgatcgcc aatcagtttaactccgccatcggcaagatccaggacagcctgtcctctacagccagcgccctgggcaagctccaggatgtggtg aatcagaacgcccaggccctgaataccctggtgaagcagctgagcagcaacttcggcgccatctctagcgtgctgaatgacatc ctgagccggctggacaaggtggaggcagaggtgcagatcgaccggctgatcaccggccggctccagagcctccagacctat gtgacacagcagctgatcagggccgccgagatcagggccagcgccaatctggcagcaaccaagatgtccgagtgcgtgctg ggccagtctaagagagtggacttttgtggcaagggctatcacctgatgtccttccctcagtctgccccacacggcgtggtgtttctg cacgtgacctacgtgcccgcccaggagaagaacttcaccacagcccctgccatctgccacgatggcaaggcccactttccaag ggagggcgtgttcgtgtccaacggcacccactggtttgtgacacagcgcaatttctacgagccccagatcatcaccacagacaa caccttcgtgagcggcaactgtgacgtggtcatcggcatcgtgaacaataccgtgtatgatccactccagcccgagctggacag ctttaaggaggagctggataagtatttcaagaatcacacctcccctgacgtggatctgggcgacatcagcggcatcaatgcctcc gtggtgaacatccagaaggagatcgaccgcctgaacgaggtggctaagaatctgaacgagagcctgatcgacctccaggagc tgggcaagtatgagcagtacatcaagtggccctggtacatctggctgggcttcatcgccggcctgatcgccatcgtgatggtgac catcatgctgtgctgtatgacatcctgctgttcttgcctgaagggctgctgtagctgtggctcctgctgtaagttattgaccattgtcgt tgctaatcgaaatagaatggagaattttgtttatcataaatgaAGTCGACTCATGGAATGCATACCAAACATTATTGACACTAATGACACACAAAATTGGTTTTAAGAAAAACCAAGAGAAC AATAGGCCAGAATGGCTGGGTCTCGGGAGATATTACTCCCTGAAGTCCATCTC AATTCACCAATTGTAAAGCATAAGCTATACTATTACATTCTACTTGGAAACCT CCCAAATGAGATCGACCTTGACGATTTAGGTCCATTACATAATCAAAATTGGAATCAGATAGCACATGAAGAGTCTAACTTAGCTCAACGCTTGGTAAATGTAAGAAATTTTCTAATTACCCACATCCCTGATCTTAGAAAGGGCCATTGGCAAGAGTATGTCAATGTAATACTGTGGCCGCGAATTCTTCCCTTGATCCCGGATTTTAAAATCAATGACCAATTGCCTCTGCTCAAAAATTGGGACAAGTTAGTTAAAGAATCATGTTCAGTAATCAATGCAGGTACTTCCCAGTGCATTCAGAATCTCAGCTATGGACTGACAGGTCGTGGGAACCTCTTTACACGATCACGTGAACTCTCTGGTGACCGCAGGGATATTGATCTTAAGACAGTTGTGGCAGCATGGCATGACTCAGACTGGAAAAGAATAAGTGATTTTTGGATTATGATCAAATTCCAGATGAGACAATTAATTGTTAGGCAAACAGATCATAATGATTCTGATTTAATCACGTATATCGAAAATAGAGAAGGCATAATCATCATAACCCCTGAACTGGTAGCATTATTTAACACTGAGAATCATACACTAACATACATGACCTTTGAAATTGTACTGATGGTTTCAGATATGTACGAAGGTCGTCACAACATTTTATCACTATGCACAGTTAGCACTTACCTGAATCCTCTGAAGAAAAGAATAACATATTTATTGAGCCTTGTAGATAACTTAGCTTTTCAGATAGGTGATGCTGTATATAACATAATTGCTTTGCTAGAATCCTTTGTATATGCACAGTTGCAAATGTCAGATCCCATCCCAGAACTCAGAGGACAATTCCATGCATTCGTATGTTCTGAGATTCTTGATGCACTAAGAGGAACTAATAGTTTCACCCAGGATGAATTAAGAACTGTGACAACTAATTTGATATCCCCATTCCAAGATCTGACCCCAGATCTTACGGCTGAATTGCTCTGTATAATGAGGCTTTGGGGACACCCCATGCTCACTGCCAGTCAAGCTGCAGGAAAGGTACGCGAGTCTATGTGTGCTGGAAAAGTATTAGACTTTCCCACCATTATGAAAACACTAGCCTTTTTCCATACTATTCTGATCAATGGATACAGGAGGAAGCATCATGGAGTATGGCCACCCTTAAACTTACCGGGTAATGCTTCAAAGGGTCTCACGGAACTTATGAATGACAATACTGAAATAAGCTATGAATTCACACTTAAGCATTGGAAGGAAGTCTCTCTTATAAAATTCAAGAAATGTTTTGATGCAGACGCAGGTGAGGAACTCAGTATATTTATGAAAGATAAGGCAATTAGTGCCCCAAAACAAGACTGGATGAGTGTGTTTAGAAGAAGCCTAATCAAACAGCGCCATCAGCATCATCAGGTCCCCCTACCAAATCCATTCAATCGACGGCTGTTGCTAAACTTTCTCGGAGATGACAAATTCGACCCGAATGTGGAGCTACAGTATGTAACATCAGGTGAGTATCTACATGATGACACGTTTTGTGCATCATATTCACTAAAAGAGAAGGAAATTAAACCTGATGGTCGAATTTTTGCAAAGTTGACTAAGAGAATGAGATCATGTCAAGTTATAGCAGAATCTCTTTTAGCGAACCATGCTGGGAAGTTAATGAAAGAGAATGGTGTTGTGATGAATCAGCTATCATTAACAAAATCACTATTAACAATGAGTCAGATTGGAATAATATCCGAGAAAGCTAGAAAGTCAACTCGAGATAACATAAATCAACCTGGTTTCCAGAATATCCAGAGAAATAAATCACATCACTCCAAGCAAGTCAATCAGCGAGATCCAAGTGATGACTTTGAATTGGCAGCATCTTTTTTAACTACTGATCTCAAAAAATATTGTTTACAATGGAGGTACCAGACAATTATCCCATTTGCTCAATCATTAAACAGAATGTATGGTTATCCTCATCTCTTTGAGTGGATTCACTTACGGCTAATGCGTAGTACACTTTACGTGGGGGATCCCTTCAACCCACCAGCAGATACCAGTCAATTTGATCTAGATAAAGTAATTAATGGAGATATCTTCATTGTATCACCCAGAGGTGGAATTGAAGGGCTGTGTCAAAAGGCTTGGACAATGATATCTATCGCTGTGATAATTCTATCTGCCACAGAGTCTGGCACACGAGTAATGAGTATGGTGCAGGGAGATAATCAAGCAATTGCTGTCACCACACGAGTACCAAGGAGCCTGCCGACTCTTGAGAAAAAGACTATTGCTTTTAGATCTTGTAATCTATTCTTTGAGAGGTTAAAATGTAATAATTTTGGATTAGGTCACCATTTGAAAGAACAAGAGACTATCATTAGTTCTCACTTCTTTGTTTATAGCAAGAGAATATTCTATCAGGGGAGGATTCTAACGCAAGCCTTAAAAAATGCTAGTAAGCTCTGCTTGACAGCTGATGTCCTAGGAGAATGCACCCAATCATCATGTTCTAATCTTGCAACTACTGTCATGAGGTTAACTGAGAATGGTGTTGAAAAAGATATCTGTTTCTACTTGAATATCTATATGACCATCAAACAGCTCTCCTATGATATCATCTTCCCTCAAGTGTCAATTCCTGGAGATCAGATCACATTAGAATACATAAATAATCCACACCTGGTATCACGATTGGCTCTTTTGCCATCCCAGTTAGGAGGTCTAAACTACCTGTCATGCAGTAGGCTGTTCAATCGAAACATAGGCGACCCGGTGGTTTCCGCAGTTGCAGATCTTAAGAGATTAATTAAATCAGGATGTATGGATTACTGGATCCTTTATAACTTATTAGGGAGAAAACCGGGAAACGGCTCATGGGCTACTTTAGCAGCTGACCCGTACTCAATCAATATAGAGTATCAATACCCTCCAACTACAGCTCTTAAGAGGCACACCCAACAAGCTCTGATGGAACTCAGTACGAATCCAATGTTACGTGGCATATTCTCTGACAATGCACAGGCAGAAGAAAATAACCTTGCTAGGTTTCTCCTGGATAGGGAGGTGATCTTTCCGCGTGTAGCTCACATCATCATTGAGCAAACCAGTGTCGGGAGGAGAAAACAGATTCAAGGATATTTGGATTCAACTAGATCGATAATGAGGAAATCACTAGAAATTAAGCCCTTATCCAATAGGAAGCTTAATGAAATACTGGATTACAACATCAATTACCTAGCTTACAATTTGGCATTACTCAAGAATGCTATTGAACCTCCGACTTATTTGAAGGCAATGACACTTGAAACATGTAGCATCGACATTGCAAGGAACCTCCGGAAGCTCTCCTGGGCCCCACTCTTGGGTGGGAGAAATCTTGAAGGATTAGAGACGCCAGATCCCATTGAAATTACTGCAGGAGCATTAATTGTTGGATCGGGCTACTGTGAACAGTGTGCTGCAGGAGACAATCGATTCACATGGTTTTTCTTGCCATCTGGTATCGAGATAGGAGGGGATCCCCGTGATAATCCTCCTATCCGTGTACCGTACATTGGCTCCAGGACTGATGAGAGGAGGGTAGCCTCAATGGCATACATCAGGGGTGCCTCGAGTAGCTTAAAAGCAGTTCTTAGACTGGCGGGAGTGTACATCTGGGCATTCGGAGATACTCTGGAGAATTGGATAGATGCACTGGATTTGTCTCACACTAGAGTTAACATCACACTTGAACAGCTGCAATCCCTCACCCCACTTCCAACCTCTGCCAATCTAACCCATCGGTTGGATGATGGCACAACTACCCTAAAGTTTACTCCTGCGAGCTCTTACACCTTTTCAAGTTTCACTCATATATCAAATGATGAGCAATACCTGACAATTAATGACAAAACTGCAGATTCAAATATAATCTACCAACAGTTAATGATCACTGGACTCGGAATCTTAGAAACATGGAATAATCCCCCAATCAATAGAACATTCGAAGAATCTACCCTACATTTGCACACTGGTGCATCATGTTGTGTCCGACCTGTGGACTCCTGCATTCTCTCAGAAGCATTAACAGTCAAGCCACATATTACAGTACCGTACAGCAATAAATTTGTATTTGATGAGGACCCGCTATCTGAATATGAAACTGCAAAACTGGAATCGTTATCATTCCAAGCCCAATTAGGCAACATTGATGCTGTAGATATGACAGGTAAATTAACATTATTGTCCCAATTCACTGCAAGGCAGATTATCAATGCAATCACTGGACTCGATGAGTCTGTCTCTCTTACTAATGATGCCATTGTTGCATCAGACTATGTCTCCAATTGGATTAGTGAATGCATGTATACCAAATTAGATGAATTATTTATGTATTGTGGGTGGGAACTACTATTGGAACTATCCTATCAAATGTATTATCTGAGGGTAGTTGGGTGGAGTAATATAGTGGATTATTCTTACATGATCTTGAGAAGAATCCCGGGTGCAGCATTAAACAATCTGGCATCTACATTAAGTCATCCAAAACTTTTCCGACGAGCTATCAACCTAGATATAGTTGCCCCCTTAAATGCTCCTCATTTTGCATCTCTGGACTACATCAAGATGAGTGTGGATGCAATACTCTGGGGCTGTAAAAGAGTCATCAATGTGCTCTCCAATGGAGGGGACTTAGAATTAGTTGTGACATCTGAAGATAGCCTTATTCTCAGTGACCGATCCATGAATCTCATTGCAAGGAAATTAACTTTATTATCACTGATTCACCATAATGGTTTGGAACTACCAAAGATTAAGGGGTTCTCTCCTGATGAGAAGTGTTTCGCTTTGACAGAATTTTTGAGGAAAGTGGTGAACTCAGGGTTGAGTTCAATAGAGAACCTATCAAATTTTATGTACAATGTGGAGAACCCACGGCTTGCAGCATTCGCCAGCAACAATTACTACCTGACCAGAAAATTATTGAATTCAATACGAGATACTGAGTCGGGTCAAGTAGCAGTCACCTCATATTATGAATCATTAGAATATATTGATAGTCTTAAGCTAACCCCACATGTGCCTGGCACCTCATGCATTGAGGATGATAGTCTATGTACAAATGATTACATAATCTGGATCATAGAGTCTAATGCAAACTTGGAGAAGTATCCAATTCCAAATAGCCCTGAGGATGATTCCAATTTCCATAACTTTAAGTTGAATGCTCCATCGCACCATACCTTACGCCCATTAGGGTTGTCATCAACTGCTTGGTATAAGGGTATAAGCTGCTGCAGGTACCTTGAGCGATTAAAGCTACCACAAGGTGATCATTTATATATTGCAGAAGGTAGTGGTGCCAGTATGACAATCATAGAATACCTATTCCCAGGAAGAAAGATATATTACAATTCTTTATTTAGTAGTGGTGACAATCCCCCACAAAGAAATTATGCACCAATGCCTACTCAGTTCATTGAGAGTGTCCCATACAAGCTCTGGCAAGCACACACAGATCAATATCCCGAGATTTTTGAGGACTTCATCCCTCTATGGAACGGAAACGCCGCCATGACTGACATAGGAATGACAGCTTGTGTAGAATTCATCATCAATCGAGTCGGCCCAAGGACTTGCAGTTTAGTACATGTAGATTTGGAATCAAGTGCAAGCTTAAATCAACAATGCCTGTCAAAGCCGATAATTAATGCTATCATCACTGCTACAACTGTTTTGTGCCCTCATGGGGTGCTTATTCTGAAATATAGTTGGTTGCCATTTACTAGATTTAGTACTTTGATCACTTTCTTATGGTGCTACTTTGAGAGAATCACTGTTCTTAGGAGCACATATTCTGATCCAGCTAATCATGAGGTTTATTTAATTTGTATCCTTGCCAACAACTTTGCATTCCAGACTGTCTCGCAGGCAACAGGAATGGCGATGACTTTAACTGATCAAGGGTTTACTTTGATATCACCTGAAAGAATAAATCAGTATTGGGATGGTCACTTGAAGCAAGAACGTATCGTAGCAGAAGCAATTGATAAGGTGGTTCTAGGAGAAAATGCTCTATTTAATTCGAGTGATAATGAATTAATTCTCAAATGTGGAGGGACACCAAATGCACGGAATCTCATCGATATCGAGCCAGTCGCAACTTTCATAGAATTTGAACAATTGATCTGCACAATGTTGACAACCCACTTGAAGGAAATAATTGATATAACAAGGTCTGGAACCCAGGATTATGAAAGTTTATTACTCACTCCTTACAATTTAGGTCTTCTTGGTAAAATCAGTACGATAGTGAGATTATTAACAGAAAGGATTCTAAATCATACTATCAGGAATTGGTTGATCCTCCCACCTTCGCTCCGGATGATCGTGAAGCAGGACTTGGAATTCGGCATATTCAGGATTACTTCCATCCTCAATTCTGATCGGTTCCTGAAGCTTTCTCCAAATAGGAAATACTTGATTGCACAATTAACTGCAGGCTACATTAGGAAATTGATTGAGGGGGATTGCAATATCGATCTAACCAGACCTATCCAAAAGCAAATCTGGAAAGCATTAGGTTGTGTAGTCTATTGTCACGATCCAATGGATCAAAGGGAGTCAACAGAGTTTATTGATATAAATATTAATGAAGAAATAGACCGCGGGATCGATGGCGAGGAAATCTAAACATATCAAGAATCAGAATTAGTTTAAGAAAAAAGAAGAGGATTAATCTTGGTTTTCCCCTTGGTGGGTCGGCATGGCATCTCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCACTCGGATGGCTAAGGGAGCGGCCGGGGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAGTTGGCTGCTGCCACCGCTGAGCAATAACTAGCATAACCCCTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTGCTGAAAGGAGGAACTATATCCGGATCATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAA ATAGGGGTTCCGCGCACATTTCCCCGAAAAGT (SEQ ID NO: 5). iv. CVL83
[0164] The nucleic acid sequence for CVL83 is:GCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCTAATACGACTCACTATAGGGACCAAGGGGAAAATGAAGTGGTGACTCAAATCATCGAAGACCCTCGAGATTACATAGGTCCGGAACCTATGGCCTTCGTGACCGACCTCGAGTCAGAGTAGTTCAATAAGGACCTATCAAGTTTGGGCAATTTTTCGTCCCCGACACAAAAATGTCATCCGTGCTTAAAGCATATGAGCGATTCACGCTCACTCAAGAACTGCAAGATCAGAGTGAGGAAGGTACAATCCCACCTACAACACTAAAACCGGTAATCAGGGTATTTATACTAACCTCTAATAACCCAGAGCTAAGATCCCGGCTTCTTCTATTCTGCCTACGGATTGTTCTCAGTAATGGTGCAAGGGATTCCCATCGCTTTGGAGCATTACTCACAATGTTTTCGCTACCATCAGCCACAATGCTCAATCATGTCAAATTAGCTGACCAGTCACCAGAAGCTGATATCGAAAGGGTAGAGATCGATGGCTTTGAGGAGGGATCATTCCGCTTAATCCCCAATGCTCGTTCAGGTATGAGCCGTGGAGAGATCAATGCCTATGCTGCACTTGCAGAAGATCTACCTGACACACTAAACCATGCAACACCTTTCGTTGATTCCGAAGTCGAGGGAACTGCATGGGATGAGATTGAGACTTTCTTAGATATGTGTTACAGTGTCCTAATGCAGGCATGGATAGTGACTTGCAAGTGCATGACTGCGCCAGACCAACCTGCTGCTTCTATTGAGAAACGCCTGCAAAAATATCGTCAGCAAGGCAGGATCAACCCGAGATATCTCCTGCAACCGGAGGCTCGACGAATAATCCAGAATGTAATCCGGAAGGGAATGGTGGTCAGACATTTCCTCACCTTTGAACTGCAGCTTGCCCGAGCACAAAGCCTTGTATCAAATAGGTATTATGCTATGGTAGGGGATGTTGGAAAGTATATAGAGAATTGTGGAATGGGAGGCTTCTTTTTGACACTAAAATATGCATTAGGAACTAGATGGCCCACACTTGCTTTAGCTGCATTTTCAGGAGAGCTAACAAAGCTAAAGTCCCTCATGGCATTATACCAGACCCTTGGTGAGCAGGCCCGATATTTGGCCCTATTGGAGTCACCACATTTGATGGATTTTGCTGCAGCAAACTACCCACTGCTATATAGCTATGCTATGGGAATAGGCTATGTGTTAGATGTCAACATGAGGAACTACGCTTTCTCCAGATCATACATGAACAAGACATATTTCCAATTGGGAATGGAAACTGCAAGAAAACAACAGGGTGCAGTTGACATGAGGATGGCAGAAGATCTCGGTCTAACTCAAGCCGAACGCACCGAGATGGCAAATACACTTGCCAAATTGACCACAGCAAATCGAGGGGCAGACACCAGGGGAGGAGTCAACCCGTTCTCATCTGTCACTGGGACAACTCAGGTGCCCGCTGCAGCAACAGGTGACACACTCGAGAGTTACATGGCAGCGGATCGACTGAGGCAGAGATATGCTGATGCAGGCACCCATGATGATGAGATGCCACCATTGGAAGAGGAGGAAGAGGACGACACATCTGCAGGTCCACGCACTGGACCAACTCTTGAACAAGTGGCCTTGGACATCCAGAACGCAGCAGTTGGAGCTCCCATCCATACAGATGACCTGAATGCCGCACTGGGTGATCTTGACATCTAGACAATTCAGATCCCAATCTAAAATTGACATACCTAATTGATTAGTTAGATGGAACTACAGTGGATTCCATAAGGTTCCTGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACAAGCGACTGCCGGTGCCAACAGCGCAATCCACAATCTACAATGGATCCCACTGATCTGAGCTTCTCCCCAGATGAGATCAATAAGCTCATAGAGACAGGCCTGAATACTGTAGAGTATTTTACTTCCCAACAAGTCACAGGAACATCCTCTCTTGGAAAGAATACAATACCACCAGGGGTCACAGGACTACTAACCAATGCTGCAGAGGCAAAGATCCAAGAGTCAACTAACCATCAGAAGGGCTCAGTTGGTGGGGGTGCAAAACCAAAGAAACCGCGACCAAAAATTGCCATTGTGCCAGCAGATGACAAAACAGTGCCCGGAAAGCCGATCCCAAACCCTCTATTAGGTCTGGACTCCACCCCGAGCACCCAAACTGTGCTTGATCTAAGTGGGAAAACATTACCATCAGGATCCTATAAGGGGGTTAAGCTTGCGAAATTTGGAAAAGAAAATCTGATGACACGGTTCATCGAGGAACCCAGAGAGAATCCTATCGCAACCAGTTtCCCCATCGATTTTAAGAGGGGCAGGGATACCGGCGGGTTCCATAGAAGGGAGTACTCAATCGGATGGGTGGGAGATGAAGTCAAGGTCACTGAGTGGTGCAATCCATCCTGTTCTCCAATCACCGCTGCAGCAAGGCGATTTGAATGCACTTGTCACCAGTGTCCAGTCACTTGCTCTGAATGTGAACGAGATACTTAATACAGTGAGAAATTTGGACTCTCGGATGAATCAACTGGAGACAAAAGTAGATCGCATTCTCTCATCTCAGTCTCTAATCCAGACCATCAAGAATGACATAGTTGGACTTAAAGCAGGGATGGCTACTTTAGAAGGAATGATTACAACTGTGAAAATCATGGACCCGGGAGTTCCCAGTAATGTTACTGTGGAAGATGTACGCAAGACACTAAGTAACCATGCTGTTGTTGTGCCAGAATCATTCAATGATAGTTTCTTGACTCAATCTGAAGATGTAATTTCACTTGATGAGTTGGCTCGACCAACTGCAACAAGTGTTAAGAAGATTGTCAGGAAGGTTCCTCCTCAGAAGGATCTGACTGGATTGAAGATTACACTAGAGCAATTGGCAAAGGATTGCATCAGCAAACCGAAGATGAGGGAAGAGTATCTCCTCAAAATCAACCAGGCTTCCAGTGAGGCTCAGCTAATTGACCTCAAGAAAGCAATCATCCGCAGTGCAATTTGATCAAGAAACACCCAATTACACTACACTGGTATGACACTGTACTAACCCTGAGGGTTTTAGAAAAAACGATTAACGATAAATAAGCCCGAACACTACACACTACCTGAGGCAGCCATGCCATCCATCAGCATTCCCGCAGACCCCACCAATCCACGTCAATCAATAAAAGCGTTCCCAATTGTGATCAACAGTGATGGGGGTGAGAAAGGCCGCTTGGTTAAACAACTACGCACAACCTACTTGAATGACCTAGATACTCATGAGCCACTGGTGACATTCATAAATACCTATGGATTCATCTACGAACAGGATCGGGGGAATACCATTGTCGGAGAGGATCAACTTGGGAAGAAAAGAGAGGCTGTGACCGCTGCAATGGTTACCCTTGGATGTGGGCCTAATCTACCATCATTAGGGAATGTCCTGGGACAACTGAGGGAATTCCAGGTCACTGTTAGGAAGACATCCAGCAAAGCGGAAGAGATGGTCTTTGAAATTGTTAAGTATCCGAGAATATTTCGGGGTCATACATTAATCCAGAAAGGACTAGTCTGTGTCTCCGCAGAAAAATTTGTTAAGTCACCAGGGAAAATACAATCTGGAATGGACTATCTCTTCATTCCGACATTTCTGTCAGTGACTTACTGTCCAGCTGCAATCAAATTTCAGGTACCTGGCCCCATGTTGAAAATGAGATCAAGATACACTCAGAGCTTACAACTTGAACTAATGATAAGAATCCTGTGTAAGCCCGATTCGCCACTTATGAAGGTCCATACCCCTGACAAGGAGGGAAGAGGATGTCTTGTATCAGTATGGCTGCATGTATGCAACATCTTCAAATCAGGAAACAAGAATGGCAGTGAGTGGCAGGAATACTGGATGAGAAAGTGTGCTAACATGCAACTTGAAGTGTCGATTGCAGATATGTGGGGACCAACTATCATAATTCATGCCAGAGGTCACATTCCCAAAAGTGCTAAGTTGTTTTTTGGAAAGGGTGGATGGAGCTGCCATCCACTTCACGAAGTTGTTCCAAGTGTCACTAAAACACTATGGTCCGTGGGCTGTGAGATTACAAAGGCGAAGGCAATAATACAAGAGAGTAGCATCTCTCTTCTCGTGGAGACTACTGACATCATAAGTCCAAAAGTCAAAATTTCATCTAAGCATCGCCGCTTTGGGAAATCAAATTGGGGTCTGTTCAAGAAAACTAAATCACTGCCTAACCTGACGGAGCTGGAATGACTGACCTCTAATCGAGACTACACCGCCGCAAACTATAGGTGGGTGGTACCTCAGTGATTAATCTTGTAAGCACTGATCGTAGGCTACAACACACTAATATTATCCAGATTAGAGAGCTTAATTAGCTCTGTATTAATAATAACACTACTATTCCAATAACTGGAATCACCAGCTTGATTTATCTCCAAAATGATTCAAAGAAAACAAATCATATTAAGACTATCCTAAGCACGAACCCATATCGTCCTTCAAATCATGGGTACTATAATTCAATTTCTGGTGGTCTCCTGTCTATTGGCAGGAGCAGGCAGCCTTGATCCAGCAGCCCTCATGCAAATCGGTGTCATTCCAACAAATGTCCGGCAACTTATGTATTATACTGAAGCTTCATCAGCATTCATTGTTGTGAAGTTAATGCCTACAATTGACTCGCCGATTAGTGGATGTAATATAACATCAATTTCAAGCTATAATGCAACAGTGACAAAACTCCTACAGCCGATCGGTGAGAATTTGGAGACGATTAGGAACCAGTTGATTCCAACTCGGAGGAGACGCCGGTTTGCAGGGGTGGTGATTGGATTAGCTGCATTAGGAGTAGCTACTGCCGCACAGGTCACTGCCGCAGTGGCACTAGTAAAGGCAAATGAAAATGCTGCGGCTATACTCAATCTCAAAAATGCAATCCAAAAAACAAATGCAGCAGTTGCAGATGTGGTCCAGGCCACACAATCACTAGGAACGGCAGTTCAAGCAGTTCAAGATCACATAAACAGTGTGGTAAGTCCAGCAATTACAGCAGCCAATTGTAAGGCCCAAGATGCTATCATTGGCTCAATCCTCAATCTCTATTTGACCGAGTTGACAACCATCTTCCACAATCAAATTACAAACCCTGCATTGAGTCCCATTACAATTCAAGCTTTAAGGATCCTACTGGGGAGTACCTTGCCGACTGTGGTCGAAAAATCTTTCAATACCCAGATAAGTGCAGCTGAGCTTCTCTCATCAGGGTTATTGACAGGCCAGATTGTGGGATTAGATTTGACCTATATGCAGATGGTCATAAAAATTGAGCTGCCAACTTTAACTGTACAACCTGCAACCCAGATCATAGATCTGGCCACCATTTCTGCATTCATTAACAATCAAGAAGTCATGGCCCAATTACCAACACGTGTTATGGTGACTGGCAGCTTGATCCAAGCCTATCCCGCATCGCAATGCACCATTACACCCAACACTGTGTACTGTAGGTATAATGATGCCCAAGTACTCTCAGATGATACTATGGCTTGCCTCCAAGGTAACTTGACAAGATGCACCTTCTCTCCAGTGGTTGGGAGCTTTCTCACTCGATTCGTGCTGTTCGATGGAATAGTTTATGCAAATTGCAGGTCGATGTTGTGCAAGTGCATGCAACCTGCTGCTGTGATCCTACAGCCGAGTTCATCCCCTGTAACTGTCATTGACATGTACAAATGTGTGAGTCTGCAGCTTGACAATCTCAGATTCACCATCACTCAATTGGCCAATGTAACCTACAATAGCACCATCAAGCTTGAATCATCCCAGATCTTGTCTATTGATCCGTTGGATATATCCCAGAATCTAGCTGCGGTGAATAAGAGTCTAAGTGATGCACTACAACACTTAGCACAAAGTGACACATATCTTTCTGCAATCACATCAGCTACGACTACAAGTGTATTATCCATAATAGCAATCTGTCTTGGATCGTTAGGTTTAATATTAATAATCTTGCTCAGTGTAGTTGTGTGGAAGTTATTGACCATTGTCGTTGCTAATCGAAATAGAATGGAGAATTTTGTTTATCATAAATAAGCATTCCACCACTCACGATCTGATCTCAGTGAGAAAAATCAACCTGCAACTCTTGGAACAAGATAAGACAGTCATCCATTAGTAATTTTTAAGAAAAAAACGATAGGACCGAACCTAGTATTGAAAGAACCGTCTCGGTCAATCTAGGTAATCGAGCTGATACCGTCTCGGAAAGCTCAAATCGCGCGCCACCatgtcagataacggacca cagaaccagaggaacgcacccaggattactttcggaggaccaagcgatagcaccgggagcaaccagaatggagagcggag cggagcaagatccaagcagagacggccccagggcctgccaaacaataccgcatcctggttcaccgccctgacacagcacgg caaggaggacctgaagtttccaaggggacagggagtgcctatcaacaccaatagctcccctgacgatcagatcggctactatag gagggcaacaaggagaatcaggggaggcgacggcaagatgaaggatctgagcccacgctggtactctactatctgggaacc ggacctgaggcaggcctgccatatggcgccaacaaggacggaatcatctgggtggcaaccgagggcgccctgaacacacca aaggatcacatcggcacaagaaatcccgccaacaatgcagcaatcgtgctgcagctgccacagggaaccacactgcccaagg gcttttacgcagagggctctcggggaggcagccaggcatctagcagatcctctagccggagcagaaactcctctaggaattcca ccccaggaagctccaggggcacatcccctgcccgcatggcaggaaacggaggcgacgccgccctggccctgctgctgctgg atcgcctgaatcagctggagtccaagatgtctggcaagggacagcagcagcagggacagaccgtgacaaagaagtccgccgccgaggcctctaagaagccaaggcagaagcgcaccgccacaaaggcctacaacgtgacccaggccttcggcaggcgcgga ccagagcagacacagggcaattttggcgaccaggagctgatcaggcagggaaccgattataagcactggcctcagatcgccc agttcgccccatctgccagcgccttctttggcatgtctagaatcggcatggaggtgacccccagcggcacatggctgacctacac aggcgccatcaagctggacgataaggaccctaacttcaaggatcaggtcatcctgctgaacaagcacatcgacgcctataagac ctttccccctacagagcccaagaaggacaagaagaagaaggccgatgagacacaggccctgcctcagaggcagaagaagca gcagaccgtgacactgctgccagccgccgatctggacgattctccaaacagctgcagcagagcatgtccagtgccgactcca cccaggcttgaCGTACGACCTGCTATAGGCTATCCACTGCATCATCTCTCCTGCCATACTTCCTACTCACATCATATCTATTTTAAAGAAAAAATAGGCCCGAACACTAATCGTGCCGGCAGTGCCACTGCACACACAACACTACACATACAATACACTACAATGGTTGCAGAAGATGCCCCTGTTAGGGCCACTTGCCGAGTATTATTTCGAACAACAACTTTAATCTTTCTATGCACACTACTAGCATTAAGCATCTCTATCCTTTATGAGAGTTTAATAACCCAAAAGCAAATCATGAGCCAAGCAGGCTCAACTGGATCTAATTCTGGATTAGGAAGTATCACTGATCTTCTTAATAATATTCTCTCTGTCGCAAATCAGATTATATATAACTCTGCAGTCGCTCTACCTCTACAATTGGACACTCTTGAATCAACACTCCTTACAGCCATTAAGTCTCTTCAAACCAGTGACAAGCTAGAACAGAACTGCTCGTGGAGTGCTGCACTGATTAATGATAATAGATACATTAATGGCATCAATCAGTTCTATTTTTCAATTGCTGAGGGTCGCAATCTGACACTTGGCCCACTTCTTAATATGCCTAGTTTCATTCCAACTGCCACGACACCAGAGGGCTGCACCAGGATCCCATCATTCTCGCTCACTAAGACACACTGGTGTTATACACACAATGTTATCCTGAATGGATGCCAGGATCATGTATCCTCAAATCAATTTGTTTCTATGGGAATCATTGAACCCACTTCTGCCGGGTTTCCATTCTTTCGAACCCTAAAGACTCTATATCTCAGCGATGGGGTCAATCGTAAGAGCTGCTCTATCAGTACAGTTCCGGGGGGTTGTATGATGTACTGTTTTGTTTCTACTCAACCAGAGAGGGATGACTACTTTTCTGCCGCTCCTCCAGAACAACGAATTATTATAATGTACTATAATGATACAATCGTGGAGCGCATAATTAATCCACCCGGGGTACTAGATGTATGGGCAACATTGAACCCAGGAACAGGAAGCGGGGTATATTATTTAGGTTGGGTGCTCTTTCCAATATATGGCGGCGTGATTAAAGGTACGAGTTTATGGAATAATCAAGCAAATAAATACTTTATCCCCCAGATGGTTGCTGCTCTCTGCTCACAAAACCAGGCAACTCAAGTCCAAAATGCTAAGTCATCATACTATAGCAGCTGGTTTGGCAATCGAATGATTCAGTCTGGGATCCTGGCATGTCCTCTTCGACAGGATCTAACCAATGAGTGTTTAGTTCTGCCCTTTTCTAATGATCAGGTGCTTATGGGTGCTGAAGGGAGATTATACATGTATGGTGACTCGGTGTATTACTATCAAAGAAGCAATAGTTGGTGGCCTATGACCATGCTGTATAAGGTAACCATAACATTCACTAATGGTCAGCCATCTGCTATATCAGCTCAGAATGTGCCCACACAGCAGGTCCCTAGACCTGGGACAGGAGACTGCTCTGCAACCAATAGATGTCCCGGTTTTTGCTT GACAGGAGTGTATGCCGATGCCTGGTTACTGACCAACCCTTCGTCTACCAGTA CATTTGGATCAGAAGCAACCTTCACTGGTTCTTATCTCAACACAGCAACTCAG CGTATCAATCCGACGATGTATATCGCGAACAACACACAGATCATAAGCTCAC AGCAATTTGGATCAAGCGGTCAAGAAGCAGCATATGGCCACACAACTTGTTT TAGGGACACAGGCTCTGTTATGGTATACTGTATCTATATTATTGAATTGTCCT CATCTCTCTTAGGACAATTTCAGATTGTCCCATTTATCCGTCAGGTGACACTAT CCTAAAGGCAGAAGCCTTCAGGTCTGACCCAGCCAATCAAAGCATTATACCA GACCATGGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAG CAACAAGCGGCGGCCGCCACCatgttcgtcttcctggtcctgctgcctctggtctcctcacagtgcgtcaatctg acaactcggactcagctgccacctgcttatactaatagcttcaccagaggcgtgtactatcctgacaaggtgtttagaagctccgtg ctgcactctacacaggatctgtttctgccattctttagcaacgtgacctggttccacGTGatcagcggcaccaatggcacaaagc ggttcgacaatcccgtgctgccttttaacgatggcgtgtacttcgcctctATCgagaagagcaacatcatcagaggctggatctt tggcaccacactggactccaagacacagtctctgctgatcgtgaacaatgccaccaacgtggtcatcaaggtgtgcgagttccag ttttgtaatgatcccttcctgGATcacaagaacaataagagctggatggagtccgagtttagagtgtattctagcgccaacaact gcacatttgagtacgtgagccagcctttcctgatggacctggagggcaagcagggcaatttcaagaacctgagggagttcgtgtt taagaatatcgacggctacttcaaaatctactctaagcacacccccATCATCgtgcgcGAGCCTGAGgacctgcct cagggcttcagcgccctggagcccctggtggatctgcctatcggcatcaacatcacccggtttcagacactgctggccctgcac agaagctacctgacacccggcgactcctctagcggatggaccgccggcgctgccgcctactatgtgggctacctccagccccg gaccttcctgctgaagtacaacgagaatggcaccatcacagacgcagtggattgcgccctggaccccctgagcgagacaaagt gtacactgaagtcctttaccgtggagaagggcatctatcagacatccaatttcagggtgcagccaaccgagtctatcgtgcgcttt cctaatatcacaaacctgtgcccatttGACgaggtgttcaacgcaacccgcttcgccagcgtgtacgcctggaataggaagcg gatcagcaactgcgtggccgactatagcgtgctgtacaacCTGgccCCCttcTTCacctttaagtgctatggcgtgtcccc cacaaagctgaatgacctgtgctttaccaacgtctacgccgattctttcgtgatcaggggcgacgaggtgcgccagatcgccccc ggccagacaggcAATatcgcagactacaattataagctgccagacgatttcaccggctgcgtgatcgcctggaacagcaacAAGctggattccaaagtgTCCggcaactacaattatctgtaccggctgtttagaaagagcaatctgaagcccttcgagaggg acatctctacagaaatctaccaggccggcAATAAGccttgcaatggcgtgGCCggctttaactgttatttcccactcAAGtcctacTCCttcCGCcccacaTATggcgtgggcCACcagccttaccgcgtggtggtgctgagctttgagctgctgca cgccccagcaacagtgtgcggccccaagaagtccaccaatctggtgaagaacaagtgcgtgaacttcaacttcaacggcctgA AGggcacaggcgtgctgaccgagtccaacaagaagttcctgccatttcagcagttcggcagggacatcgcagataccacaga cgccgtgcgcgacccacagaccctggagatcctggacatcacaccctgctctttcggcggcgtgagcgtgatcacacccggca ccaatacaagcaaccaggtggccgtgctgtatcagGGCgtgaattgtaccgaggtgcccgtggctatccacgccgatcagct gaccccaacatggcgggtgtacagcaccggctccaacgtcttccagacaagagccggatgcctgatcggagcagagTACg tgaacaattcctatgagtgcgacatcccaatcggcgccggcatctgtgcctcttaccagacccagacaAAGtctCACagaagagcccggagcgtggcctcccagtctatcatcgcctataccatgtccctgggcgccgagaacagcgtggcctactctaacaata gcatcgccatcccaaccaacttcacaatctctgtgaccacagagatcctgcccgtgtccatgaccaagacatctgtggactgcac aatgtatatctgtggcgattctaccgagtgcagcaacctgctgctccagtacggcagcttttgtacccagctgAAGagagccct gacaggcatcgccgtggagcaggataagaacacacaggaggtgttcgcccaggtgaagcaaatctacaagaccccccctatc aagTACtttggcggcttcaatttttcccagatcctgcctgatccatccaagccttctaagcggagctttatcgaggacctgctgttc aacaaggtgaccctggccgatgccggcttcatcaagcagtatggcgattgcctgggcgacatcgcagccagggacctgatctg cgcccagaagtttAAGggcctgaccgtgctgccacccctgctgacagatgagatgatcgcacagtacacaagcgccctgctg gccggcaccatcacatccggatggaccttcggcgcaggagccgccctccagatcccctttgccatgcagatggcctataggttc aacggcatcggcgtgacccagaatgtgctgtacgagaaccagaagctgatcgccaatcagtttaactccgccatcggcaagatc caggacagcctgtcctctacagccagcgccctgggcaagctccaggatgtggtgaatCACaacgcccaggccctgaatacc ctggtgaagcagctgagcagcAAGttcggcgccatctctagcgtgctgaatgacatcTTTagccggctggacaaggtgga ggcagaggtgcagatcgaccggctgatcaccggccggctccagagcctccagacctatgtgacacagcagctgatcagggcc gccgagatcagggccagcgccaatctggcagcaaccaagatgtccgagtgcgtgctgggccagtctaagagagtggacttttg tggcaagggctatcacctgatgtccttccctcagtctgccccacacggcgtggtgtttctgcacgtgacctacgtgcccgcccag gagaagaacttcaccacagcccctgccatctgccacgatggcaaggcccactttccaagggagggcgtgttcgtgtccaacgg cacccactggtttgtgacacagcgcaatttctacgagccccagatcatcaccacagacaacaccttcgtgagcggcaactgtgac gtggtcatcggcatcgtgaacaataccgtgtatgatccactccagcccgagctggacagctttaaggaggagctggataagtattt caagaatcacacctcccctgacgtggatctgggcgacatcagcggcatcaatgcctccgtggtgaacatccagaaggagatcg accgcctgaacgaggtggctaagaatctgaacgagagcctgatcgacctccaggagctgggcaagtatgagcagtacatcaag tggccctggtacatctggctgggcttcatcgccggcctgatcgccatcgtgatggtgaccatcatgctgtgctgtatgacatcctgc tgttcttgcctgaagggctgctgtagctgtggctcctgctgtaagttattgaccattgtcgttgctaatcgaaatagaatggagaatttt gtttatcataaatgaAGTCGACTCATGGAATGCATACCAAACATTATTGACACTAATGA CACACAAAATTGGTTTTAAGAAAAACCAAGAGAACAATAGGCCAGAATGGCT GGGTCTCGGGAGATATTACTCCCTGAAGTCCATCTCAATTCACCAATTGTAAA GCATAAGCTATACTATTACATTCTACTTGGAAACCTCCCAAATGAGATCGACC TTGACGATTTAGGTCCATTACATAATCAAAATTGGAATCAGATAGCACATGA AGAGTCTAACTTAGCTCAACGCTTGGTAAATGTAAGAAATTTTCTAATTACCC ACATCCCTGATCTTAGAAAGGGCCATTGGCAAGAGTATGTCAATGTAATACT GTGGCCGCGAATTCTTCCCTTGATCCCGGATTTTAAAATCAATGACCAATTGC CTCTGCTCAAAAATTGGGACAAGTTAGTTAAAGAATCATGTTCAGTAATCAAT GCAGGTACTTCCCAGTGCATTCAGAATCTCAGCTATGGACTGACAGGTCGTGG GAACCTCTTTACACGATCACGTGAACTCTCTGGTGACCGCAGGGATATTGATC TTAAGACAGTTGTGGCAGCATGGCATGACTCAGACTGGAAAAGAATAAGTGATTTTTGGATTATGATCAAATTCCAGATGAGACAATTAATTGTTAGGCAAACAGATCATAATGATTCTGATTTAATCACGTATATCGAAAATAGAGAAGGCATAATCATCATAACCCCTGAACTGGTAGCATTATTTAACACTGAGAATCATACACTAACATACATGACCTTTGAAATTGTACTGATGGTTTCAGATATGTACGAAGGTCGTCACAACATTTTATCACTATGCACAGTTAGCACTTACCTGAATCCTCTGAAGAAAAGAATAACATATTTATTGAGCCTTGTAGATAACTTAGCTTTTCAGATAGGTGATGCTGTATATAACATAATTGCTTTGCTAGAATCCTTTGTATATGCACAGTTGCAAATGTCAGATCCCATCCCAGAACTCAGAGGACAATTCCATGCATTCGTATGTTCTGAGATTCTTGATGCACTAAGAGGAACTAATAGTTTCACCCAGGATGAATTAAGAACTGTGACAACTAATTTGATATCCCCATTCCAAGATCTGACCCCAGATCTTACGGCTGAATTGCTCTGTATAATGAGGCTTTGGGGACACCCCATGCTCACTGCCAGTCAAGCTGCAGGAAAGGTACGCGAGTCTATGTGTGCTGGAAAAGTATTAGACTTTCCCACCATTATGAAAACACTAGCCTTTTTCCATACTATTCTGATCAATGGATACAGGAGGAAGCATCATGGAGTATGGCCACCCTTAAACTTACCGGGTAATGCTTCAAAGGGTCTCACGGAACTTATGAATGACAATACTGAAATAAGCTATGAATTCACACTTAAGCATTGGAAGGAAGTCTCTCTTATAAAATTCAAGAAATGTTTTGATGCAGACGCAGGTGAGGAACTCAGTATATTTATGAAAGATAAGGCAATTAGTGCCCCAAAACAAGACTGGATGAGTGTGTTTAGAAGAAGCCTAATCAAACAGCGCCATCAGCATCATCAGGTCCCCCTACCAAATCCATTCAATCGACGGCTGTTGCTAAACTTTCTCGGAGATGACAAATTCGACCCGAATGTGGAGCTACAGTATGTAACATCAGGTGAGTATCTACATGATGACACGTTTTGTGCATCATATTCACTAAAAGAGAAGGAAATTAAACCTGATGGTCGAATTTTTGCAAAGTTGACTAAGAGAATGAGATCATGTCAAGTTATAGCAGAATCTCTTTTAGCGAACCATGCTGGGAAGTTAATGAAAGAGAATGGTGTTGTGATGAATCAGCTATCATTAACAAAATCACTATTAACAATGAGTCAGATTGGAATAATATCCGAGAAAGCTAGAAAGTCAACTCGAGATAACATAAATCAACCTGGTTTCCAGAATATCCAGAGAAATAAATCACATCACTCCAAGCAAGTCAATCAGCGAGATCCAAGTGATGACTTTGAATTGGCAGCATCTTTTTTAACTACTGATCTCAAAAAATATTGTTTACAATGGAGGTACCAGACAATTATCCCATTTGCTCAATCATTAAACAGAATGTATGGTTATCCTCATCTCTTTGAGTGGATTCACTTACGGCTAATGCGTAGTACACTTTACGTGGGGGATCCCTTCAACCCACCAGCAGATACCAGTCAATTTGATCTAGATAAAGTAATTAATGGAGATATCTTCATTGTATCACCCAGAGGTGGAATTGAAGGGCTGTGTCAAAAGGCTTGGACAATGATATCTATCGCTGTGATAATTCTATCTGCCACAGAGTCTGGCACACGAGTAATGAGTATGGTGCAGGGAGATAATCAAGCAATTGCTGTCACCACACGAGTACCAAGGAGCCTGCCGACTCTTGAGAAAAAGACTATTGCTTTTAGATCTTGTAATCTATTCTTTGAGAGGTTAAAATGTAATAATTTTGGATTAGGTCACCATTTGAAAGAACAAGAGACTATCATTAGTTCTCACTTCTTTGTTTATAGCAAGAGAATATTCTATCAGGGGAGGATTCTAACGCAAGCCTTAAAAAATGCTAGTAAGCTCTGCTTGACAGCTGATGTCCTAGGAGAATGCACCCAATCATCATGTTCTAATCTTGCAACTACTGTCATGAGGTTAACTGAGAATGGTGTTGAAAAAGATATCTGTTTCTACTTGAATATCTATATGACCATCAAACAGCTCTCCTATGATATCATCTTCCCTCAAGTGTCAATTCCTGGAGATCAGATCACATTAGAATACATAAATAATCCACACCTGGTATCACGATTGGCTCTTTTGCCATCCCAGTTAGGAGGTCTAAACTACCTGTCATGCAGTAGGCTGTTCAATCGAAACATAGGCGACCCGGTGGTTTCCGCAGTTGCAGATCTTAAGAGATTAATTAAATCAGGATGTATGGATTACTGGATCCTTTATAACTTATTAGGGAGAAAACCGGGAAACGGCTCATGGGCTACTTTAGCAGCTGACCCGTACTCAATCAATATAGAGTATCAATACCCTCCAACTACAGCTCTTAAGAGGCACACCCAACAAGCTCTGATGGAACTCAGTACGAATCCAATGTTACGTGGCATATTCTCTGACAATGCACAGGCAGAAGAAAATAACCTTGCTAGGTTTCTCCTGGATAGGGAGGTGATCTTTCCGCGTGTAGCTCACATCATCATTGAGCAAACCAGTGTCGGGAGGAGAAAACAGATTCAAGGATATTTGGATTCAACTAGATCGATAATGAGGAAATCACTAGAAATTAAGCCCTTATCCAATAGGAAGCTTAATGAAATACTGGATTACAACATCAATTACCTAGCTTACAATTTGGCATTACTCAAGAATGCTATTGAACCTCCGACTTATTTGAAGGCAATGACACTTGAAACATGTAGCATCGACATTGCAAGGAACCTCCGGAAGCTCTCCTGGGCCCCACTCTTGGGTGGGAGAAATCTTGAAGGATTAGAGACGCCAGATCCCATTGAAATTACTGCAGGAGCATTAATTGTTGGATCGGGCTACTGTGAACAGTGTGCTGCAGGAGACAATCGATTCACATGGTTTTTCTTGCCATCTGGTATCGAGATAGGAGGGGATCCCCGTGATAATCCTCCTATCCGTGTACCGTACATTGGCTCCAGGACTGATGAGAGGAGGGTAGCCTCAATGGCATACATCAGGGGTGCCTCGAGTAGCTTAAAAGCAGTTCTTAGACTGGCGGGAGTGTACATCTGGGCATTCGGAGATACTCTGGAGAATTGGATAGATGCACTGGATTTGTCTCACACTAGAGTTAACATCACACTTGAACAGCTGCAATCCCTCACCCCACTTCCAACCTCTGCCAATCTAACCCATCGGTTGGATGATGGCACAACTACCCTAAAGTTTACTCCTGCGAGCTCTTACACCTTTTCAAGTTTCACTCATATATCAAATGATGAGCAATACCTGACAATTAATGACAAAACTGCAGATTCAAATATAATCTACCAACAGTTAATGATCACTGGACTCGGAATCTTAGAAACATGGAATAATCCCCCAATCAATAGAACATTCGAAGAATCTACCCTACATTTGCACACTGGTGCATCATGTTGTGTCCGACCTGTGGACTCCTGCATTCTCTCAGAAGCATTAACAGTCAAGCCACATATTACAGTACCGTACAGCAATAAATTTGTATTTGATGAGGACCCGCTATCTGAATATGAAACTGCAAAACTGGAATCGTTATCATTCCAAGCCCAATTAGGCAACATTGATGCTGTAGATATGACAGGTAAATTAACATTATTGTCCCAATTCACTGCAAGGCAGATTATCAATGCAATCACTGGACTCGATGAGTCTGTCTCTCTTACTAATGATGCCATTGTTGCATCAGACTATGTCTCCAATTGGATTAGTGAATGCATGTATACCAAATTAGATGAATTATTTATGTATTGTGGGTGGGAACTACTATTGGAACTATCCTATCAAATGTATTATCTGAGGGTAGTTGGGTGGAGTAATATAGTGGATTATTCTTACATGATCTTGAGAAGAATCCCGGGTGCAGCATTAAACAATCTGGCATCTACATTAAGTCATCCAAAACTTTTCCGACGAGCTATCAACCTAGATATAGTTGCCCCCTTAAATGCTCCTCATTTTGCATCTCTGGACTACATCAAGATGAGTGTGGATGCAATACTCTGGGGCTGTAAAAGAGTCATCAATGTGCTCTCCAATGGAGGGGACTTAGAATTAGTTGTGACATCTGAAGATAGCCTTATTCTCAGTGACCGATCCATGAATCTCATTGCAAGGAAATTAACTTTATTATCACTGATTCACCATAATGGTTTGGAACTACCAAAGATTAAGGGGTTCTCTCCTGATGAGAAGTGTTTCGCTTTGACAGAATTTTTGAGGAAAGTGGTGAACTCAGGGTTGAGTTCAATAGAGAACCTATCAAATTTTATGTACAATGTGGAGAACCCACGGCTTGCAGCATTCGCCAGCAACAATTACTACCTGACCAGAAAATTATTGAATTCAATACGAGATACTGAGTCGGGTCAAGTAGCAGTCACCTCATATTATGAATCATTAGAATATATTGATAGTCTTAAGCTAACCCCACATGTGCCTGGCACCTCATGCATTGAGGATGATAGTCTATGTACAAATGATTACATAATCTGGATCATAGAGTCTAATGCAAACTTGGAGAAGTATCCAATTCCAAATAGCCCTGAGGATGATTCCAATTTCCATAACTTTAAGTTGAATGCTCCATCGCACCATACCTTACGCCCATTAGGGTTGTCATCAACTGCTTGGTATAAGGGTATAAGCTGCTGCAGGTACCTTGAGCGATTAAAGCTACCACAAGGTGATCATTTATATATTGCAGAAGGTAGTGGTGCCAGTATGACAATCATAGAATACCTATTCCCAGGAAGAAAGATATATTACAATTCTTTATTTAGTAGTGGTGACAATCCCCCACAAAGAAATTATGCACCAATGCCTACTCAGTTCATTGAGAGTGTCCCATACAAGCTCTGGCAAGCACACACAGATCAATATCCCGAGATTTTTGAGGACTTCATCCCTCTATGGAACGGAAACGCCGCCATGACTGACATAGGAATGACAGCTTGTGTAGAATTCATCATCAATCGAGTCGGCCCAAGGACTTGCAGTTTAGTACATGTAGATTTGGAATCAAGTGCAAGCTTAAATCAACAATGCCTGTCAAAGCCGATAATTAATGCTATCATCACTGCTACAACTGTTTTGTGCCCTCATGGGGTGCTTATTCTGAAATATAGTTGGTTGCCATTTACTAGATTTAGTACTTTGATCACTTTCTTATGGTGCTACTTTGAGAGAATCACTGTTCTTAGGAGCACATATTCTGATCCAGCTAATCATGAGGTTTATTTAATTTGTATCCTTGCCAACAACTTTGCATTCCAGACTGTCTCGCAGGCAACAGGAATGGCGATGACTTTAACTGATCAAGGGTTTACTTTGATATCACCTGAAAGAATAAATCAGTATTGGGATGGTCACTTGAAGCAAGAACGTATCGTAGCAGAAGCAATTGATAAGGTGGTTCTAGGAGAAAATGCTCTATTTAATTCGAGTGATAATGAATTAATTCTCAAATGTGGAGGGACACCAAATGCACGGAATCTCATCGATATCGAGCCAGTCGCAACTTTCATAGAATTTGAACAATTGATCTGCACAATGTTGACAACCCACTTGAAGGAAATAATTGATATAACAAGGTCTGGAACCCAGGATTATGAAAGTTTATTACTCACTCCTTACAATTTAGGTCTTCTTGGTAAAATCAGTACGATAGTGAGATTATTAACAGAAAGGATTCTAAATCATACTATCAGGAATTGGTTGATCCTCCCACCTTCGCTCCGGATGATCGTGAAGCAGGACTTGGAATTCGGCATATTCAGGATTACTTCCATCCTCAATTCTGATCGGTTCCTGAAGCTTTCTCCAAATAGGAAATACTTGATTGCACAATTAACTGCAGGCTACATTAGGAAATTGATTGAGGGGGATTGCAATATCGATCTAACCAGACCTATCCAAAAGCAAATCTGGAAAGCATTAGGTTGTGTAGTCTATTGTCACGATCCAATGGATCAAAGGGAGTCAACAGAGTTTATTGATATAAATATTAATGAAGAAATAGACCGCGGGATCGATGGCGAGGAAATCTAAACATATCAAGAATCAGAATTAGTTTAAGAAAAAAGAAGAGGATTAATCTTGGTTTTCCCCTTGGTGGGTCGGCATGGCATCTCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCACTCGGATGGCTAAGGGAGCGGCCGGGGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAGTTGGCTGCTGCCACCGCTGAGCAATAACTAGCATAACCCCTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTGCTGAAAGGAGGAACTATATCCGGATCATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATA TTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCG AAAAGT (SEQ ID NO: 6). v. CVL109
[0165] The nucleic acid sequence for CVL109 is:GCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCTAATACGACTCACTATAGGGACCAAGGGGAAAATGAAGTGGTGACTCAAATCATCGAAGACCCTCGAGATTACATAGGTCCGGAACCTATGGCCTTCGTGACCGACCTCGAGTCAGAGTAGTTCAATAAGGACCTATCAAGTTTGGGCAATTTTTCGTCCCCGACACAAAAATGTCATCCGTGCTTAAAGCATATGAGCGATTCACGCTCACTCAAGAACTGCAAGATCAGAGTGAGGAAGGTACAATCCCACCTACAACACTAAAACCGGTAATCAGGGTATTTATACTAACCTCTAATAACCCAGAGCTAAGATCCCGGCTTCTTCTATTCTGCCTACGGATTGTTCTCAGTAATGGTGCAAGGGATTCCCATCGCTTTGGAGCATTACTCACAATGTTTTCGCTACCATCAGCCACAATGCTCAATCATGTCAAATTAGCTGACCAGTCACCAGAAGCTGATATCGAAAGGGTAGAGATCGATGGCTTTGAGGAGGGATCATTCCGCTTAATCCCCAATGCTCGTTCAGGTATGAGCCGTGGAGAGATCAATGCCTATGCTGCACTTGCAGAAGATCTACCTGACACACTAAACCATGCAACACCTTTCGTTGATTCCGAAGTCGAGGGAACTGCATGGGATGAGATTGAGACTTTCTTAGATATGTGTTACAGTGTCCTAATGCAGGCATGGATAGTGACTTGCAAGTGCATGACTGCGCCAGACCAACCTGCTGCTTCTATTGAGAAACGCCTGCAAAAATATCGTCAGCAAGGCAGGATCAACCCGAGATATCTCCTGCAACCGGAGGCTCGACGAATAATCCAGAATGTAATCCGGAAGGGAATGGTGGTCAGACATTTCCTCACCTTTGAACTGCAGCTTGCCCGAGCACAAAGCCTTGTATCAAATAGGTATTATGCTATGGTAGGGGATGTTGGAAAGTATATAGAGAATTGTGGAATGGGAGGCTTCTTTTTGACACTAAAATATGCATTAGGAACTAGATGGCCCACACTTGCTTTAGCTGCATTTTCAGGAGAGCTAACAAAGCTAAAGTCCCTCATGGCATTATACCAGACCCTTGGTGAGCAGGCCCGATATTTGGCCCTATTGGAGTCACCACATTTGATGGATTTTGCTGCAGCAAACTACCCACTGCTATATAGCTATGCTATGGGAATAGGCTATGTGTTAGATGTCAACATGAGGAACTACGCTTTCTCCAGATCATACATGAACAAGACATATTTCCAATTGGGAATGGAAACTGCAAGAAAACAACAGGGTGCAGTTGACATGAGGATGGCAGAAGATCTCGGTCTAACTCAAGCCGAACGCACCGAGATGGCAAATACACTTGCCAAATTGACCACAGCAAATCGAGGGGCAGACACCAGGGGAGGAGTCAACCCGTTCTCATCTGTCACTGGGACAACTCAGGTGCCCGCTGCAGCAACAGGTGACACACTCGAGAGTTACATGGCAGCGGATCGACTGAGGCAGAGATATGCTGATGCAGGCACCCATGATGATGAGATGCCACCATTGGAAGAGGAGGAAGAGGACGACACATCTGCAGGTCCACGCACTGGACCAACTCTTGAACAAGTGGCCTTGGACATCCAGAACGCAGCAGTTGGAGCTCCCATCCATACAGATGACCTGAATGCCGCACTGGGTGATCTTGACATCTAGACAATTCAGATCCCAATCTAAAATTGACATACCTAATTGATTAGTTAGATGGAACTACAGTGGATTCCATAAGGTTCCTGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACAAGCGACTGCCGGTGCCAACAGCGCAATCCACAATCTACAATGGATCCCACTGATCTGAGCTTCTCCCCAGATGAGATCAATAAGCTCATAGAGACAGGCCTGAATACTGTAGAGTATTTTACTTCCCAACAAGTCACAGGAACATCCTCTCTTGGAAAGAATACAATACCACCAGGGGTCACAGGACTACTAACCAATGCTGCAGAGGCAAAGATCCAAGAGTCAACTAACCATCAGAAGGGCTCAGTTGGTGGGGGTGCAAAACCAAAGAAACCGCGACCAAAAATTGCCATTGTGCCAGCAGATGACAAAACAGTGCCCGGAAAGCCGATCCCAAACCCTCTATTAGGTCTGGACTCCACCCCGAGCACCCAAACTGTGCTTGATCTAAGTGGGAAAACATTACCATCAGGATCCTATAAGGGGGTTAAGCTTGCGAAATTTGGAAAAGAAAATCTGATGACACGGTTCATCGAGGAACCCAGAGAGAATCCTATCGCAACCAGTTtCCCCATCGATTTTAAGAGGGGCAGGGATACCGGCGGGTTCCATAGAAGGGAGTACTCAATCGGATGGGTGGGAGATGAAGTCAAGGTCACTGAGTGGTGCAATCCATCCTGTTCTCCAATCACCGCTGCAGCAAGGCGATTTGAATGCACTTGTCACCAGTGTCCAGTCACTTGCTCTGAATGTGAACGAGATACTTAATACAGTGAGAAATTTGGACTCTCGGATGAATCAACTGGAGACAAAAGTAGATCGCATTCTCTCATCTCAGTCTCTAATCCAGACCATCAAGAATGACATAGTTGGACTTAAAGCAGGGATGGCTACTTTAGAAGGAATGATTACAACTGTGAAAATCATGGACCCGGGAGTTCCCAGTAATGTTACTGTGGAAGATGTACGCAAGACACTAAGTAACCATGCTGTTGTTGTGCCAGAATCATTCAATGATAGTTTCTTGACTCAATCTGAAGATGTAATTTCACTTGATGAGTTGGCTCGACCAACTGCAACAAGTGTTAAGAAGATTGTCAGGAAGGTTCCTCCTCAGAAGGATCTGACTGGATTGAAGATTACACTAGAGCAATTGGCAAAGGATTGCATCAGCAAACCGAAGATGAGGGAAGAGTATCTCCTCAAAATCAACCAGGCTTCCAGTGAGGCTCAGCTAATTGACCTCAAGAAAGCAATCATCCGCAGTGCAATTTGATCAAGAAACACCCAATTACACTACACTGGTATGACACTGTACTAACCCTGAGGGTTTTAGAAAAAACGATTAACGATAAATAAGCCCGAACACTACACACTACCTGAGGCAGCCATGCCATCCATCAGCATTCCCGCAGACCCCACCAATCCACGTCAATCAATAAAAGCGTTCCCAATTGTGATCAACAGTGATGGGGGTGAGAAAGGCCGCTTGGTTAAACAACTACGCACAACCTACTTGAATGACCTAGATACTCATGAGCCACTGGTGACATTCATAAATACCTATGGATTCATCTACGAACAGGATCGGGGGAATACCATTGTCGGAGAGGATCAACTTGGGAAGAAAAGAGAGGCTGTGACCGCTGCAATGGTTACCCTTGGATGTGGGCCTAATCTACCATCATTAGGGAATGTCCTGGGACAACTGAGGGAATTCCAGGTCACTGTTAGGAAGACATCCAGCAAAGCGGAAGAGATGGTCTTTGAAATTGTTAAGTATCCGAGAATATTTCGGGGTCATACATTAATCCAGAAAGGACTAGTCTGTGTCTCCGCAGAAAAATTTGTTAAGTCACCAGGGAAAATACAATCTGGAATGGACTATCTCTTCATTCCGACATTTCTGTCAGTGACTTACTGTCCAGCTGCAATCAAATTTCAGGTACCTGGCCCCATGTTGAAAATGAGATCAAGATACACTCAGAGCTTACAACTTGAACTAATGATAAGAATCCTGTGTAAGCCCGATTCGCCACTTATGAAGGTCCATACCCCTGACAAGGAGGGAAGAGGATGTCTTGTATCAGTATGGCTGCATGTATGCAACATCTTCAAATCAGGAAACAAGAATGGCAGTGAGTGGCAGGAATACTGGATGAGAAAGTGTGCTAACATGCAACTTGAAGTGTCGATTGCAGATATGTGGGGACCAACTATCATAATTCATGCCAGAGGTCACATTCCCAAAAGTGCTAAGTTGTTTTTTGGAAAGGGTGGATGGAGCTGCCATCCACTTCACGAAGTTGTTCCAAGTGTCACTAAAACACTATGGTCCGTGGGCTGTGAGATTACAAAGGCGAAGGCAATAATACAAGAGAGTAGCATCTCTCTTCTCGTGGAGACTACTGACATCATAAGTCCAAAAGTCAAAATTTCATCTAAGCATCGCCGCTTTGGGAAATCAAATTGGGGTCTGTTCAAGAAAACTAAATCACTGCCTAACCTGACGGAGCTGGAATGACTGACCTCTAATCGAGACTACACCGCCGCAAACTATAGGTGGGTGGTACCTCAGTGATTAATCTTGTAAGCACTGATCGTAGGCTACAACACACTAATATTATCCAGATTAGAGAGCTTAATTAGCTCTGTATTAATAATAACACTACTATTCCAATAACTGGAATCACCAGCTTGATTTATCTCCAAAATGATTCAAAGAAAACAAATCATATTAAGACTATCCTAAGCACGAACCCATATCGTCCTTCAAATCATGGGTACTATAATTCAATTTCTGGTGGTCTCCTGTCTATTGGCAGGAGCAGGCAGCCTTGATCCAGCAGCCCTCATGCAAATCGGTGTCATTCCAACAAATGTCCGGCAACTTATGTATTATACTGAAGCTTCATCAGCATTCATTGTTGTGAAGTTAATGCCTACAATTGACTCGCCGATTAGTGGATGTAATATAACATCAATTTCAAGCTATAATGCAACAGTGACAAAACTCCTACAGCCGATCGGTGAGAATTTGGAGACGATTAGGAACCAGTTGATTCCAACTCGGAGGAGACGCCGGTTTGCAGGGGTGGTGATTGGATTAGCTGCATTAGGAGTAGCTACTGCCGCACAGGTCACTGCCGCAGTGGCACTAGTAAAGGCAAATGAAAATGCTGCGGCTATACTCAATCTCAAAAATGCAATCCAAAAAACAAATGCAGCAGTTGCAGATGTGGTCCAGGCCACACAATCACTAGGAACGGCAGTTCAAGCAGTTCAAGATCACATAAACAGTGTGGTAAGTCCAGCAATTACAGCAGCCAATTGTAAGGCCCAAGATGCTATCATTGGCTCAATCCTCAATCTCTATTTGACCGAGTTGACAACCATCTTCCACAATCAAATTACAAACCCTGCATTGAGTCCCATTACAATTCAAGCTTTAAGGATCCTACTGGGGAGTACCTTGCCGACTGTGGTCGAAAAATCTTTCAATACCCAGATAAGTGCAGCTGAGCTTCTCTCATCAGGGTTATTGACAGGCCAGATTGTGGGATTAGATTTGACCTATATGCAGATGGTCATAAAAATTGAGCTGCCAACTTTAACTGTACAACCTGCAACCCAGATCATAGATCTGGCCACCATTTCTGCATTCATTAACAATCAAGAAGTCATGGCCCAATTACCAACACGTGTTATGGTGACTGGCAGCTTGATCCAAGCCTATCCCGCATCGCAATGCACCATTACACCCAACACTGTGTACTGTAGGT ATAATGATGCCCAAGTACTCTCAGATGATACTATGGCTTGCCTCCAAGGTAAC TTGACAAGATGCACCTTCTCTCCAGTGGTTGGGAGCTTTCTCACTCGATTCGTGCTGTTCGATGGAATAGTTTATGCAAATTGCAGGTCGATGTTGTGCAAGTGCA TGCAACCTGCTGCTGTGATCCTACAGCCGAGTTCATCCCCTGTAACTGTCATTGACATGTACAAATGTGTGAGTCTGCAGCTTGACAATCTCAGATTCACCATCAC TCAATTGGCCAATGTAACCTACAATAGCACCATCAAGCTTGAATCATCCCAGA TCTTGTCTATTGATCCGTTGGATATATCCCAGAATCTAGCTGCGGTGAATAAG AGTCTAAGTGATGCACTACAACACTTAGCACAAAGTGACACATATCTTTCTGC AATCACATCAGCTACGACTACAAGTGTATTATCCATAATAGCAATCTGTCTTG GATCGTTAGGTTTAATATTAATAATCTTGCTCAGTGTAGTTGTGTGGAAGTTA TTGACCATTGTCGTTGCTAATCGAAATAGAATGGAGAATTTTGTTTATCATAA ATAAGCATTCCACCACTCACGATCTGATCTCAGTGAGAAAAATCAACCTGCA ACTCTTGGAACAAGATAAGACAGTCATCCATTAGTAATTTTTAAGAAAAAAA CGATAGGACCGAACCTAGTATTGAAAGAACCGTCTCGGTCAATCTAGGTAAT CGAGCTGATACCGTCTCGGAAAGCTCAAATCGCGCGCCACCatgtcagataacggacca cagaaccagaggaacgcacccaggattactttcggaggaccaagcgatagcaccgggagcaaccagaatggagagcggag cggagcaagatccaagcagagacggccccagggcctgccaaacaataccgcatcctggttcaccgccctgacacagcacgg caaggaggacctgaagtttccaaggggacagggagtgcctatcaacaccaatagctcccctgacgatcagatcggctactatag gagggcaacaaggagaatcaggggaggcgacggcaagatgaaggatctgagcccacgctggtactctactatctgggaacc ggacctgaggcaggcctgccatatggcgccaacaaggacggaatcatctgggtggcaaccgagggcgccctgaacacacca aaggatcacatcggcacaagaaatcccgccaacaatgcagcaatcgtgctgcagctgccacagggaaccacactgcccaagg gcttttacgcagagggctctcggggaggcagccaggcatctagcagatcctctagccggagcagaaactcctctaggaattcca ccccaggaagctccaggggcacatcccctgcccgcatggcaggaaacggaggcgacgccgccctggccctgctgctgctgg atcgcctgaatcagctggagtccaagatgtctggcaagggacagcagcagcagggacagaccgtgacaaagaagtccgccg ccgaggcctctaagaagccaaggcagaagcgcaccgccacaaaggcctacaacgtgacccaggccttcggcaggcgcgga ccagagcagacacagggcaattttggcgaccaggagctgatcaggcagggaaccgattataagcactggcctcagatcgccc agttcgccccatctgccagcgccttctttggcatgtctagaatcggcatggaggtgacccccagcggcacatggctgacctacac aggcgccatcaagctggacgataaggaccctaacttcaaggatcaggtcatcctgctgaacaagcacatcgacgcctataagac ctttccccctacagagcccaagaaggacaagaagaagaaggccgatgagacacaggccctgcctcagaggcagaagaagca gcagaccgtgacactgctgccagccgccgatctggacgatttctccaaacagctgcagcagagcatgtccagtgccgactcca cccaggcttgaCGTACGACCTGCTATAGGCTATCCACTGCATCATCTCTCCTGCCATACTTCCTACTCACATCATATCTATTTTAAAGAAAAAATAGGCCCGAACACTAA TCGTGCCGGCAGTGCCACTGCACACACAACACTACACATACAATACACTACAATGGTTGCAGAAGATGCCCCTGTTAGGGCCACTTGCCGAGTATTATTTCGAACAACAACTTTAATCTTTCTATGCACACTACTAGCATTAAGCATCTCTATCCTTTATGAGAGTTTAATAACCCAAAAGCAAATCATGAGCCAAGCAGGCTCAACTGGATCTAATTCTGGATTAGGAAGTATCACTGATCTTCTTAATAATATTCTCTCTGTCGCAAATCAGATTATATATAACTCTGCAGTCGCTCTACCTCTACAATTGGACACTCTTGAATCAACACTCCTTACAGCCATTAAGTCTCTTCAAACCAGTGACAAGCTAGAACAGAACTGCTCGTGGAGTGCTGCACTGATTAATGATAATAGATACATTAATGGCATCAATCAGTTCTATTTTTCAATTGCTGAGGGTCGCAATCTGACACTTGGCCCACTTCTTAATATGCCTAGTTTCATTCCAACTGCCACGACACCAGAGGGCTGCACCAGGATCCCATCATTCTCGCTCACTAAGACACACTGGTGTTATACACACAATGTTATCCTGAATGGATGCCAGGATCATGTATCCTCAAATCAATTTGTTTCTATGGGAATCATTGAACCCACTTCTGCCGGGTTTCCATTCTTTCGAACCCTAAAGACTCTATATCTCAGCGATGGGGTCAATCGTAAGAGCTGCTCTATCAGTACAGTTCCGGGGGGTTGTATGATGTACTGTTTTGTTTCTACTCAACCAGAGAGGGATGACTACTTTTCTGCCGCTCCTCCAGAACAACGAATTATTATAATGTACTATAATGATACAATCGTGGAGCGCATAATTAATCCACCCGGGGTACTAGATGTATGGGCAACATTGAACCCAGGAACAGGAAGCGGGGTATATTATTTAGGTTGGGTGCTCTTTCCAATATATGGCGGCGTGATTAAAGGTACGAGTTTATGGAATAATCAAGCAAATAAATACTTTATCCCCCAGATGGTTGCTGCTCTCTGCTCACAAAACCAGGCAACTCAAGTCCAAAATGCTAAGTCATCATACTATAGCAGCTGGTTTGGCAATCGAATGATTCAGTCTGGGATCCTGGCATGTCCTCTTCGACAGGATCTAACCAATGAGTGTTTAGTTCTGCCCTTTTCTAATGATCAGGTGCTTATGGGTGCTGAAGGGAGATTATACATGTATGGTGACTCGGTGTATTACTATCAAAGAAGCAATAGTTGGTGGCCTATGACCATGCTGTATAAGGTAACCATAACATTCACTAATGGTCAGCCATCTGCTATATCAGCTCAGAATGTGCCCACACAGCAGGTCCCTAGACCTGGGACAGGAGACTGCTCTGCAACCAATAGATGTCCCGGTTTTTGCTTGACAGGAGTGTATGCCGATGCCTGGTTACTGACCAACCCTTCGTCTACCAGTACATTTGGATCAGAAGCAACCTTCACTGGTTCTTATCTCAACACAGCAACTCAGCGTATCAATCCGACGATGTATATCGCGAACAACACACAGATCATAAGCTCACAGCAATTTGGATCAAGCGGTCAAGAAGCAGCATATGGCCACACAACTTGTTTTAGGGACACAGGCTCTGTTATGGTATACTGTATCTATATTATTGAATTGTCCTCATCTCTCTTAGGACAATTTCAGATTGTCCCATTTATCCGTCAGGTGACACTATCCTAAAGGCAGAAGCCTTCAGGTCTGACCCAGCCAATCAAAGCATTATACCAGACCATGGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACAAGCGGCGGCCGCCACCatgttcgtcttcctggtcctgctgcctctggtctcctcacagtgcgtcaatctg atcactcggactcagtcctatactaatagcttcaccagaggcgtgtactatcctgacaaggtgtttagaagctccgtgctgcactcta cacaggatctgtttctgccattctttagcaacgtgacctggttccacgccatcagcggcaccaatggcacaaagcggttcgacaat cccgtgctgccttttaacgatggcgtgtacttcgcctctaccgagaagagcaacatcatcagaggctggatctttggcaccacact ggactccaagacacagtctctgctgatcgtgaacaatgccaccaacgtggtcatcaaggtgtgcgagttccagttttgtaatgatc ccttcctggacgtgtactatcacaagaacaataagagctggatggagtccgagtttagagtgtattctagcgccaacaactgcaca tttgagtacgtgagccagcctttcctgatggacctggagggcaagcagggcaatttcaagaacctgagggagttcgtgtttaaga atatcgacggctacttcaaaatctactctaagcacacccccatcaacctgggccgcgacctgcctcagggcttcagcgccctgga gcccctggtggatctgcctatcggcatcaacatcacccggtttcagacactgctggccctgcacagaagctacctgacacccgg cgactcctctagcggatggaccgccggcgctgccgcctactatgtgggctacctccagccccggaccttcctgctgaagtacaa cgagaatggcaccatcacagacgcagtggattgcgccctggaccccctgagcgagacaaagtgtacactgaagtcctttaccgt ggagaagggcatctatcagacatccaatttcagggtgcagccaaccgagtctatcgtgcgctttcctaatatcacaaacctgtgcc catttgacgaggtgttcaacgcaacccgcttcgccagcgtgtacgcctggaataggaagcggatcagcaactgcgtggccgact atagcgtgctgtacaacctggcccccttcttcgcctttaagtgctatggcgtgtcccccacaaagctgaatgacctgtgctttaccaa cgtctacgccgattctttcgtgatcaggggcaacgaggtgtcccagatcgcccccggccagacaggcaatatcgcagactacaa ttataagctgccagacgatttcaccggctgcgtgatcgcctggaacagcaacaagctggattccaaagtgggcggcaactacaa ttatagataccggctgtttagaaagagcaatctgaagcccttcgagagggacatctctacagaaatctaccaggccggcaataag ccttgcaatggcgtggccggcgtgaactgttatttcccactccagtcctacggcttccgccccacatatggcgtgggccaccagc cttaccgcgtggtggtgctgagctttgagctgctgcacgccccagcaacagtgtgcggccccaagaagtccaccaatctggtga agaacaagtgcgtgaacttcaacttcaacggcctgaccggcacaggcgtgctgaccgagtccaacaagaagttcctgccatttc agcagttcggcagggacatcgcagataccacagacgccgtgcgcgacccacagaccctggagatcctggacatcacaccctg ctctttcggcggcgtgagcgtgatcacacccggcaccaatacaagcaaccaggtggccgtgctgtatcagggcgtgaattgtac cgaggtgcccgtggctatccacgccgatcagctgaccccaacatggcgggtgtacagcaccggctccaacgtcttccagacaa gagccggatgcctgatcggagcagagtacgtgaacaattcctatgagtgcgacatcccaatcggcgccggcatctgtgcctctta ccagacccagacaaagtctcacagaagagcccggagcgtggcctcccagtctatcatcgcctataccatgtccctgggcgccg agaacagcgtggcctactctaacaatagcatcgccatcccaaccaacttcacaatctctgtgaccacagagatcctgcccgtgtc catgaccaagacatctgtggactgcacaatgtatatctgtggcgattctaccgagtgcagcaacctgctgctccagtacggcagct tttgtacccagctgaagagagccctgacaggcatcgccgtggagcaggataagaacacacaggaggtgttcgcccaggtgaa gcaaatctacaagaccccccctatcaagtactttggcggcttcaatttttcccagatcctgcctgatccatccaagccttctaagcgg agctttatcgaggacctgctgttcaacaaggtgaccctggccgatgccggcttcatcaagcagtatggcgattgcctgggcgaca tcgcagccagggacctgatctgcgcccagaagtttaatggcctgaccgtgctgccacccctgctgacagatgagatgatcgcac agtacacaagcgccctgctggccggcaccatcacatccggatggaccttcggcgcaggagccgccctccagatcccctttgcc atgcagatggcctataggttcaacggcatcggcgtgacccagaatgtgctgtacgagaaccagaagctgatcgccaatcagttta actccgccatcggcaagatccaggacagcctgtcctctacagccagcgccctgggcaagctccaggatgtggtgaatcacaacgcccaggccctgaataccctggtgaagcagctgagcagcaagttcggcgccatctctagcgtgctgaatgacatcctgagccg gctggacaaggtggaggcagaggtgcagatcgaccggctgatcaccggccggctccagagcctccagacctatgtgacaca gcagctgatcagggccgccgagatcagggccagcgccaatctggcagcaaccaagatgtccgagtgcgtgctgggccagtct aagagagtggacttttgtggcaagggctatcacctgatgtccttccctcagtctgccccacacggcgtggtgtttctgcacgtgac ctacgtgcccgcccaggagaagaacttcaccacagcccctgccatctgccacgatggcaaggcccactttccaagggagggc gtgttcgtgtccaacggcacccactggtttgtgacacagcgcaatttctacgagccccagatcatcaccacagacaacaccttcgt gagcggcaactgtgacgtggtcatcggcatcgtgaacaataccgtgtatgatccactccagcccgagctggacagctttaagga ggagctggataagtatttcaagaatcacacctcccctgacgtggatctgggcgacatcagcggcatcaatgcctccgtggtgaac atccagaaggagatcgaccgcctgaacgaggtggctaagaatctgaacgagagcctgatcgacctccaggagctgggcaagt atgagcagtacatcaagtggccctggtacatctggctgggcttcatcgccggcctgatcgccatcgtgatggtgaccatcatgctg tgctgtatgacatcctgctgttcttgcctgaagggctgctgtagctgtggctcctgctgtaagttattgaccattgtcgttgctaatcga aatagaatggagaattttgtttatcataaatgaAGTCGACTCATGGAATGCATACCAAACATTATT GACACTAATGACACACAAAATTGGTTTTAAGAAAAACCAAGAGAACAATAGG CCAGAATGGCTGGGTCTCGGGAGATATTACTCCCTGAAGTCCATCTCAATTCA CCAATTGTAAAGCATAAGCTATACTATTACATTCTACTTGGAAACCTCCCAAA TGAGATCGACCTTGACGATTTAGGTCCATTACATAATCAAAATTGGAATCAGA TAGCACATGAAGAGTCTAACTTAGCTCAACGCTTGGTAAATGTAAGAAATTTT CTAATTACCCACATCCCTGATCTTAGAAAGGGCCATTGGCAAGAGTATGTCAA TGTAATACTGTGGCCGCGAATTCTTCCCTTGATCCCGGATTTTAAAATCAATG ACCAATTGCCTCTGCTCAAAAATTGGGACAAGTTAGTTAAAGAATCATGTTCA GTAATCAATGCAGGTACTTCCCAGTGCATTCAGAATCTCAGCTATGGACTGAC AGGTCGTGGGAACCTCTTTACACGATCACGTGAACTCTCTGGTGACCGCAGG GATATTGATCTTAAGACAGTTGTGGCAGCATGGCATGACTCAGACTGGAAAA GAATAAGTGATTTTTGGATTATGATCAAATTCCAGATGAGACAATTAATTGTT AGGCAAACAGATCATAATGATTCTGATTTAATCACGTATATCGAAAATAGAG AAGGCATAATCATCATAACCCCTGAACTGGTAGCATTATTTAACACTGAGAAT CATACACTAACATACATGACCTTTGAAATTGTACTGATGGTTTCAGATATGTA CGAAGGTCGTCACAACATTTTATCACTATGCACAGTTAGCACTTACCTGAATC CTCTGAAGAAAAGAATAACATATTTATTGAGCCTTGTAGATAACTTAGCTTTT CAGATAGGTGATGCTGTATATAACATAATTGCTTTGCTAGAATCCTTTGTATA TGCACAGTTGCAAATGTCAGATCCCATCCCAGAACTCAGAGGACAATTCCAT GCATTCGTATGTTCTGAGATTCTTGATGCACTAAGAGGAACTAATAGTTTCAC CCAGGATGAATTAAGAACTGTGACAACTAATTTGATATCCCCATTCCAAGATCTGACCCCAGATCTTACGGCTGAATTGCTCTGTATAATGAGGCTTTGGGGACACCCCATGCTCACTGCCAGTCAAGCTGCAGGAAAGGTACGCGAGTCTATGTGTGCTGGAAAAGTATTAGACTTTCCCACCATTATGAAAACACTAGCCTTTTTCCATACTATTCTGATCAATGGATACAGGAGGAAGCATCATGGAGTATGGCCACCCTTAAACTTACCGGGTAATGCTTCAAAGGGTCTCACGGAACTTATGAATGACAATACTGAAATAAGCTATGAATTCACACTTAAGCATTGGAAGGAAGTCTCTCTTATAAAATTCAAGAAATGTTTTGATGCAGACGCAGGTGAGGAACTCAGTATATTTATGAAAGATAAGGCAATTAGTGCCCCAAAACAAGACTGGATGAGTGTGTTTAGAAGAAGCCTAATCAAACAGCGCCATCAGCATCATCAGGTCCCCCTACCAAATCCATTCAATCGACGGCTGTTGCTAAACTTTCTCGGAGATGACAAATTCGACCCGAATGTGGAGCTACAGTATGTAACATCAGGTGAGTATCTACATGATGACACGTTTTGTGCATCATATTCACTAAAAGAGAAGGAAATTAAACCTGATGGTCGAATTTTTGCAAAGTTGACTAAGAGAATGAGATCATGTCAAGTTATAGCAGAATCTCTTTTAGCGAACCATGCTGGGAAGTTAATGAAAGAGAATGGTGTTGTGATGAATCAGCTATCATTAACAAAATCACTATTAACAATGAGTCAGATTGGAATAATATCCGAGAAAGCTAGAAAGTCAACTCGAGATAACATAAATCAACCTGGTTTCCAGAATATCCAGAGAAATAAATCACATCACTCCAAGCAAGTCAATCAGCGAGATCCAAGTGATGACTTTGAATTGGCAGCATCTTTTTTAACTACTGATCTCAAAAAATATTGTTTACAATGGAGGTACCAGACAATTATCCCATTTGCTCAATCATTAAACAGAATGTATGGTTATCCTCATCTCTTTGAGTGGATTCACTTACGGCTAATGCGTAGTACACTTTACGTGGGGGATCCCTTCAACCCACCAGCAGATACCAGTCAATTTGATCTAGATAAAGTAATTAATGGAGATATCTTCATTGTATCACCCAGAGGTGGAATTGAAGGGCTGTGTCAAAAGGCTTGGACAATGATATCTATCGCTGTGATAATTCTATCTGCCACAGAGTCTGGCACACGAGTAATGAGTATGGTGCAGGGAGATAATCAAGCAATTGCTGTCACCACACGAGTACCAAGGAGCCTGCCGACTCTTGAGAAAAAGACTATTGCTTTTAGATCTTGTAATCTATTCTTTGAGAGGTTAAAATGTAATAATTTTGGATTAGGTCACCATTTGAAAGAACAAGAGACTATCATTAGTTCTCACTTCTTTGTTTATAGCAAGAGAATATTCTATCAGGGGAGGATTCTAACGCAAGCCTTAAAAAATGCTAGTAAGCTCTGCTTGACAGCTGATGTCCTAGGAGAATGCACCCAATCATCATGTTCTAATCTTGCAACTACTGTCATGAGGTTAACTGAGAATGGTGTTGAAAAAGATATCTGTTTCTACTTGAATATCTATATGACCATCAAACAGCTCTCCTATGATATCATCTTCCCTCAAGTGTCAATTCCTGGAGATCAGATCACATTAGAATACATAAATAATCCACACCTGGTATCACGATTGGCTCTTTTGCCATCCCAGTTAGGAGGTCTAAACTACCTGTCATGCAGTAGGCTGTTCAATCGAAACATAGGCGACCCGGTGGTTTCCGCAGTTGCAGATCTTAAGAGATTAATTAAATCAGGATGTATGGATTACTGGATCCTTTATAACTTATTAGGGAGAAAACCGGGAAACGGCTCATGGGCTACTTTAGCAGCTGACCCGTACTCAATCAATATAGAGTATCAATACCCTCCAACTACAGCTCTTAAGAGGCACACCCAACAAGCTCTGATGGAACTCAGTACGAATCCAATGTTACGTGGCATATTCTCTGACAATGCACAGGCAGAAGAAAATAACCTTGCTAGGTTTCTCCTGGATAGGGAGGTGATCTTTCCGCGTGTAGCTCACATCATCATTGAGCAAACCAGTGTCGGGAGGAGAAAACAGATTCAAGGATATTTGGATTCAACTAGATCGATAATGAGGAAATCACTAGAAATTAAGCCCTTATCCAATAGGAAGCTTAATGAAATACTGGATTACAACATCAATTACCTAGCTTACAATTTGGCATTACTCAAGAATGCTATTGAACCTCCGACTTATTTGAAGGCAATGACACTTGAAACATGTAGCATCGACATTGCAAGGAACCTCCGGAAGCTCTCCTGGGCCCCACTCTTGGGTGGGAGAAATCTTGAAGGATTAGAGACGCCAGATCCCATTGAAATTACTGCAGGAGCATTAATTGTTGGATCGGGCTACTGTGAACAGTGTGCTGCAGGAGACAATCGATTCACATGGTTTTTCTTGCCATCTGGTATCGAGATAGGAGGGGATCCCCGTGATAATCCTCCTATCCGTGTACCGTACATTGGCTCCAGGACTGATGAGAGGAGGGTAGCCTCAATGGCATACATCAGGGGTGCCTCGAGTAGCTTAAAAGCAGTTCTTAGACTGGCGGGAGTGTACATCTGGGCATTCGGAGATACTCTGGAGAATTGGATAGATGCACTGGATTTGTCTCACACTAGAGTTAACATCACACTTGAACAGCTGCAATCCCTCACCCCACTTCCAACCTCTGCCAATCTAACCCATCGGTTGGATGATGGCACAACTACCCTAAAGTTTACTCCTGCGAGCTCTTACACCTTTTCAAGTTTCACTCATATATCAAATGATGAGCAATACCTGACAATTAATGACAAAACTGCAGATTCAAATATAATCTACCAACAGTTAATGATCACTGGACTCGGAATCTTAGAAACATGGAATAATCCCCCAATCAATAGAACATTCGAAGAATCTACCCTACATTTGCACACTGGTGCATCATGTTGTGTCCGACCTGTGGACTCCTGCATTCTCTCAGAAGCATTAACAGTCAAGCCACATATTACAGTACCGTACAGCAATAAATTTGTATTTGATGAGGACCCGCTATCTGAATATGAAACTGCAAAACTGGAATCGTTATCATTCCAAGCCCAATTAGGCAACATTGATGCTGTAGATATGACAGGTAAATTAACATTATTGTCCCAATTCACTGCAAGGCAGATTATCAATGCAATCACTGGACTCGATGAGTCTGTCTCTCTTACTAATGATGCCATTGTTGCATCAGACTATGTCTCCAATTGGATTAGTGAATGCATGTATACCAAATTAGATGAATTATTTATGTATTGTGGGTGGGAACTACTATTGGAACTATCCTATCAAATGTATTATCTGAGGGTAGTTGGGTGGAGTAATATAGTGGATTATTCTTACATGATCTTGAGAAGAATCCCGGGTGCAGCATTAAACAATCTGGCATCTACATTAAGTCATCCAAAACTTTTCCGACGAGCTATCAACCTAGATATAGTTGCCCCCTTAAATGCTCCTCATTTTGCATCTCTGGACTACATCAAGATGAGTGTGGATGCAATACTCTGGGGCTGTAAAAGAGTCATCAATGTGCTCTCCAATGGAGGGGACTTAGAATTAGTTGTGACATCTGAAGATAGCCTTATTCTCAGTGACCGATCCATGAATCTCATTGCAAGGAAATTAACTTTATTATCACTGATTCACCATAATGGTTTGGAACTACCAAAGATTAAGGGGTTCTCTCCTGATGAGAAGTGTTTCGCTTTGACAGAATTTTTGAGGAAAGTGGTGAACTCAGGGTTGAGTTCAATAGAGAACCTATCAAATTTTATGTACAATGTGGAGAACCCACGGCTTGCAGCATTCGCCAGCAACAATTACTACCTGACCAGAAAATTATTGAATTCAATACGAGATACTGAGTCGGGTCAAGTAGCAGTCACCTCATATTATGAATCATTAGAATATATTGATAGTCTTAAGCTAACCCCACATGTGCCTGGCACCTCATGCATTGAGGATGATAGTCTATGTACAAATGATTACATAATCTGGATCATAGAGTCTAATGCAAACTTGGAGAAGTATCCAATTCCAAATAGCCCTGAGGATGATTCCAATTTCCATAACTTTAAGTTGAATGCTCCATCGCACCATACCTTACGCCCATTAGGGTTGTCATCAACTGCTTGGTATAAGGGTATAAGCTGCTGCAGGTACCTTGAGCGATTAAAGCTACCACAAGGTGATCATTTATATATTGCAGAAGGTAGTGGTGCCAGTATGACAATCATAGAATACCTATTCCCAGGAAGAAAGATATATTACAATTCTTTATTTAGTAGTGGTGACAATCCCCCACAAAGAAATTATGCACCAATGCCTACTCAGTTCATTGAGAGTGTCCCATACAAGCTCTGGCAAGCACACACAGATCAATATCCCGAGATTTTTGAGGACTTCATCCCTCTATGGAACGGAAACGCCGCCATGACTGACATAGGAATGACAGCTTGTGTAGAATTCATCATCAATCGAGTCGGCCCAAGGACTTGCAGTTTAGTACATGTAGATTTGGAATCAAGTGCAAGCTTAAATCAACAATGCCTGTCAAAGCCGATAATTAATGCTATCATCACTGCTACAACTGTTTTGTGCCCTCATGGGGTGCTTATTCTGAAATATAGTTGGTTGCCATTTACTAGATTTAGTACTTTGATCACTTTCTTATGGTGCTACTTTGAGAGAATCACTGTTCTTAGGAGCACATATTCTGATCCAGCTAATCATGAGGTTTATTTAATTTGTATCCTTGCCAACAACTTTGCATTCCAGACTGTCTCGCAGGCAACAGGAATGGCGATGACTTTAACTGATCAAGGGTTTACTTTGATATCACCTGAAAGAATAAATCAGTATTGGGATGGTCACTTGAAGCAAGAACGTATCGTAGCAGAAGCAATTGATAAGGTGGTTCTAGGAGAAAATGCTCTATTTAATTCGAGTGATAATGAATTAATTCTCAAATGTGGAGGGACACCAAATGCACGGAATCTCATCGATATCGAGCCAGTCGCAACTTTCATAGAATTTGAACAATTGATCTGCACAATGTTGACAACCCACTTGAAGGAAATAATTGATATAACAAGGTCTGGAACCCAGGATTATGAAAGTTTATTACTCACTCCTTACAATTTAGGTCTTCTTGGTAAAATCAGTACGATAGTGAGATTATTAACAGAAAGGATTCTAAATCATACTATCAGGAATTGGTTGATCCTCCCACCTTCGCTCCGGATGATCGTGAAGCAGGACTTGGAATTCGGCATATTCAGGATTACTTCCATCCTCAATTCTGATCGGTTCCTGAAGCTTTCTCCAAATAGGAAATACTTGATTGCACAATTAACTGCAGGCTACATTAGGAAATTGATTGAGGGGGATTGCAATATCGATCTAACCAGACCTATCCAAAAGCAAATCTGGAAAGCATTAGGTTGTGTAGTCTATTGTCACGATCCAATGGATCAAAGGGAGTCAACAGAGTTTATTGATATAAATATTAATGAAGAAATAGACCGCGGGATCGATGGCGAGGAAATCTAAACATATCAAGAATCAGAATTAGTTTAAGAAAAAAGAAGAGGATTAATCTTGGTTTTCCCCTTGGTGGGTCGGCATGGCATCTCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCACTCGGATGGCTAAGGGAGCGGCCGGGGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAGTTGGCTGCTGCCACCGCTGAGCAATAACTAGCATAACCCCTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTGCTGAAAGGAGGAACTATATCCGGATCATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGT (SEQ ID NO: 7). vi. CVL110
[0166] The nucleic acid sequence for CVL110 is:GCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCTAATACGACTCACTATAGGGACCAAGGGGAAAATGAAGTGGTGACTCAAATCATCGAAGACCCTCGAGATTACATAGGTCCGGAACCTATGGCCTTCGTGACCGACCTCGAGTCAGAGTAGTTCAATAAGGACCTATCAAGTTTGGGCAATTTTTCGTCCCCGACACAAAAATGTCATCCGTGCTTAAAGCATATGAGCGATTCACGCTCACTCAAGAACTGCAAGATCAGAGTGAGGAAGGTACAATCCCACCTACAACACTAAAACCGGTAATCAGGGTATTTATACTAACCTCTAATAACCCAGAGCTAAGATCCCGGCTTCTTCTATTCTGCCTACGGATTGTTCTCAGTAATGGTGCAAGGGATTCCCATCGCTTTGGAGCATTACTCACAATGTTTTCGCTACCATCAGCCACAATGCTCAATCATGTCAAATTAGCTGACCAGTCACCAGAAGCTGATATCGAAAGGGTAGAGATCGATGGCTTTGAGGAGGGATCATTCCGCTTAATCCCCAATGCACGTTCAGGTATGAGCCGTGGAGAGATCAATGCCTATGCTGCACTTGCAGAAGATCTACCTGACACACTAAACCATGCAACACCTTTCGTTGATTCCGAAGTCGAGGGAACTGCATGGGATGAGATTGAGACTTTCTTAGATATGTGTTACAGTGTCCTAATGCAGGCATGGATAGTGACTTGCAAGTGCATGACTGCGCCAGACCAACCTGCTGCTTCTATTGAGAAACGCCTGCAAAAATATCGTCAGCAAGGCAGGATCAACCCGAGATATCTCCTGCAACCGGAGGCTCGACGAATAATCCAGAATGTAATCCGGAAGGGAATGGTGGTCAGACATTTCCTCACCTTTGAACTGCAGCTTGCCCGAGCACAAAGCCTTGTATCAAATAGGTATTATGCTATGGTAGGGGATGTTGGAAAGTATATAGAGAATTGTGGAATGGGAGGCTTCTTTTTGACACTAAAATATGCATTAGGAACTAGATGGCCCACACTTGCTTTAGCTGCATTTTCAGGAGAGCTAACAAAGCTAAAGTCCCTCATGGCATTATACCAGACCCTTGGTGAGCAGGCCCGATATTTGGCCCTATTGGAGTCACCACATTTGATGGATTTTGCTGCAGCAAACTACCCACTGCTATATAGCTATGCTATGGGAATAGGCTATGTGTTAGATGTCAACATGAGGAACTACGCTTTCTCCAGATCATACATGAACAAGACATATTTCCAATTGGGAATGGAAACTGCAAGAAAACAACAGGGTGCAGTTGACATGAGGATGGCAGAAGATCTCGGTCTAACTCAAGCCGAACGCACCGAGATGGCAAATACACTTGCCAAATTGACCACAGCAAATCGAGGGGCAGACACCAGGGGAGGAGTCAACCCGTTCTCATCTGTCACTGGGACAACTCAGGTGCCCGCTGCAGCAACAGGTGACACACTCGAGAGTTACATGGCAGCGGATCGACTGAGGCAGAGATATGCTGATGCAGGCACCCATGATGATGAGATGCCACCATTGGAAGAGGAGGAAGAGGACGACACATCTGCAGGTCCACGCACTGGACCAACTCTTGAACAAGTGGCCTTGGACATCCAGAACGCAGCAGTTGGAGCTCCCATCCATACAGATGACCTGAATGCCGCACTGGGTGATCTTGACATCTAGACAATTCAGATCCCAATCTAAAATTGACATACCTAATTGATTAGTTAGATGGAACTACAGTGGATTCCATAAGGTTCCTGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACAAGCGACTGCCGGTGCCAACAGCGCAATCCACAATCTACAATGGATCCCACTGATCTGAGCTTCTCCCCAGATGAGATCAATAAGCTCATAGAGACAGGCCTGAATACTGTAGAGTATTTTACTTCCCAACAAGTCACAGGAACATCCTCTCTTGGAAAGAATACAATACCACCAGGGGTCACAGGACTACTAACCAATGCTGCAGAGGCAAAGATCCAAGAGTCAACTAACCATCAGAAGGGCTCAGTTGGTGGGGGTGCAAAACCAAAGAAACCGCGACCAAAAATTGCCATTGTGCCAGCAGATGACAAAACAGTGCCCGGAAAGCCGATCCCAAACCCTCTATTAGGTCTGGACTCCACCCCGAGCACCCAAACTGTGCTTGATCTAAGTGGGAAAACATTACCATCAGGATCCTATAAGGGGGTTAAGCTTGCGAAATTTGGAAAAGAAAATCTGATGACACGGTTCATCGAGGAACCCAGAGAGAATCCTATCGCAACCAGTTtCCCCATCGATTTTAAGAGGGGCAGGGATACCGGCGGGTTCCATAGAAGGGAGTACTCAATCGGATGGGTGGGAGATGAAGTCAAGGTCACTGAGTGGTGCAATCCATCCTGTTCTCCAATCACCGCTGCAGCAAGGCGATTTGAATGCACTTGTCACCAGTGTCCAGTCACTTGCTCTGAATGTGAACGAGATACTTAATACAGTGAGAAATTTGGACTCTCGGATGAATCAACTGGAGACAAAAGTAGATCGCATTCTCTCATCTCAGTCTCTAATCCAGACCATCAAGAATGACATAGTTGGACTTAAAGCAGGGATGGCTACTTTAGAAGGAATGATTACAACTGTGAAAATCATGGACCCGGGAGTTCCCAGTAATGTTACTGTGGAAGATGTACGCAAGACACTAAGTAACCATGCTGTTGTTGTGCCAGAATCATTCAATGATAGTTTCTTGACTCAATCTGAAGATGTAATTTCACTTGATGAGTTGGCTCGACCAACTGCAACAAGTGTTAAGAAGATTGTCAGGAAGGTTCCTCCTCAGAAGGATCTGACTGGATTGAAGATTACACTAGAGCAATTGGCAAAGGATTGCATCAGCAAACCGAAGATGAGGGAAGAGTATCTCCTCAAAATCAACCAGGCTTCCAGTGAGGCTCAGCTAATTGACCTCAAGAAAGCAATCATCCGCAGTGCAATTTGATCAAGAAACACCCAATTACACTACACTGGTATGACACTGTACTAACCCTGAGGGTTTTAGAAAAAACGATTAACGATAAATAAGCCCGAACACTACACACTACCTGAGGCAGCCATGCCATCCATCAGCATTCCCGCAGACCCCACCAATCCACGTCAATCAATAAAAGCGTTCCCAATTGTGATCAACAGTGATGGGGGTGAGAAAGGCCGCTTGGTTAAACAACTACGCACAACCTACTTGAATGACCTAGATACTCATGAGCCACTGGTGACATTCATAAATACCTATGGATTCATCTACGAACAGGATCGGGGGAATACCATTGTCGGAGAGGATCAACTTGGGAAGAAAAGAGAGGCTGTGACCGCTGCAATGGTTACCCTTGGATGTGGGCCTAATCTACCATCATTAGGGAATGTCCTGGGACAACTGAGGGAATTCCAGGTCACTGTTAGGAAGACATCCAGCAAAGCGGAAGAGATGGTCTTTGAAATTGTTAAGTATCCGAGAATATTTCGGGGTCATACATTAATCCAGAAAGGACTAGTCTGTGTCTCCGCAGAAAAATTTGTTAAGTCACCAGGGAAAATACAATCTGGAATGGACTATCTCTTCATTCCGACATTTCTGTCAGTGACTTACTGTCCAGCTGCAATCAAATTTCAGGTACCTGGCCCCATGTTGAAAATGAGATCAAGATACACTCAGAGCTTACAACTTGAACTAATGATAAGAATCCTGTGTAAGCCCGATTCGCCACTTATGAAGGTCCATACCCCTGACAAGGAGGGAAGAGGATGTCTTGTATCAGTATGGCTGCATGTATGCAACATCTTCAAATCAGGAAACAAGAATGGCAGTGAGTGGCAGGAATACTGGATGAGAAAGTGTGCTAACATGCAACTTGAAGTGTCGATTGCAGATATGTGGGGACCAACTATCATAATTCATGCCAGAGGTCACATTCCCAAAAGTGCTAAGTTGTTTTTTGGAAAGGGTGGATGGAGCTGCCATCCACTTCACGAAGTTGTTCCAAGTGTCACTAAAACACTATGGTCCGTGGGCTGTGAGATTACAAAGGCGAAGGCAATAATACAAGAGAGTAGCATCTCTCTTCTCGTGGAGACTACTGACA- Ill -TCATAAGTCCAAAAGTCAAAATTTCATCTAAGCATCGCCGCTTTGTGAAATCAAATTGGGGTCTGTTCAAGAAAACTAAATCACTGCCTAACCTGACGGAGCTGGAATGACTGACCTCTAATCGAGACTACACCGCCGCAAACTATAGGTGGGTGGTACCTCAGTGATTAATCTTGTAAGCACTGACCGTAGGCTACAACACACTAATATTATCCAGATTAGAGAGCTTAATTAGCTCTGTATTAATAATAACACTACTATTCCAATAACTGGAATCACCAGCTTGATTTATCTCCAAAATGATTCAAAGAAAACAAATCATATTAAGACTATCCTAAGCACGAACCCATATCGTCCTTCAAATCATGGGTACTATAATTCAATTTCTGGTGGTCTCCTGTCTATTGGCAGGAGCAGGCAGCCTTGATCCAGCAGCCCTCATGCAAATCGGTGTCATTCCAACAAATGTCCGGCAACTTATGTATTATACTGAAGCCTCATCAGCATTCATTGTTGTGAAGTTAATGCCTACAATTGACTCGCCGATTAGTGGATGTAATATAACATCAATTTCAAGCTATAATGCAACAGTGACAAAACTCCTACAGCCGATCGGTGAGAATTTGGAGACGATTAGGAACCAGTTGATTCCAACTCGGAGGAGACGCCGGTTTGCAGGGGTGGTGATTGGATTAGCTGCATTAGGAGTAGCTACTGCCGCACAGGTCACTGCCGCAGTGGCACTAGTAAAGGCAAATGAAAATGCTGCGGCTATACTCAATCTCAAAAATGCAATCCAAAAAACAAATGCAGCAGTTGCAGATGTGGTCCAGGCCACACAATCACTAGGAACGGCAGTTCAAGCAGTTCAAGATCACATAAACAGTGTGGTAAGTCCAGCAATTACAGCAGCCAATTGTAAGGCCCAAGATGCTATCATTGGCTCAATCCTCAATCTCTATTTGACCGAGTTGACAACCATCTTCCACAATCAAATTACAAACCCTGCATTGAGTCCCATTACAATTCAAGCTTTAAGGATCCTACTGGGGAGTACCTTGCCGACTGTGGTCGAAAAATCTTTCAATACCCAGATAAGTGCAGCTGAGCTTCTCTCATCAGGGTTATTGACAGGCCAGATTGTGGGATTAGATTTGACCTATATGCAGATGGTCATAAAAATTGAGCTGCCAACTTTAACTGTACAACCTGCAACCCAGATCATAGATCTGGCCACCATTTCTGCATTCATTAACAATCAAGAAGTCATGGCCCAATTACCAACACGTGTTATGGTGACTGGCAGCTTGATCCAAGCCTATCCCGCATCGCAATGCACCATTACACCCAACACTGTGTACTGTAGGTATAATGATGCCCAAGTACTCTCAGATGATACTATGGCTTGCCTCCAAGGTAACTTGACAAGATGCACCTTCTCTCCAGTGGTTGGGAGCTTTCTCACTCGATTCGTGCTGTTCGATGGAATAGTTTATGCAAATTGCAGGTCGATGTTGTGCAAGTGCATGCAACCTGCTGCTGTGATCCTACAGCCGAGTTCATCCCCTGTAACTGTCATTGACATGTACAAATGTGTGAGTCTGCAGCTTGACAATCTCAGATTCACCATCACTCAATTGGCCAATGTAACCTACAATAGCACCATCAAGCTTGAATCATCCCAGATCTTGTCTATTGATCCGTTGGATATATCCCAAAATCTAGCTGCGGTGAATAAGAGTCTAAGTGATGCACTACAACACTTAGCACAAAGTGACACATATCTTTCTGCAATCACATCAGCTACGACTACAAGTGTATTATCCATAATAGCAATCTGTCTTGGATCGTTAGGTTTAATATTAATAATCTTGCTCAGTGTAGTTGTGTGGAAGTTATTGACCATTGTCGTTGCTAATCGAAATAGAATGGAGAATTTTGTTTATCATAAATAAGCATTCCACCACTCACGATCTGATCTCAGTGAGAAAAATCAACCTGCAACTCTTGGAACAAGATAAGACAGTCATCCATTAGTAATTTTTAAGAAAAAAACGATAGGACCGAACCTAGTATTGAAAGAACCGTCTCGGTCAATCTAGGTAATCGAGCTGATACCGTCTCGGAAAGCTCAAATCAGCTAGCCGGCAGTGCCACTGCACACACAACACTACACATACAATACACTACAATGGTTGCAGAAGATGCCCCTGTTAGGGCCACTTGCCGAGTATTATTTCGAACAACAACTTTAATCTTTCTATGCACACTACTAGCATTAAGCATCTCTATCCTTTATGAGAGTTTAATAACCCAAAAGCAAATCATGAGCCAAGCAGGCTCAACTGGATCTAATTCTGGATTAGGAAGTATCACTGATCTTCTTAATAATATTCTCTCTGTCGCAAATCAGATTATATATAACTCTGCAGTCGCTCTACCTCTACAATTGGACACTCTTGAATCAACACTCCTTACAGCCATTAAGTCTCTTCAAACCAGTGACAAGCTAGAACAGAACTGCTCGTGGAGTGCTGCACTGATTAATGATAATAGATACATTAATGGCATCAATCAGTTCTATTTTTCAATTGCTGAGGGTCGCAATCTGACACTTGGCCCACTTCTTAATATGCCTAGTTTCATTCCAACTGCCACGACACCAGAGGGCTGCACCAGGATCCCATCATTCTCGCTCACTAAGACACACTGGTGTTATACACACAATGTTATCCTGAATGGATGCCAGGATCATGTATCCTCAAATCAATTTGTTTCTATGGGAATCATTGAACCCACTTCTGCCGGGTTTCCATTCTTTCGAACCCTAAAGACTCTATATCTCAGCGATGGGGTCAATCGTAAGAGCTGCTCTATCAGTACAGTTCCGGGGGGTTGTATGATGTACTGTTTTGTTTCTACTCAACCAGAGAGGGATGACTACTTTTCTGCCGCTCCTCCAGAACAACGAATTATTATAATGTACTATAATGATACAATCGTGGAGCGCATAATTAATCCACCCGGGGTACTAGATGTATGGGCAACATTGAACCCAGGAACAGGAAGCGGGGTATATTATTTAGGTTGGGTGCTCTTTCCAATATATGGCGGCGTGATTAAAGGTACGAGTTTATGGAATAATCAAGCAAATAAATACTTTATCCCCCAGATGGTTGCTGCTCTCTGCTCACAAAACCAGGCAACTCAAGTCCAAAATGCTAAGTCATCATACTATAGCAGCTGGTTTGGCAATCGAATGATTCAGTCTGGGATCCTGGCATGTCCTCTTCGACAGGATCTAACCAATGAGTGTTTAGTTCTGCCCTTTTCTAATGATCAGGTGCTTATGGGTGCTGAAGGGAGATTATACATGTATGGTGACTCGGTGTATTACTATCAAAGAAGCAATAGTTGGTGGCCTATGACCATGCTGTATAAGGTAACCATAACATTCACTAATGGTCAGCCATCTGCTATATCAGCTCAGAATGTGCCCACACAGCAGGTCCCTAGACCTGGGACAGGAGACTGCTCTGCAACCAATAGATGTCCCGGTTTTTGCTTGACAGGAGTGTATGCCGATGCCTGGTTACTGACCAACCCTTCGTCTACCAGTACATTTGGATCAGAAGCAACC TTCACTGGTTCTTATCTCAACACAGCAACTCAGCGTATCAATCCGACGATGTA TATCGCGAACAACACACAGATCATAAGCTCACAGCAATTTGGATCAAGCGGT CAAGAAGCAGCATATGGCCACACAACtTGTTTTAGGGACACAGGCTCTGTTAT GGTATACTGTATCTATATTATTGAATTGTCCTCATCTCTCTTAGGACAATTTCA GATTGTCCCATTTATCCGTCAGGTGACACTATCCTAAAGGCAGAAGCCTTCAG GTCTGACCCAGCCAATCAAAGCATTATACCAGACCATGGCCTACCATCGGCTT TAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACAAGCGcGCGGCCGCCACC atgttcgtcttcctggtcctgctgcctctggtctcctcacagtgcgtcaatctgatcactcggactcagtcctatactaatagcttcacc agaggcgtgtactatcctgacaaggtgtttagaagctccgtgctgcactctacacaggatctgtttctgccattctttagcaacgtga cctggttccacgccatcagcggcaccaatggcacaaagcggttcgacaatcccgtgctgccttttaacgatggcgtgtacttcgc ctctaccgagaagagcaacatcatcagaggctggatctttggcaccacactggactccaagacacagtctctgctgatcgtgaac aatgccaccaacgtggtcatcaaggtgtgcgagttccagttttgtaatgatcccttcctggacgtgtactatcacaagaacaataag agctggatggagtccgagtttagagtgtattctagcgccaacaactgcacatttgagtacgtgagccagcctttcctgatggacct ggagggcaagcagggcaatttcaagaacctgagggagttcgtgtttaagaatatcgacggctacttcaaaatctactctaagcac acccccatcaacctgggccgcgacctgcctcagggcttcagcgccctggagcccctggtggatctgcctatcggcatcaacatc acccggtttcagacactgctggccctgcacagaagctacctgacacccggcgactcctctagcggatggaccgccggcgctgc cgcctactatgtgggctacctccagccccggaccttcctgctgaagtacaacgagaatggcaccatcacagacgcagtggattg cgccctggaccccctgagcgagacaaagtgtacactgaagtcctttaccgtggagaagggcatctatcagacatccaatttcagg gtgcagccaaccgagtctatcgtgcgctttcctaatatcacaaacctgtgcccatttgacgaggtgttcaacgcaacccgcttcgc cagcgtgtacgcctggaataggaagcggatcagcaactgcgtggccgactatagcgtgctgtacaacctggcccccttcttcgc ctttaagtgctatggcgtgtcccccacaaagctgaatgacctgtgctttaccaacgtctacgccgattctttcgtgatcaggggcaa cgaggtgtcccagatcgcccccggccagacaggcaatatcgcagactacaattataagctgccagacgatttcaccggctgcgt gatcgcctggaacagcaacaagctggattccaaagtgggcggcaactacaattatagataccggctgtttagaaagagcaatct gaagcccttcgagagggacatctctacagaaatctaccaggccggcaataagccttgcaatggcgtggccggcgtgaactgtta tttcccactccagtcctacggcttccgccccacatatggcgtgggccaccagccttaccgcgtggtggtgctgagctttgagctgc tgcacgccccagcaacagtgtgcggccccaagaagtccaccaatctggtgaagaacaagtgcgtgaacttcaacttcaacggc ctgaccggcacaggcgtgctgaccgagtccaacaagaagttcctgccatttcagcagttcggcagggacatcgcagataccac agacgccgtgcgcgacccacagaccctggagatcctggacatcacaccctgctctttcggcggcgtgagcgtgatcacacccg gcaccaatacaagcaaccaggtggccgtgctgtatcagggcgtgaattgtaccgaggtgcccgtggctatccacgccgatcag ctgaccccaacatggcgggtgtacagcaccggctccaacgtcttccagacaagagccggatgcctgatcggagcagagtacgt gaacaattcctatgagtgcgacatcccaatcggcgccggcatctgtgcctcttaccagacccagacaaagtctcacagaagagc ccggagcgtggcctcccagtctatcatcgcctataccatgtccctgggcgccgagaacagcgtggcctactctaacaatagcatc gccatcccaaccaacttcacaatctctgtgaccacagagatcctgcccgtgtccatgaccaagacatctgtggactgcacaatgtatatctgtggcgattctaccgagtgcagcaacctgctgctccagtacggcagcttttgtacccagctgaagagagccctgacaggc atcgccgtggagcaggataagaacacacaggaggtgttcgcccaggtgaagcaaatctacaagaccccccctatcaagtacttt ggcggcttcaatttttcccagatcctgcctgatccatccaagccttctaagcggagctttatcgaggacctgctgttcaacaaggtg accctggccgatgccggcttcatcaagcagtatggcgattgcctgggcgacatcgcagccagggacctgatctgcgcccagaa gtttaatggcctgaccgtgctgccacccctgctgacagatgagatgatcgcacagtacacaagcgccctgctggccggcaccat cacatccggatggaccttcggcgcaggagccgccctccagatcccctttgccatgcagatggcctataggttcaacggcatcgg cgtgacccagaatgtgctgtacgagaaccagaagctgatcgccaatcagtttaactccgccatcggcaagatccaggacagcct gtcctctacagccagcgccctgggcaagctccaggatgtggtgaatcacaacgcccaggccctgaataccctggtgaagcagc tgagcagcaagttcggcgccatctctagcgtgctgaatgacatcctgagccggctggacaaggtggaggcagaggtgcagatc gaccggctgatcaccggccggctccagagcctccagacctatgtgacacagcagctgatcagggccgccgagatcagggcc agcgccaatctggcagcaaccaagatgtccgagtgcgtgctgggccagtctaagagagtggacttttgtggcaagggctatcac ctgatgtccttccctcagtctgccccacacggcgtggtgtttctgcacgtgacctacgtgcccgcccaggagaagaacttcacca cagcccctgccatctgccacgatggcaaggcccactttccaagggagggcgtgttcgtgtccaacggcacccactggtttgtga cacagcgcaatttctacgagccccagatcatcaccacagacaacaccttcgtgagcggcaactgtgacgtggtcatcggcatcg tgaacaataccgtgtatgatccactccagcccgagctggacagctttaaggaggagctggataagtatttcaagaatcacacctcc cctgacgtggatctgggcgacatcagcggcatcaatgcctccgtggtgaacatccagaaggagatcgaccgcctgaacgaggt ggctaagaatctgaacgagagcctgatcgacctccaggagctgggcaagtatgagcagtacatcaagtggccctggtacatctg gctgggcttcatcgccggcctgatcgccatcgtgatggtgaccatcatgctgtgctgtatgacatcctgctgttcttgcctgaaggg ctgctgtagctgtggctcctgctgtaagttattgaccattgtcgttgctaatcgaaatagaatggagaattttgtttatcataaatgaA CGCGTGTCGACTCATGGAATGCATACCAAACATTATTGACACTAATGACACA CAAAATTGGTTTTAAGAAAAACCAAGAGAACAATAGGCCAGAATGGCTGGGT CTCGGGAGATATTACTCCCTGAAGTCCATCTCAATTCACCAATTGTAAAGCAT AAGCTATACTATTACATTCTACTTGGAAACCTCCCAAATGAGATCGACCTTGA CGATTTAGGTCCATTACATAATCAAAATTGGAATCAGATAGCACATGAAGAG TCTAACTTAGCTCAACGCTTGGTAAATGTAAGAAATTTTCTAATTACCCACAT CCCTGATCTTAGAAAGGGCCATTGGCAAGAGTATGTCAATGTAATACTGTGG CCGCGAATTCTTCCCTTGATCCCGGATTTTAAAATCAATGACCAATTGCCTCT GCTCAAAAATTGGGACAAGTTAGTTAAAGAATCATGTTCAGTAATCAATGCA GGTACTTCCCAGTGCATTCAGAATCTCAGCTATGGACTGACAGGTCGTGGGA ACCTCTTTACACGATCACGTGAACTCTCTGGTGACCGCAGGGATATTGATCTT AAGACAGTTGTGGCAGCATGGCATGACTCAGACTGGAAAAGAATAAGTGATT TTTGGATTATGATCAAATTCCAGATGAGACAATTAATTGTTAGGCAAACAGAT CATAATGATTCTGATTTAATCACGTATATCGAAAATAGAGAAGGCATAATCATCATAACCCCTGAACTGGTAGCATTATTTAACACTGAGAATCATACACTAACATACATGACCTTTGAAATTGTACTGATGGTTTCAGATATGTACGAAGGTCGTCACAACATTTTATCACTATGCACAGTTAGCACTTACCTGAATCCTCTGAAGAAAAGAATAACATATTTATTGAGCCTTGTAGATAACTTAGCTTTTCAGATAGGTGATGCTGTATATAACATAATTGCTTTGCTAGAATCCTTTGTATATGCACAGTTGCAAATGTCAGATCCCATCCCAGAACTCAGAGGACAATTCCATGCATTCGTATGTTCTGAGATTCTTGATGCACTAAGAGGAACTAATAGTTTCACCCAGGATGAATTAAGAACTGTGACAACTAATTTGATATCCCCATTCCAAGATCTGACCCCAGATCTTACGGCTGAATTGCTCTGTATAATGAGGCTTTGGGGACACCCCATGCTCACTGCCAGTCAAGCTGCAGGAAAGGTACGCGAGTCTATGTGTGCTGGAAAAGTATTAGACTTTCCCACCATTATGAAAACACTAGCCTTTTTCCATACTATTCTGATCAATGGATACAGGAGGAAGCATCATGGAGTATGGCCACCCTTAAACTTACCGGGTAATGCTTCAAAGGGTCTCACGGAACTTATGAATGACAATACTGAAATAAGCTATGAATTCACACTTAAGCATTGGAAGGAAGTCTCTCTTATAAAATTCAAGAAATGTTTTGATGCAGACGCAGGTGAGGAACTCAGTATATTTATGAAAGATAAGGCAATTAGTGCCCCAAAACAAGACTGGATGAGTGTGTTTAGAAGAAGCCTAATCAAACAGCGCCATCAGCATCATCAGGTCCCCCTACCAAATCCATTCAATCGACGGCTGTTGCTAAACTTTCTCGGAGATGACAAATTCGACCCGAATGTGGAGCTACAGTATGTAACATCAGGTGAGTATCTACATGATGACACGTTTTGTGCATCATATTCACTAAAAGAGAAGGAAATTAAACCTGATGGTCGAATTTTTGCAAAGTTGACTAAGAGAATGAGATCATGTCAAGTTATAGCAGAATCTCTTTTAGCGAACCATGCTGGGAAGTTAATGAAAGAGAATGGTGTTGTGATGAATCAGCTATCATTAACAAAATCACTATTAACAATGAGTCAGATTGGAATAATATCCGAGAAAGCTAGAAAGTCAACTCGAGATAACATAAATCAACCTGGTTTCCAGAATATCCAGAGAAATAAATCACATCACTCCAAGCAAGTCAATCAGCGAGATCCAAGTGATGACTTTGAATTGGCAGCATCTTTTTTAACTACTGATCTCAAAAAATATTGTTTACAATGGAGGTACCAGACAATTATCCCATTTGCTCAATCATTAAACAGAATGTATGGTTATCCTCATCTCTTTGAGTGGATTCACTTACGGCTAATGCGTAGTACACTTTACGTGGGGGATCCCTTCAACCCACCAGCAGATACCAGTCAATTTGATCTAGATAAAGTAATTAATGGAGATATCTTCATTGTATCACCCAGAGGTGGAATTGAAGGGCTGTGTCAAAAGGCTTGGACAATGATATCTATCGCTGTGATAATTCTATCTGCCACAGAGTCTGGCACACGAGTAATGAGTATGGTGCAGGGAGATAATCAAGCAATTGCTGTCACCACACGAGTACCAAGGAGCCTGCCGACTCTTGAGAAAAAGACTATTGCTTTTAGATCTTGTAATCTATTCTTTGAGAGGTTAAAATGTAATAATTTTGGATTAGGTCACCATTTGAAAGAACAAGAGACTATCATTAGTTCTCACTTCTTTGTTTATAGCAAGAGAATATTCTATCAGGGGAGGATTCTAACGCAAGCCTTAAAAAATGCTAGTAAGCTCTGCTTGACAGCTGATGTCCTAGGAGAATGCACCCAATCATCATGTTCTAATCTTGCAACTACTGTCATGAGGTTAACTGAGAATGGTGTTGAAAAAGATATCTGTTTCTACTTGAATATCTATATGACCATCAAACAGCTCTCCTATGATATCATCTTCCCTCAAGTGTCAATTCCTGGAGATCAGATCACATTAGAATACATAAATAATCCACACCTGGTATCACGATTGGCTCTTTTGCCATCCCAGTTAGGAGGTCTAAACTACCTGTCATGCAGTAGGCTGTTCAATCGAAACATAGGCGACCCGGTGGTTTCCGCAGTTGCAGATCTTAAGAGATTAATTAAATCAGGATGTATGGATTACTGGATCCTTTATAACTTATTAGGGAGAAAACCGGGAAACGGCTCATGGGCTACTTTAGCAGCTGACCCGTACTCAATCAATATAGAGTATCAATACCCTCCAACTACAGCTCTTAAGAGGCACACCCAACAAGCTCTGATGGAACTCAGTACGAATCCAATGTTACGTGGCATATTCTCTGACAATGCACAGGCAGAAGAAAATAACCTTGCTAGGTTTCTCCTGGATAGGGAGGTGATCTTTCCGCGTGTAGCTCACATCATCATTGAGCAAACCAGTGTCGGGAGGAGAAAACAGATTCAAGGATATTTGGATTCAACTAGATCGATAATGAGGAAATCACTAGAAATTAAGCCCTTATCCAATAGGAAGCTTAATGAAATACTGGATTACAACATCAATTACCTAGCTTACAATTTGGCATTACTCAAGAATGCTATTGAACCTCCGACTTATTTGAAGGCAATGACACTTGAAACATGTAGCATCGACATTGCAAGGAACCTCCGGAAGCTCTCCTGGGCCCCACTCTTGGGTGGGAGAAATCTTGAAGGATTAGAGACGCCAGATCCCATTGAAATTACTGCAGGAGCATTAATTGTTGGATCGGGCTACTGTGAACAGTGTGCTGCAGGAGACAATCGATTCACATGGTTTTTCTTGCCATCTGGTATCGAGATAGGAGGGGATCCCCGTGATAATCCTCCTATCCGTGTACCGTACATTGGCTCCAGGACTGATGAGAGGAGGGTAGCCTCAATGGCATACATCAGGGGTGCCTCGAGTAGCTTAAAAGCAGTTCTTAGACTGGCGGGAGTGTACATCTGGGCATTCGGAGATACTCTGGAGAATTGGATAGATGCACTGGATTTGTCTCACACTAGAGTTAACATCACACTTGAACAGCTGCAATCCCTCACCCCACTTCCAACCTCTGCCAATCTAACCCATCGGTTGGATGATGGCACAACTACCCTAAAGTTTACTCCTGCGAGCTCTTACACCTTTTCAAGTTTCACTCATATATCAAATGATGAGCAATACCTGACAATTAATGACAAAACTGCAGATTCAAATATAATCTACCAACAGTTAATGATCACTGGACTCGGAATCTTAGAAACATGGAATAATCCCCCAATCAATAGAACATTCGAAGAATCTACCCTACATTTGCACACTGGTGCATCATGTTGTGTCCGACCTGTGGACTCCTGCATTCTCTCAGAAGCATTAACAGTCAAGCCACATATTACAGTACCGTACAGCAATAAATTTGTATTTGATGAGGACCCGCTATCTGAATATGAAACTGCAAAACTGGAATCGTTATCATTCCAAGCCCAATTAGGCAACATTGATGCTGTAGATATGACAGGTAAATTAACATTATTGTCCCAATTCACTGCAAGGCAGATTATCAATGCAATCACTGGACTCGATGAGTCTGTCTCTCTTACTAATGATGCCATTGTTGCATCAGACTATGTCTCCAATTGGATTAGTGAATGCATGTATACCAAATTAGATGAATTATTTATGTATTGTGGGTGGGAACTACTATTGGAACTATCCTATCAAATGTATTATCTGAGGGTAGTTGGGTGGAGTAATATAGTGGATTATTCTTACATGATCTTGAGAAGAATCCCGGGTGCAGCATTAAACAATCTGGCATCTACATTAAGTCATCCAAAACTTTTCCGACGAGCTATCAACCTAGATATAGTTGCCCCCTTAAATGCTCCTCATTTTGCATCTCTGGACTACATCAAGATGAGTGTGGATGCAATACTCTGGGGCTGTAAAAGAGTCATCAATGTGCTCTCCAATGGAGGGGACTTAGAATTAGTTGTGACATCTGAAGATAGCCTTATTCTCAGTGACCGATCCATGAATCTCATTGCAAGGAAATTAACTTTATTATCACTGATTCACCATAATGGTTTGGAACTACCAAAGATTAAGGGGTTCTCTCCTGATGAGAAGTGTTTCGCTTTGACAGAATTTTTGAGGAAAGTGGTGAACTCAGGGTTGAGTTCAATAGAGAACCTATCAAATTTTATGTACAATGTGGAGAACCCACGGCTTGCAGCATTCGCCAGCAACAATTACTACCTGACCAGAAAATTATTGAATTCAATACGAGATACTGAGTCGGGTCAAGTAGCAGTCACCTCATATTATGAATCATTAGAATATATTGATAGTCTTAAGCTAACCCCACATGTGCCTGGCACCTCATGCATTGAGGATGATAGTCTATGTACAAATGATTACATAATCTGGATCATAGAGTCTAATGCAAACTTGGAGAAGTATCCAATTCCAAATAGCCCTGAGGATGATTCCAATTTCCATAACTTTAAGTTGAATGCTCCATCGCACCATACCTTACGCCCATTAGGGTTGTCATCAACTGCTTGGTATAAGGGTATAAGCTGCTGCAGGTACCTTGAGCGATTAAAGCTACCACAAGGTGATCATTTATATATTGCAGAAGGTAGTGGTGCCAGTATGACAATCATAGAATACCTATTCCCAGGAAGAAAGATATATTACAATTCTTTATTTAGTAGTGGTGACAATCCCCCACAAAGAAATTATGCACCAATGCCTACTCAGTTCATTGAGAGTGTCCCATACAAGCTCTGGCAAGCACACACAGATCAATATCCCGAGATTTTTGAGGACTTCATCCCTCTATGGAACGGAAACGCCGCCATGACTGACATAGGAATGACAGCTTGTGTAGAATTCATCATCAATCGAGTCGGCCCAAGGACTTGCAGTTTAGTACATGTAGATTTGGAATCAAGTGCAAGCTTAAATCAACAATGCCTGTCAAAGCCGATAATTAATGCTATCATCACTGCTACAACTGTTTTGTGCCCTCATGGGGTGCTTATTCTGAAATATAGTTGGTTGCCATTTACTAGATTTAGTACTTTGATCACTTTCTTATGGTGCTACTTTGAGAGAATCACTGTTCTTAGGAGCACATATTCTGATCCAGCTAATCATGAGGTTTATTTAATTTGTATCCTTGCCAACAACTTTGCATTCCAGACTGTCTCGCAGGCAACAGGAATGGCGATGACTTTAACTGATCAAGGGTTTACTTTGATATCACCTGAAAGAATAAATCAGTATTGGGATGGTCACTTGAAGCAAGAACGTATCGTAGCAGAAGCAATTGATAAGGTGGTTCTAGGAGAAAATGCTCTATTTAATTCGAGTGATAATGAATTAATTCTCAAATGTGGAGGGACACCAAATGCACGGAATCTCATCGATATCGAGCCAGTCGCAACTTTCATAGAATTTGAACAATTGATCTGCACAATGTTGACAACCCACTTGAAGGAAATAATTGATATAACAAGGTCTGGAACCCAGGATTATGAAAGTTTATTACTCACTCCTTACAATTTAGGTCTTCTTGGTAAAATCAGTACGATAGTGAGATTATTAACAGAAAGGATTCTAAATCATACTATCAGGAATTGGTTGATCCTCCCACCTTCGCTCCGGATGATCGTGAAGCAGGACTTGGAATTCGGCATATTCAGGATTACTTCCATCCTCAATTCTGATCGGTTCCTGAAGCTTTCTCCAAATAGGAAATACTTGATTGCACAATTAACTGCAGGCTACATTAGGAAATTGATTGAGGGGGATTGCAATATCGATCTAACCAGACCTATCCAAAAGCAAATCTGGAAAGCATTAGGTTGTGTAGTCTATTGTCACGATCCAATGGATCAAAGGGAGTCAACAGAGTTTATTGATATAAATATTAATGAAGAAATAGACCGCGGGATCGATGGCGAGGAAATCTAAACATATCAAGAATCAGAATTAGTTTAAGAAAAAAGAAGAGGATTAATCTTGGTTTTCCCCTTGGTGGGTCGGCATGGCATCTCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCACTCGGATGGCTAAGGGAGCGGCCGGGGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAGTTGGCTGCTGCCACCGCTGAGCAATAACTAGCATAACCCCTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTGCTGAAAGGAGGAACTATATCCGGATCATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGGACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATA TTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCG AAAAGT (SEQ ID NO: 8). vii. CVL112
[0167] The nucleic acid sequence for CVL112 is:GCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCTAATACGACTCACTATAGGGACCAAGGGGAAAATGAAGTGGTGACTCAAATCATCGAAGACCCTCGAGATTACATAGGTCCGGAACCTATGGCCTTCGTGACCGACCTCGAGTCAGAGTAGTTCAATAAGGACCTATCAAGTTTGGGCAATTTTTCGTCCCCGACACAAAAATGTCATCCGTGCTTAAAGCATATGAGCGATTCACGCTCACTCAAGAACTGCAAGATCAGAGTGAGGAAGGTACAATCCCACCTACAACACTAAAACCGGTAATCAGGGTATTTATACTAACCTCTAATAACCCAGAGCTAAGATCCCGGCTTCTTCTATTCTGCCTACGGATTGTTCTCAGTAATGGTGCAAGGGATTCCCATCGCTTTGGAGCATTACTCACAATGTTTTCGCTACCATCAGCCACAATGCTCAATCATGTCAAATTAGCTGACCAGTCACCAGAAGCTGATATCGAAAGGGTAGAGATCGATGGCTTTGAGGAGGGATCATTCCGCTTAATCCCCAATGCTCGTTCAGGTATGAGCCGTGGAGAGATCAATGCCTATGCTGCACTTGCAGAAGATCTACCTGACACACTAAACCATGCAACACCTTTCGTTGATTCCGAAGTCGAGGGAACTGCATGGGATGAGATTGAGACTTTCTTAGATATGTGTTACAGTGTCCTAATGCAGGCATGGATAGTGACTTGCAAGTGCATGACTGCGCCAGACCAACCTGCTGCTTCTATTGAGAAACGCCTGCAAAAATATCGTCAGCAAGGCAGGATCAACCCGAGATATCTCCTGCAACCGGAGGCTCGACGAATAATCCAGAATGTAATCCGGAAGGGAATGGTGGTCAGACATTTCCTCACCTTTGAACTGCAGCTTGCCCGAGCACAAAGCCTTGTATCAAATAGGTATTATGCTATGGTAGGGGATGTTGGAAAGTATATAGAGAATTGTGGAATGGGAGGCTTCTTTTTGACACTAAAATATGCATTAGGAACTAGATGGCCCACACTTGCTTTAGCTGCATTTTCAGGAGAGCTAACAAAGCTAAAGTCCCTCATGGCATTATACCAGACCCTTGGTGAGCAGGCCCGATATTTGGCCCTATTGGAGTCACCACATTTGATGGATTTTGCTGCAGCAAACTACCCACTGCTATATAGCTATGCTATGGGAATAGGCTATGTGTTAGATGTCAACATGAGGAACTACGCTTTCTCCAGATCATACATGAACAAGACATATTTCCAATTGGGAATGGAAACTGCAAGAAAACAACAGGGTGCAGTTGACATGAGGATGGCAGAAGATCTCGGTCTAACTCAAGCCGAACGCACCGAGATGGCAAATACACTTGCCAAATTGACCACAGCAAATCGAGGGGCAGACACCAGGGGAGGAGTCAACCCGTTCTCATCTGTCACTGGGACAACTCAGGTGCCCGCTGCAGCAACAGGTGACACACTCGAGAGTTACATGGCAGCGGATCGACTGAGGCAGAGATATGCTGATGCAGGCACCCATGATGATGAGATGCCACCATTGGAAGAGGAGGAAGAGGACGACACATCTGCAGGTCCACGCACTGGACCAACTCTTGAACAAGTGGCCTTGGACATCCAGAACGCAGCAGTTGGAGCTCCCATCCATACAGATGACCTGAATGCCGCACTGGGTGATCTTGACATCTAGACAATTCAGATCCCAATCTAAAATTGACATACCTAATTGATTAGTTAGATGGAACTACAGTGGATTCCATAAGGTTCCTGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACAAGCGACTGCCGGTGCCAACAGCGCAATCCACAATCTACAATGGATCCCACTGATCTGAGCTTCTCCCCAGATGAGATCAATAAGCTCATAGAGACAGGCCTGAATACTGTAGAGTATTTTACTTCCCAACAAGTCACAGGAACATCCTCTCTTGGAAAGAATACAATACCACCAGGGGTCACAGGACTACTAACCAATGCTGCAGAGGCAAAGATCCAAGAGTCAACTAACCATCAGAAGGGCTCAGTTGGTGGGGGTGCAAAACCAAAGAAACCGCGACCAAAAATTGCCATTGTGCCAGCAGATGACAAAACAGTGCCCGGAAAGCCGATCCCAAACCCTCTATTAGGTCTGGACTCCACCCCGAGCACCCAAACTGTGCTTGATCTAAGTGGGAAAACATTACCATCAGGATCCTATAAGGGGGTTAAGCTTGCGAAATTTGGAAAAGAAAATCTGATGACACGGTTCATCGAGGAACCCAGAGAGAATCCTATCGCAACCAGTTtCCCCATCGATTTTAAGAGGGGCAGGGATACCGGCGGGTTCCATAGAAGGGAGTACTCAATCGGATGGGTGGGAGATGAAGTCAAGGTCACTGAGTGGTGCAATCCATCCTGTTCTCCAATCACCGCTGCAGCAAGGCGATTTGAATGCACTTGTCACCAGTGTCCAGTCACTTGCTCTGAATGTGAACGAGATACTTAATACAGTGAGAAATTTGGACTCTCGGATGAATCAACTGGAGACAAAAGTAGATCGCATTCTCTCATCTCAGTCTCTAATCCAGACCATCAAGAATGACATAGTTGGACTTAAAGCAGGGATGGCTACTTTAGAAGGAATGATTACAACTGTGAAAATCATGGACCCGGGAGTTCCCAGTAATGTTACTGTGGAAGATGTACGCAAGACACTAAGTAACCATGCTGTTGTTGTGCCAGAATCATTCAATGATAGTTTCTTGACTCAATCTGAAGATGTAATTTCACTTGATGAGTTGGCTCGACCAACTGCAACAAGTGTTAAGAAGATTGTCAGGAAGGTTCCTCCTCAGAAGGATCTGACTGGATTGAAGATTACACTAGAGCAATTGGCAAAGGATTGCATCAGCAAACCGAAGATGAGGGAAGAGTATCTCCTCAAAATCAACCAGGCTTCCAGTGAGGCTCAGCTAATTGACCTCAAGAAAGCAATCATCCGCAGTGCAATTTGATCAAGAAACACCCAATTACACTACACTGGTATGACACTGTACTAACCCTGAGGGTTTTAGAAAAAACGATTAACGATAAATAAGCCCGAACACTACACACTACCTGAGGCAGCCATGCCATCCATCAGCATTCCCGCAGACCCCACCAATCCACGTCAATCAATAAAAGCGTTCCCAATTGTGATCAACAGTGATGGGGGTGAGAAAGGCCGCTTGGTTAAACAACTACGCACAACCTACTTGAATGACCTAGATACTCATGAGCCACTGGTGACATTCATAAATACCTATGGATTCATCTACGAACAGGATCGGGGGAATACCATTGTCGGAGAGGATCAACTTGGGAAGAAAAGAGAGGCTGTGACCGCTGCAATGGTTACCCTTGGATGTGGGCCTAATCTACCATCATTAGGGAATGTCCTGGGACAACTGAGGGAATTCCAGGTCACTGTTAGGAAGACATCCAGCAAAGCGGAAGAGATGGTCTTTGAAATTGTTAAGTATCCGAGAATATTTCGGGGTCATACATTAATCCAGAAAGGACTAGTCTGTGTCTCCGCAGAAAAATTTGTTAAGTCACCAGGGAAAATACAATCTGGAATGGACTATCTCTTCATTCCGACATTTCTGTCAGTGACTTACTGTCCAGCTGCAATCAAATTTCAGGTACCTGGCCCCATGTTGAAAATGAGATCAAGATACACTCAGAGCTTACAACTTGAACTAATGATAAGAATCCTGTGTAAGCCCGATTCGCCACTTATGAAGGTCCATACCCCTGACAAGGAGGGAAGAGGATGTCTTGTATCAGTATGGCTGCAT GTATGCAACATCTTCAAATCAGGAAACAAGAATGGCAGTGAGTGGCAGGAAT ACTGGATGAGAAAGTGTGCTAACATGCAACTTGAAGTGTCGATTGCAGATAT GTGGGGACCAACTATCATAATTCATGCCAGAGGTCACATTCCCAAAAGTGCT AAGTTGTTTTTTGGAAAGGGTGGATGGAGCTGCCATCCACTTCACGAAGTTGT TCCAAGTGTCACTAAAACACTATGGTCCGTGGGCTGTGAGATTACAAAGGCG AAGGCAATAATACAAGAGAGTAGCATCTCTCTTCTCGTGGAGACTACTGACA TCATAAGTCCAAAAGTCAAAATTTCATCTAAGCATCGCCGCTTTGGGAAATCA AATTGGGGTCTGTTCAAGAAAACTAAATCACTGCCTAACCTGACGGAGCTGG AATGAgctagcGGCAGAAGCCTTCAGGTCTGACCCAGCCAATCAAAGCATTATA CCAGACCATGGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGT TAGCAACAAGCGGCGGCCGCCatgttcgtcttcctggtcctgctgcctctggtctcctcacagtgcgtcaatctg acaactcggactcagctgccacctgcttatactaatagcttcaccagaggcgtgtactatcctgacaaggtgtttagaagctccgtg ctgcactctacacaggatctgtttctgccattctttagcaacgtgacctggttccacgccatccacgtgagcggcaccaatggcac aaagcggttcgacaatcccgtgctgccttttaacgatggcgtgtacttcgcctctaccgagaagagcaacatcatcagaggctgg atctttggcaccacactggactccaagacacagtctctgctgatcgtgaacaatgccaccaacgtggtcatcaaggtgtgcgagtt ccagttttgtaatgatcccttcctgggcgtgtactatcacaagaacaataagagctggatggagtccgagtttagagtgtattctagc gccaacaactgcacatttgagtacgtgagccagcctttcctgatggacctggagggcaagcagggcaatttcaagaacctgagg gagttcgtgtttaagaatatcgacggctacttcaaaatctactctaagcacacccccatcaacctggtgcgcgacctgcctcaggg cttcagcgccctggagcccctggtggatctgcctatcggcatcaacatcacccggtttcagacactgctggccctgcacagaagc tacctgacacccggcgactcctctagcggatggaccgccggcgctgccgcctactatgtgggctacctccagccccggaccttc ctgctgaagtacaacgagaatggcaccatcacagacgcagtggattgcgccctggaccccctgagcgagacaaagtgtacact gaagtcctttaccgtggagaagggcatctatcagacatccaatttcagggtgcagccaaccgagtctatcgtgcgctttcctaatat cacaaacctgtgcccatttggcgaggtgttcaacgcaacccgcttcgccagcgtgtacgcctggaataggaagcggatcagcaa ctgcgtggccgactatagcgtgctgtacaactccgcctctttcagcacctttaagtgctatggcgtgtcccccacaaagctgaatga cctgtgctttaccaacgtctacgccgattctttcgtgatcaggggcgacgaggtgcgccagatcgcccccggccagacaggcaa gatcgcagactacaattataagctgccagacgatttcaccggctgcgtgatcgcctggaacagcaacaatctggattccaaagtg ggcggcaactacaattatctgtaccggctgtttagaaagagcaatctgaagcccttcgagagggacatctctacagaaatctacca ggccggcagcaccccttgcaatggcgtggagggctttaactgttatttcccactccagtcctacggcttccagcccacaaacggc gtgggctatcagccttaccgcgtggtggtgctgagctttgagctgctgcacgccccagcaacagtgtgcggccccaagaagtcc accaatctggtgaagaacaagtgcgtgaacttcaacttcaacggcctgaccggcacaggcgtgctgaccgagtccaacaagaa gttcctgccatttcagcagttcggcagggacatcgcagataccacagacgccgtgcgcgacccacagaccctggagatcctgg acatcacaccctgctctttcggcggcgtgagcgtgatcacacccggcaccaatacaagcaaccaggtggccgtgctgtatcagg acgtgaattgtaccgaggtgcccgtggctatccacgccgatcagctgaccccaacatggcgggtgtacagcaccggctccaacgtcttccagacaagagccggatgcctgatcggagcagagcacgtgaacaattcctatgagtgcgacatcccaatcggcgccgg catctgtgcctcttaccagacccagacaaactctcccagaagagcccggagcgtggcctcccagtctatcatcgcctataccatgt ccctgggcgccgagaacagcgtggcctactctaacaatagcatcgccatcccaaccaacttcacaatctctgtgaccacagaga tcctgcccgtgtccatgaccaagacatctgtggactgcacaatgtatatctgtggcgattctaccgagtgcagcaacctgctgctcc agtacggcagcttttgtacccagctgaatagagccctgacaggcatcgccgtggagcaggataagaacacacaggaggtgttc gcccaggtgaagcaaatctacaagaccccccctatcaaggactttggcggcttcaatttttcccagatcctgcctgatccatccaa gccttctaagcggagctttatcgaggacctgctgttcaacaaggtgaccctggccgatgccggcttcatcaagcagtatggcgatt gcctgggcgacatcgcagccagggacctgatctgcgcccagaagtttaatggcctgaccgtgctgccacccctgctgacagat gagatgatcgcacagtacacaagcgccctgctggccggcaccatcacatccggatggaccttcggcgcaggagccgccctcc agatcccctttgccatgcagatggcctataggttcaacggcatcggcgtgacccagaatgtgctgtacgagaaccagaagctgat cgccaatcagtttaactccgccatcggcaagatccaggacagcctgtcctctacagccagcgccctgggcaagctccaggatgt ggtgaatcagaacgcccaggccctgaataccctggtgaagcagctgagcagcaacttcggcgccatctctagcgtgctgaatg acatcctgagccggctggacaaggtggaggcagaggtgcagatcgaccggctgatcaccggccggctccagagcctccaga cctatgtgacacagcagctgatcagggccgccgagatcagggccagcgccaatctggcagcaaccaagatgtccgagtgcgt gctgggccagtctaagagagtggacttttgtggcaagggctatcacctgatgtccttccctcagtctgccccacacggcgtggtgt ttctgcacgtgacctacgtgcccgcccaggagaagaacttcaccacagcccctgccatctgccacgatggcaaggcccactttc caagggagggcgtgttcgtgtccaacggcacccactggtttgtgacacagcgcaatttctacgagccccagatcatcaccacag acaacaccttcgtgagcggcaactgtgacgtggtcatcggcatcgtgaacaataccgtgtatgatccactccagcccgagctgg acagctttaaggaggagctggataagtatttcaagaatcacacctcccctgacgtggatctgggcgacatcagcggcatcaatgc ctccgtggtgaacatccagaaggagatcgaccgcctgaacgaggtggctaagaatctgaacgagagcctgatcgacctccagg agctgggcaagtatgagcagtacatcaagtggccctggtacatctggctgggcttcatcgccggcctgatcgccatcgtgatggt gaccatcatgctgtgctgtatgacatcctgctgttcttgcctgaagggctgctgtagctgtggctcctgctgtaagttattgaccattg tcgttgctaatcgaaatagaatggagaattttgtttatcataaatga AGTCGAC TC AT GGA AT GC AT AC C A A ACATTATTGACACTAATGACACACAAAATTGGTTTTAAGAAAAACCAAGAGA ACAATAGGCCAGAATGGCTGGGTCTCGGGAGATATTACTCCCTGAAGTCCAT CTCAATTCACCAATTGTAAAGCATAAGCTATACTATTACATTCTACTTGGAAA CCTCCCAAATGAGATCGACCTTGACGATTTAGGTCCATTACATAATCAAAATT GGAATCAGATAGCACATGAAGAGTCTAACTTAGCTCAACGCTTGGTAAATGT AAGAAATTTTCTAATTACCCACATCCCTGATCTTAGAAAGGGCCATTGGCAAG AGTATGTCAATGTAATACTGTGGCCGCGAATTCTTCCCTTGATCCCGGATTTT AAAATCAATGACCAATTGCCTCTGCTCAAAAATTGGGACAAGTTAGTTAAAG AATCATGTTCAGTAATCAATGCAGGTACTTCCCAGTGCATTCAGAATCTCAGCTATGGACTGACAGGTCGTGGGAACCTCTTTACACGATCACGTGAACTCTCTGG TGACCGCAGGGATATTGATCTTAAGACAGTTGTGGCAGCATGGCATGACTCAGACTGGAAAAGAATAAGTGATTTTTGGATTATGATCAAATTCCAGATGAGACAATTAATTGTTAGGCAAACAGATCATAATGATTCTGATTTAATCACGTATATCGAAAATAGAGAAGGCATAATCATCATAACCCCTGAACTGGTAGCATTATTTAACACTGAGAATCATACACTAACATACATGACCTTTGAAATTGTACTGATGGTTTCAGATATGTACGAAGGTCGTCACAACATTTTATCACTATGCACAGTTAGCACTTACCTGAATCCTCTGAAGAAAAGAATAACATATTTATTGAGCCTTGTAGATAACTTAGCTTTTCAGATAGGTGATGCTGTATATAACATAATTGCTTTGCTAGAATCCTTTGTATATGCACAGTTGCAAATGTCAGATCCCATCCCAGAACTCAGAGGACAATTCCATGCATTCGTATGTTCTGAGATTCTTGATGCACTAAGAGGAACTAATAGTTTCACCCAGGATGAATTAAGAACTGTGACAACTAATTTGATATCCCCATTCCAAGATCTGACCCCAGATCTTACGGCTGAATTGCTCTGTATAATGAGGCTTTGGGGACACCCCATGCTCACTGCCAGTCAAGCTGCAGGAAAGGTACGCGAGTCTATGTGTGCTGGAAAAGTATTAGACTTTCCCACCATTATGAAAACACTAGCCTTTTTCCATACTATTCTGATCAATGGATACAGGAGGAAGCATCATGGAGTATGGCCACCCTTAAACTTACCGGGTAATGCTTCAAAGGGTCTCACGGAACTTATGAATGACAATACTGAAATAAGCTATGAATTCACACTTAAGCATTGGAAGGAAGTCTCTCTTATAAAATTCAAGAAATGTTTTGATGCAGACGCAGGTGAGGAACTCAGTATATTTATGAAAGATAAGGCAATTAGTGCCCCAAAACAAGACTGGATGAGTGTGTTTAGAAGAAGCCTAATCAAACAGCGCCATCAGCATCATCAGGTCCCCCTACCAAATCCATTCAATCGACGGCTGTTGCTAAACTTTCTCGGAGATGACAAATTCGACCCGAATGTGGAGCTACAGTATGTAACATCAGGTGAGTATCTACATGATGACACGTTTTGTGCATCATATTCACTAAAAGAGAAGGAAATTAAACCTGATGGTCGAATTTTTGCAAAGTTGACTAAGAGAATGAGATCATGTCAAGTTATAGCAGAATCTCTTTTAGCGAACCATGCTGGGAAGTTAATGAAAGAGAATGGTGTTGTGATGAATCAGCTATCATTAACAAAATCACTATTAACAATGAGTCAGATTGGAATAATATCCGAGAAAGCTAGAAAGTCAACTCGAGATAACATAAATCAACCTGGTTTCCAGAATATCCAGAGAAATAAATCACATCACTCCAAGCAAGTCAATCAGCGAGATCCAAGTGATGACTTTGAATTGGCAGCATCTTTTTTAACTACTGATCTCAAAAAATATTGTTTACAATGGAGGTACCAGACAATTATCCCATTTGCTCAATCATTAAACAGAATGTATGGTTATCCTCATCTCTTTGAGTGGATTCACTTACGGCTAATGCGTAGTACACTTTACGTGGGGGATCCCTTCAACCCACCAGCAGATACCAGTCAATTTGATCTAGATAAAGTAATTAATGGAGATATCTTCATTGTATCACCCAGAGGTGGAATTGAAGGGCTGTGTCAAAAGGCTTGGACAATGATATCTATCGCTGTGATAATTCTATCTGCCACAGAGTCTGGCACACGAGTAATGAGTATGGTGCAGGGAGATAATCAAGCAATTGCTGTCACCACACGAGTACCAAGGAGCCTGCCGACTCTTGAGAAAAAGACTATTGCTTTTAGATCTTGTAATCTATTCTTTGAGAGGTTAAAATGTAATAATTTTGGATTAGGTCACCATTTGAAAGAACAAGAGACTATCATTAGTTCTCACTTCTTTGTTTATAGCAAGAGAATATTCTATCAGGGGAGGATTCTAACGCAAGCCTTAAAAAATGCTAGTAAGCTCTGCTTGACAGCTGATGTCCTAGGAGAATGCACCCAATCATCATGTTCTAATCTTGCAACTACTGTCATGAGGTTAACTGAGAATGGTGTTGAAAAAGATATCTGTTTCTACTTGAATATCTATATGACCATCAAACAGCTCTCCTATGATATCATCTTCCCTCAAGTGTCAATTCCTGGAGATCAGATCACATTAGAATACATAAATAATCCACACCTGGTATCACGATTGGCTCTTTTGCCATCCCAGTTAGGAGGTCTAAACTACCTGTCATGCAGTAGGCTGTTCAATCGAAACATAGGCGACCCGGTGGTTTCCGCAGTTGCAGATCTTAAGAGATTAATTAAATCAGGATGTATGGATTACTGGATCCTTTATAACTTATTAGGGAGAAAACCGGGAAACGGCTCATGGGCTACTTTAGCAGCTGACCCGTACTCAATCAATATAGAGTATCAATACCCTCCAACTACAGCTCTTAAGAGGCACACCCAACAAGCTCTGATGGAACTCAGTACGAATCCAATGTTACGTGGCATATTCTCTGACAATGCACAGGCAGAAGAAAATAACCTTGCTAGGTTTCTCCTGGATAGGGAGGTGATCTTTCCGCGTGTAGCTCACATCATCATTGAGCAAACCAGTGTCGGGAGGAGAAAACAGATTCAAGGATATTTGGATTCAACTAGATCGATAATGAGGAAATCACTAGAAATTAAGCCCTTATCCAATAGGAAGCTTAATGAAATACTGGATTACAACATCAATTACCTAGCTTACAATTTGGCATTACTCAAGAATGCTATTGAACCTCCGACTTATTTGAAGGCAATGACACTTGAAACATGTAGCATCGACATTGCAAGGAACCTCCGGAAGCTCTCCTGGGCCCCACTCTTGGGTGGGAGAAATCTTGAAGGATTAGAGACGCCAGATCCCATTGAAATTACTGCAGGAGCATTAATTGTTGGATCGGGCTACTGTGAACAGTGTGCTGCAGGAGACAATCGATTCACATGGTTTTTCTTGCCATCTGGTATCGAGATAGGAGGGGATCCCCGTGATAATCCTCCTATCCGTGTACCGTACATTGGCTCCAGGACTGATGAGAGGAGGGTAGCCTCAATGGCATACATCAGGGGTGCCTCGAGTAGCTTAAAAGCAGTTCTTAGACTGGCGGGAGTGTACATCTGGGCATTCGGAGATACTCTGGAGAATTGGATAGATGCACTGGATTTGTCTCACACTAGAGTTAACATCACACTTGAACAGCTGCAATCCCTCACCCCACTTCCAACCTCTGCCAATCTAACCCATCGGTTGGATGATGGCACAACTACCCTAAAGTTTACTCCTGCGAGCTCTTACACCTTTTCAAGTTTCACTCATATATCAAATGATGAGCAATACCTGACAATTAATGACAAAACTGCAGATTCAAATATAATCTACCAACAGTTAATGATCACTGGACTCGGAATCTTAGAAACATGGAATAATCCCCCAATCAATAGAACATTCGAAGAATCTACCCTACATTTGCACACTGGTGCATCATGTTGTGTCCGACCTGTGGACTCCTGCATTCTCTCAGAAGCATTAACAGTCAAGCCACATATTACAGTACCGTACAGCAATAAATTTGTATTTGATGAGGACCCGCTATCTGAATATGAAACTGCAAAACTGGAATCGTTATCATTCCAAGCCCAATTAGGCAACATTGATGCTGTAGATATGACAGGTAAATTAACATTATTGTCCCAATTCACTGCAAGGCAGATTATCAATGCAATCACTGGACTCGATGAGTCTGTCTCTCTTACTAATGATGCCATTGTTGCATCAGACTATGTCTCCAATTGGATTAGTGAATGCATGTATACCAAATTAGATGAATTATTTATGTATTGTGGGTGGGAACTACTATTGGAACTATCCTATCAAATGTATTATCTGAGGGTAGTTGGGTGGAGTAATATAGTGGATTATTCTTACATGATCTTGAGAAGAATCCCGGGTGCAGCATTAAACAATCTGGCATCTACATTAAGTCATCCAAAACTTTTCCGACGAGCTATCAACCTAGATATAGTTGCCCCCTTAAATGCTCCTCATTTTGCATCTCTGGACTACATCAAGATGAGTGTGGATGCAATACTCTGGGGCTGTAAAAGAGTCATCAATGTGCTCTCCAATGGAGGGGACTTAGAATTAGTTGTGACATCTGAAGATAGCCTTATTCTCAGTGACCGATCCATGAATCTCATTGCAAGGAAATTAACTTTATTATCACTGATTCACCATAATGGTTTGGAACTACCAAAGATTAAGGGGTTCTCTCCTGATGAGAAGTGTTTCGCTTTGACAGAATTTTTGAGGAAAGTGGTGAACTCAGGGTTGAGTTCAATAGAGAACCTATCAAATTTTATGTACAATGTGGAGAACCCACGGCTTGCAGCATTCGCCAGCAACAATTACTACCTGACCAGAAAATTATTGAATTCAATACGAGATACTGAGTCGGGTCAAGTAGCAGTCACCTCATATTATGAATCATTAGAATATATTGATAGTCTTAAGCTAACCCCACATGTGCCTGGCACCTCATGCATTGAGGATGATAGTCTATGTACAAATGATTACATAATCTGGATCATAGAGTCTAATGCAAACTTGGAGAAGTATCCAATTCCAAATAGCCCTGAGGATGATTCCAATTTCCATAACTTTAAGTTGAATGCTCCATCGCACCATACCTTACGCCCATTAGGGTTGTCATCAACTGCTTGGTATAAGGGTATAAGCTGCTGCAGGTACCTTGAGCGATTAAAGCTACCACAAGGTGATCATTTATATATTGCAGAAGGTAGTGGTGCCAGTATGACAATCATAGAATACCTATTCCCAGGAAGAAAGATATATTACAATTCTTTATTTAGTAGTGGTGACAATCCCCCACAAAGAAATTATGCACCAATGCCTACTCAGTTCATTGAGAGTGTCCCATACAAGCTCTGGCAAGCACACACAGATCAATATCCCGAGATTTTTGAGGACTTCATCCCTCTATGGAACGGAAACGCCGCCATGACTGACATAGGAATGACAGCTTGTGTAGAATTCATCATCAATCGAGTCGGCCCAAGGACTTGCAGTTTAGTACATGTAGATTTGGAATCAAGTGCAAGCTTAAATCAACAATGCCTGTCAAAGCCGATAATTAATGCTATCATCACTGCTACAACTGTTTTGTGCCCTCATGGGGTGCTTATTCTGAAATATAGTTGGTTGCCATTTACTAGATTTAGTACTTTGATCACTTTCTTATGGTGCTACTTTGAGAGAATCACTGTTCTTAGGAGCACATATTCTGATCCAGCTAATCATGAGGTTTATTTAATTTGTATCCTTGCCAACAACTTTGCATTCCAGACTGTCTCGCAGGCAACAGGAATGGCGATGACTTTAACTGATCAAGGGTTTACTTTGATATCACCTGAAAGAATAAATCAGTATTGGGATGGTCACTTGAAGCAAGAACGTATCGTAGCAGAAGCAATTGATAAGGTGGTTCTAGGAGAAAATGCTCTATTTAATTCGAGTGATAATGAATTAATTCTCAAATGTGGAGGGACACCAAATGCACGGAATCTCATCGATATCGAGCCAGTCGCAACTTTCATAGAATTTGAACAATTGATCTGCACAATGTTGACAACCCACTTGAAGGAAATAATTGATATAACAAGGTCTGGAACCCAGGATTATGAAAGTTTATTACTCACTCCTTACAATTTAGGTCTTCTTGGTAAAATCAGTACGATAGTGAGATTATTAACAGAAAGGATTCTAAATCATACTATCAGGAATTGGTTGATCCTCCCACCTTCGCTCCGGATGATCGTGAAGCAGGACTTGGAATTCGGCATATTCAGGATTACTTCCATCCTCAATTCTGATCGGTTCCTGAAGCTTTCTCCAAATAGGAAATACTTGATTGCACAATTAACTGCAGGCTACATTAGGAAATTGATTGAGGGGGATTGCAATATCGATCTAACCAGACCTATCCAAAAGCAAATCTGGAAAGCATTAGGTTGTGTAGTCTATTGTCACGATCCAATGGATCAAAGGGAGTCAACAGAGTTTATTGATATAAATATTAATGAAGAAATAGACCGCGGGATCGATGGCGAGGAAATCTAAACATATCAAGAATCAGAATTAGTTTAAGAAAAAAGAAGAGGATTAATCTTGGTTTTCCCCTTGGTGGGTCGGCATGGCATCTCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCACTCGGATGGCTAAGGGAGCGGCCGGGGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAGTTGGCTGCTGCCACCGCTGAGCAATAACTAGCATAACCCCTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTGCTGAAAGGAGGAACTATATCCGGATCATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAA ATAGGGGTTCCGCGCACATTTCCCCGAAAAGT (SEQ ID NO: 9). viii. CVL119
[0168] The nucleic acid sequence for CVL119 is:GCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCTAATACGACTCACTATAGGGACCAAGGGGAAAATGAAGTGGTGACTCAAATCATCGAAGACCCTCGAGATTACATAGGTCCGGAACCTATGGCCTTCGTGACCGACCTCGAGTCAGAGTAGTTCAATAAGGACCTATCAAGTTTGGGCAATTTTTCGTCCCCGACACAAAAATGTCATCCGTGCTTAAAGCATATGAGCGATTCACGCTCACTCAAGAACTGCAAGATCAGAGTGAGGAAGGTACAATCCCACCTACAACACTAAAACCGGTAATCAGGGTATTTATACTAACCTCTAATAACCCAGAGCTAAGATCCCGGCTTCTTCTATTCTGCCTACGGATTGTTCTCAGTAATGGTGCAAGGGATTCCCATCGCTTTGGAGCATTACTCACAATGTTTTCGCTACCATCAGCCACAATGCTCAATCATGTCAAATTAGCTGACCAGTCACCAGAAGCTGATATCGAAAGGGTAGAGATCGATGGCTTTGAGGAGGGATCATTCCGCTTAATCCCCAATGCTCGTTCAGGTATGAGCCGTGGAGAGATCAATGCCTATGCTGCACTTGCAGAAGATCTACCTGACACACTAAACCATGCAACACCTTTCGTTGATTCCGAAGTCGAGGGAACTGCATGGGATGAGATTGAGACTTTCTTAGATATGTGTTACAGTGTCCTAATGCAGGCATGGATAGTGACTTGCAAGTGCATGACTGCGCCAGACCAACCTGCTGCTTCTATTGAGAAACGCCTGCAAAAATATCGTCAGCAAGGCAGGATCAACCCGAGATATCTCCTGCAACCGGAGGCTCGACGAATAATCCAGAATGTAATCCGGAAGGGAATGGTGGTCAGACATTTCCTCACCTTTGAACTGCAGCTTGCCCGAGCACAAAGCCTTGTATCAAATAGGTATTATGCTATGGTAGGGGATGTTGGAAAGTATATAGAGAATTGTGGAATGGGAGGCTTCTTTTTGACACTAAAATATGCATTAGGAACTAGATGGCCCACACTTGCTTTAGCTGCATTTTCAGGAGAGCTAACAAAGCTAAAGTCCCTCATGGCATTATACCAGACCCTTGGTGAGCAGGCCCGATATTTGGCCCTATTGGAGTCACCACATTTGATGGATTTTGCTGCAGCAAACTACCCACTGCTATATAGCTATGCTATGGGAATAGGCTATGTGTTAGATGTCAACATGAGGAACTACGCTTTCTCCAGATCATACATGAACAAGACATATTTCCAATTGGGAATGGAAACTGCAAGAAAACAACAGGGTGCAGTTGACATGAGGATGGCAGAAGATCTCGGTCTAACTCAAGCCGAACGCACCGAGATGGCAAATACACTTGCCAAATTGACCACAGCAAATCGAGGGGCAGACACCAGGGGAGGAGTCAACCCGTTCTCATCTGTCACTGGGACAACTCAGGTGCCCGCTGCAGCAACAGGTGACACACTCGAGAGTTACATGGCAGCGGATCGACTGAGGCAGAGATATGCTGATGCAGGCACCCATGATGATGAGATGCCACCATTGGAAGAGGAGGAAGAGGACGACACATCTGCAGGTCCACGCACTGGACCAACTCTTGAACAAGTGGCCTTGGACATCCAGAACGCAGCAGTTGGAGCTCCCATCCATACAGATGACCTGAATGCCGCACTGGGTGATCTTGACATCTAGACAATTCAGATCCCAATCTAAAATTGACATACCTAATTGATTAGTTAGATGGAACTACAGTGGATTCCATAAGGTTCCTGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACAAGCGACTGCCGGTGCCAACAGCGCAATCCACAATCTACAATGGATCCCACTGATCTGAGCTTCTCCCCAGATGAGATCAATAAGCTCATAGAGACAGGCCTGAATACTGTAGAGTATTTTACTTCCCAACAAGTCACAGGAACATCCTCTCTTGGAAAGAATACAATACCACCAGGGGTCACAGGACTACTAACCAATGCTGCAGAGGCAAAGATCCAAGAGTCAACTAACCATCAGAAGGGCTCAGTTGGTGGGGGTGCAAAACCAAAGAAACCGCGACCAAAAATTGCCATTGTGCCAGCAGATGACAAAACAGTGCCCGGAAAGCCGATCCCAAACCCTCTATTAGGTCTGGACTCCACCCCGAGCACCCAAACTGTGCTTGATCTAAGTGGGAAAACATTACCATCAGGATCCTATAAGGGGGTTAAGCTTGCGAAATTTGGAAAAGAAAATCTGATGACACGGTTCATCGAGGAACCCAGAGAGAATCCTATCGCAACCAGTTtCCCCATCGATTTTAAGAGGGGCAGGGATACCGGCGGGTTCCATAGAAGGGAGTACTCAATCGGATGGGTGGGAGATGAAGTCAAGGTCACTGAGTGGTGCAATCCATCCTGTTCTCCAATCACCGCTGCAGCAAGGCGATTTGAATGCACTTGTCACCAGTGTCCAGTCACTTGCTCTGAATGTGAACGAGATACTTAATACAGTGAGAAATTTGGACTCTCGGATGAATCAACTGGAGACAAAAGTAGATCGCATTCTCTCATCTCAGTCTCTAATCCAGACCATCAAGAATGACATAGTTGGACTTAAAGCAGGGATGGCTACTTTAGAAGGAATGATTACAACTGTGAAAATCATGGACCCGGGAGTTCCCAGTAATGTTACTGTGGAAGATGTACGCAAGACACTAAGTAACCATGCTGTTGTTGTGCCAGAATCATTCAATGATAGTTTCTTGACTCAATCTGAAGATGTAATTTCACTTGATGAGTTGGCTCGACCAACTGCAACAAGTGTTAAGAAGATTGTCAGGAAGGTTCCTCCTCAGAAGGATCTGACTGGATTGAAGATTACACTAGAGCAATTGGCAAAGGATTGCATCAGCAAACCGAAGATGAGGGAAGAGTATCTCCTCAAAATCAACCAGGCTTCCAGTGAGGCTCAGCTAATTGACCTCAAGAAAGCAATCATCCGCAGTGCAATTTGATCAAGAAACACCCAATTACACTACACTGGTATGACACTGTACTAACCCTGAGGGTTTTAGAAAAAACGATTAACGATAAATAAGCCCGAACACTACACACTACCTGAGGCAGCCATGCCATCCATCAGCATTCCCGCAGACCCCACCAATCCACGTCAATCAATAAAAGCGTTCCCAATTGTGATCAACAGTGATGGGGGTGAGAAAGGCCGCTTGGTTAAACAACTACGCACAACCTACTTGAATGACCTAGATACTCATGAGCCACTGGTGACATTCATAAATACCTATGGATTCATCTACGAACAGGATCGGGGGAATACCATTGTCGGAGAGGATCAACTTGGGAAGAAAAGAGAGGCTGTGACCGCTGCAATGGTTACCCTTGGATGTGGGCCTAATCTACCATCATTAGGGAATGTCCTGGGACAACTGAGGGAATTCCAGGTCACTGTTAGGAAGACATCCAGCAAAGCGGAAGAGATGGTCTTTGAAATTGTTAAGTATCCGAGAATATTTCGGGGTCATACATTAATCCAGAAAGGACTAGTCTGTGTCTCCGCAGAAAAATTTGTTAAGTCACCAGGGAAAATACAATCTGGAATGGACTATCTCTTCATTCCGACATTTCTGTCAGTGACTTACTGTCCAGCTGCAATCAAATTTCAGGTACCTGGCCCCATGTTGAAAATGAGATCAAGATACACTCAGAGCTTACAACTTGAACTAATGATAAGAATCCTGTGTAAGCCCGATTCGCCACTTATGAAGGTCCATACCCCTGACAAGGAGGGAAGAGGATGTCTTGTATCAGTATGGCTGCATGTATGCAACATCTTCAAATCAGGAAACAAGAATGGCAGTGAGTGGCAGGAATACTGGATGAGAAAGTGTGCTAACATGCAACTTGAAGTGTCGATTGCAGATATGTGGGGACCAACTATCATAATTCATGCCAGAGGTCACATTCCCAAAAGTGCTAAGTTGTTTTTTGGAAAGGGTGGATGGAGCTGCCATCCACTTCACGAAGTTGTTCCAAGTGTCACTAAAACACTATGGTCCGTGGGCTGTGAGATTACAAAGGCGAAGGCAATAATACAAGAGAGTAGCATCTCTCTTCTCGTGGAGACTACTGACATCATAAGTCCAAAAGTCAAAATTTCATCTAAGCATCGCCGCTTTGGGAAATCAAATTGGGGTCTGTTCAAGAAAACTAAATCACTGCCTAACCTGACGGAGCTGGAATGACTGACCTCTAATCGAGACTACACCGCCGCAAACTATAGGTGGGTGGTACCTCAGTGATTAATCTTGTAAGCACTGATCGTAGGCTACAACACACTAATATTATCCAGATTAGAGAGCTTAATTAGCTCTGTATTAATAATAACACTACTATTCCAATAACTGGAATCACCAGCTTGATTTATCTCCAAAATGATTCAAAGAAAACAAATCATATTAAGACTATCCTAAGCACGAACCCATATCGTCCTTCAAATCATGGGTACTATAATTCAATTTCTGGTGGTCTCCTGTCTATTGGCAGGAGCAGGCAGCCTTGATCCAGCAGCCCTCATGCAAATCGGTGTCATTCCAACAAATGTCCGGCAACTTATGTATTATACTGAAGCTTCATCAGCATTCATTGTTGTGAAGTTAATGCCTACAATTGACTCGCCGATTAGTGGATGTAATATAACATCAATTTCAAGCTATAATGCAACAGTGACAAAACTCCTACAGCCGATCGGTGAGAATTTGGAGACGATTAGGAACCAGTTGATTCCAACTCGGAGGAGACGCCGGTTTGCAGGGGTGGTGATTGGATTAGCTGCATTAGGAGTAGCTACTGCCGCACAGGTCACTGCCGCAGTGGCACTAGTAAAGGCAAATGAAAATGCTGCGGCTATACTCAATCTCAAAAATGCAATCCAAAAAACAAATGCAGCAGTTGCAGATGTGGTCCAGGCCACACAATCACTAGGAACGGCAGTTCAAGCAGTTCAAGATCACATAAACAGTGTGGTAAGTCCAGCAATTACAGCAGCCAATTGTAAGGCCCAAGATGCTATCATTGGCTCAATCCTCAATCTCTATTTGACCGAGTTGACAACCATCTTCCACAATCAAATTACAAACCCTGCATTGAGTCCCATTACAATTCAAGCTTTAAGGATCCTACTGGGGAGTACCTTGCCGACTGTGGTCGAAAAATCTTTCAATACCCAGATAAGTGCAGCTGAGCTTCTCTCATCAGGGTTATTGACAGGCCAGATTGTGGGATTAGATTTGACCTATATGCAGATGGTCATAAAAATTGAGCTGCCAACTTTAACTGTACAACCTGCAACCCAGATCATAGATCTGGCCACCATTTCTGCATTCATTAACAATCAAGAAGTCATGGCCCAATTACCAACACGTGTTATGGTGACTGGCAGCTTGATCCAAGCCTATCCCGCATCGCAATGCACCATTACACCCAACACTGTGTACTGTAGGTATAATGATGCCCAAGTACTCTCAGATGATACTATGGCTTGCCTCCAAGGTAACTTGACAAGATGCACCTTCTCTCCAGTGGTTGGGAGCTTTCTCACTCGATTCGTGCTGTTCGATGGAATAGTTTATGCAAATTGCAGGTCGATGTTGTGCAAGTGCATGCAACCTGCTGCTGTGATCCTACAGCCGAGTTCATCCCCTGTAACTGTCATTGACATGTACAAATGTGTGAGTCTGCAGCTTGACAATCTCAGATTCACCATCACTCAATTGGCCAATGTAACCTACAATAGCACCATCAAGCTTGAATCATCCCAGATCTTGTCTATTGATCCGTTGGATATATCCCAGAATCTAGCTGCGGTGAATAAGAGTCTAAGTGATGCACTACAACACTTAGCACAAAGTGACACATATCTTTCTGCAATCACATCAGCTACGACTACAAGTGTATTATCCATAATAGCAATCTGTCTTGGATCGTTAGGTTTAATATTAATAATCTTGCTCAGTGTAGTTGTGTGGAAGTTATTGACCATTGTCGTTGCTAATCGAAATAGAATGGAGAATTTTGTTTATCATAAATAAGCATTCCACCACTCACGATCTGATCTCAGTGAGAAAAATCAACCTGCAACTCTTGGAACAAGATAAGACAGTCATCCATTAGTAATTTTTAAGAAAAAAACGATAGGACCGAACCTAGTATTGAAAGAACCGTCTCGGTCAATCTAGGTAATCGAGCTGATACCGTCTCGGAAAGCTCAAATCGCGCGCCACCatgtcagataacggacca cagaaccagaggaacgcacccaggattactttcggaggaccaagcgatagcaccgggagcaaccagaatggagagcggag cggagcaagatccaagcagagacggccccagggcctgccaaacaataccgcatcctggttcaccgccctgacacagcacgg caaggaggacctgaagtttccaaggggacagggagtgcctatcaacaccaatagctcccctgacgatcagatcggctactatag gagggcaacaaggagaatcaggggaggcgacggcaagatgaaggatctgagcccacgctggtactctactatctgggaacc ggacctgaggcaggcctgccatatggcgccaacaaggacggaatcatctgggtggcaaccgagggcgccctgaacacacca aaggatcacatcggcacaagaaatcccgccaacaatgcagcaatcgtgctgcagctgccacagggaaccacactgcccaagg gcttttacgcagagggctctcggggaggcagccaggcatctagcagatcctctagccggagcagaaactcctctaggaattcca ccccaggaagctccaggggcacatcccctgcccgcatggcaggaaacggaggcgacgccgccctggccctgctgctgctgg atcgcctgaatcagctggagtccaagatgtctggcaagggacagcagcagcagggacagaccgtgacaaagaagtccgccg ccgaggcctctaagaagccaaggcagaagcgcaccgccacaaaggcctacaacgtgacccaggccttcggcaggcgcgga ccagagcagacacagggcaattttggcgaccaggagctgatcaggcagggaaccgattataagcactggcctcagatcgccc agttcgccccatctgccagcgccttctttggcatgtctagaatcggcatggaggtgacccccagcggcacatggctgacctacac aggcgccatcaagctggacgataaggaccctaacttcaaggatcaggtcatcctgctgaacaagcacatcgacgcctataagac ctttccccctacagagcccaagaaggacaagaagaagaaggccgatgagacacaggccctgcctcagaggcagaagaagca gcagaccgtgacactgctgccagccgccgatctggacgatttctccaaacagctgcagcagagcatgtccagtgccgactcca cccaggcttgaCGTACGACCTGCTATAGGCTATCCACTGCATCATCTCTCCTGCCATACTTCCTACTCACATCATATCTATTTTAAAGAAAAAATAGGCCCGAACACTAATCGTGCCGGCAGTGCCACTGCACACACAACACTACACATACAATACACTACAATGGTTGCAGAAGATGCCCCTGTTAGGGCCACTTGCCGAGTATTATTTCGAACAACAACTTTAATCTTTCTATGCACACTACTAGCATTAAGCATCTCTATCCTTTATGAGAGTTTAATAACCCAAAAGCAAATCATGAGCCAAGCAGGCTCAACTGGATCTAATTCTGGATTAGGAAGTATCACTGATCTTCTTAATAATATTCTCTCTGTCGCAAATCAGATTATATATAACTCTGCAGTCGCTCTACCTCTACAATTGGACACTCTTGAATCAACACTCCTTACAGCCATTAAGTCTCTTCAAACCAGTGACAAGCTAGAACAGAACTGCTCGTGGAGTGCTGCACTGATTAATGATAATAGATACATTAATGGCATCAATCAGTTCTATTTTTCAATTGCTGAGGGTCGCAATCTGACACTTGGCCCACTTCTTAATATGCCTAGTTTCATTCCAACTGCCACGACACCAGAGGGCTGCACCAGGATCCCATCATTCTCGCTCACTAAGACACACTGGTGTTATACACACAATGTTATCCTGAATGGATGCCAGGATCATGTATCCTCAAATCAATTTGTTTCTATGGGAATCATTGAACCCACTTCTGCCGGGTTTCCATTCTTTCGAACCCTAAAGACTCTATATCTCAGCGATGGGGTCAATCGTAAGAGCTGCTCTATCAGTACAGTTCCGGGGGGTTGTATGATGTACTGTTTTGTTTCTACTCAACCAGAGAGGGATGACTACTTTTCTGCCGCTCCTCCAGAACAACGAATTATTATAATGTACTATAATGATACAATCGTGGAGCGCATAATTAATCCACCCGGGGTACTAGATGTATGGGCAACATTGAACCCAGGAACAGGAAGCGGGGTATATTATTTAGGTTGGGTGCTCTTTCCAATATATGGCGGCGTGATTAAAGGTACGAGTTTATGGAATAATCAAGCAAATAAATACTTTATCCCCCAGATGGTTGCTGCTCTCTGCTCACAAAACCAGGCAACTCAAGTCCAAAATGCTAAGTCATCATACTATAGCAGCTGGTTTGGCAATCGAATGATTCAGTCTGGGATCCTGGCATGTCCTCTTCGACAGGATCTAACCAATGAGTGTTTAGTTCTGCCCTTTTCTAATGATCAGGTGCTTATGGGTGCTGAAGGGAGATTATACATGTATGGTGACTCGGTGTATTACTATCAAAGAAGCAATAGTTGGTGGCCTATGACCATGCTGTATAAGGTAACCATAACATTCACTAATGGTCAGCCATCTGCTATATCAGCTCAGAATGTGCCCACACAGCAGGTCCCTAGACCTGGGACAGGAGACTGCTCTGCAACCAATAGATGTCCCGGTTTTTGCTTGACAGGAGTGTATGCCGATGCCTGGTTACTGACCAACCCTTCGTCTACCAGTACATTTGGATCAGAAGCAACCTTCACTGGTTCTTATCTCAACACAGCAACTCAGCGTATCAATCCGACGATGTATATCGCGAACAACACACAGATCATAAGCTCACAGCAATTTGGATCAAGCGGTCAAGAAGCAGCATATGGCCACACAACTTGTTTTAGGGACACAGGCTCTGTTATGGTATACTGTATCTATATTATTGAATTGTCCTCATCTCTCTTAGGACAATTTCAGATTGTCCCATTTATCCGTCAGGTGACACTATCCTAAAGGCAGAAGCCTTCAGGTCTGACCCAGCCAATCAAAGCATTATACCAGACCATGGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAG CAACAAGCGGCGGCCGCCGCCACCatgttcgtcttcctggtcctgctgcctctggtctcctcacagtgcgtc aatctgacaactcggactcagctgccacctgcttatactaatagcttcaccagaggcgtgtactatcctgacaaggtgtttagaagc tccgtgctgcactctacacaggatctgtttctgccattctttagcaacgtgacctggttccacgccatccacgtgagcggcaccaat ggcacaaagcggttcgacaatcccgtgctgccttttaacgatggcgtgtacttcgcctctaccgagaagagcaacatcatcagag gctggatctttggcaccacactggactccaagacacagtctctgctgatcgtgaacaatgccaccaacgtggtcatcaaggtgtg cgagttccagttttgtaatgatcccttcctgggcgtgtactatcacaagaacaataagagctggatggagtccgagtttagagtgtat tctagcgccaacaactgcacatttgagtacgtgagccagcctttcctgatggacctggagggcaagcagggcaatttcaagaac ctgagggagttcgtgtttaagaatatcgacggctacttcaaaatctactctaagcacacccccatcaacctggtgcgcgacctgcc tcagggcttcagcgccctggagcccctggtggatctgcctatcggcatcaacatcacccggtttcagacactgctggccctgcac agaagctacctgacacccggcgactcctctagcggatggaccgccggcgctgccgcctactatgtgggctacctccagccccg gaccttcctgctgaagtacaacgagaatggcaccatcacagacgcagtggattgcgccctggaccccctgagcgagacaaagt gtacactgaagtcctttaccgtggagaagggcatctatcagacatccaatttcagggtgcagccaaccgagtctatcgtgcgcttt cctaatatcacaaacctgtgcccatttggcgaggtgttcaacgcaacccgcttcgccagcgtgtacgcctggaataggaagcgg atcagcaactgcgtggccgactatagcgtgctgtacaactccgcctctttcagcacctttaagtgctatggcgtgtcccccacaaa gctgaatgacctgtgctttaccaacgtctacgccgattctttcgtgatcaggggcgacgaggtgcgccagatcgcccccggcca gacaggcaagatcgcagactacaattataagctgccagacgatttcaccggctgcgtgatcgcctggaacagcaacaatctgga ttccaaagtgggcggcaactacaattatctgtaccggctgtttagaaagagcaatctgaagcccttcgagagggacatctctacag aaatctaccaggccggcagcaccccttgcaatggcgtggagggctttaactgttatttcccactccagtcctacggcttccagccc acaaacggcgtgggctatcagccttaccgcgtggtggtgctgagctttgagctgctgcacgccccagcaacagtgtgcggccc caagaagtccaccaatctggtgaagaacaagtgcgtgaacttcaacttcaacggcctgaccggcacaggcgtgctgaccgagt ccaacaagaagttcctgccatttcagcagttcggcagggacatcgcagataccacagacgccgtgcgcgacccacagaccctg gagatcctggacatcacaccctgctctttcggcggcgtgagcgtgatcacacccggcaccaatacaagcaaccaggtggccgt gctgtatcaggacgtgaattgtaccgaggtgcccgtggctatccacgccgatcagctgaccccaacatggcgggtgtacagcac cggctccaacgtcttccagacaagagccggatgcctgatcggagcagagcacgtgaacaattcctatgagtgcgacatcccaat cggcgccggcatctgtgcctcttaccagacccagacaaactctcccagaagagcccggagcgtggcctcccagtctatcatcgc ctataccatgtccctgggcgccgagaacagcgtggcctactctaacaatagcatcgccatcccaaccaacttcacaatctctgtga ccacagagatcctgcccgtgtccatgaccaagacatctgtggactgcacaatgtatatctgtggcgattctaccgagtgcagcaa cctgctgctccagtacggcagcttttgtacccagctgaatagagccctgacaggcatcgccgtggagcaggataagaacacaca ggaggtgttcgcccaggtgaagcaaatctacaagaccccccctatcaaggactttggcggcttcaatttttcccagatcctgcctg atccatccaagccttctaagcggagctttatcgaggacctgctgttcaacaaggtgaccctggccgatgccggcttcatcaagca gtatggcgattgcctgggcgacatcgcagccagggacctgatctgcgcccagaagtttaatggcctgaccgtgctgccacccct gctgacagatgagatgatcgcacagtacacaagcgccctgctggccggcaccatcacatccggatggaccttcggcgcagga gccgccctccagatcccctttgccatgcagatggcctataggttcaacggcatcggcgtgacccagaatgtgctgtacgagaaccagaagctgatcgccaatcagtttaactccgccatcggcaagatccaggacagcctgtcctctacagccagcgccctgggcaag ctccaggatgtggtgaatcagaacgcccaggccctgaataccctggtgaagcagctgagcagcaacttcggcgccatctctagc gtgctgaatgacatcctgagccggctggacaaggtggaggcagaggtgcagatcgaccggctgatcaccggccggctccaga gcctccagacctatgtgacacagcagctgatcagggccgccgagatcagggccagcgccaatctggcagcaaccaagatgtc cgagtgcgtgctgggccagtctaagagagtggacttttgtggcaagggctatcacctgatgtccttccctcagtctgccccacacg gcgtggtgtttctgcacgtgacctacgtgcccgcccaggagaagaacttcaccacagcccctgccatctgccacgatggcaagg cccactttccaagggagggcgtgttcgtgtccaacggcacccactggtttgtgacacagcgcaatttctacgagccccagatcat caccacagacaacaccttcgtgagcggcaactgtgacgtggtcatcggcatcgtgaacaataccgtgtatgatccactccagcc cgagctggacagctttaaggaggagctggataagtatttcaagaatcacacctcccctgacgtggatctgggcgacatcagcgg catcaatgcctccgtggtgaacatccagaaggagatcgaccgcctgaacgaggtggctaagaatctgaacgagagcctgatcg acctccaggagctgggcaagtatgagcagtacatcaagtggccctggtacatctggctgggcttcatcgccggcctgatcgcca tcgtgatggtgaccatcatgctgtgctgtatgacatcctgctgttcttgcctgaagggctgctgtagctgtggctcctgctgtaagttt gacgaggatgactctgaacctgtgctgaagggcgtgaagctgcattacacctaaTAAGGTCGACTCATGGAAT GCATACCAAACATTATTGACACTAATGACACACAAAATTGGTTTTAAGAAAA ACCAAGAGAACAATAGGCCAGAATGGCTGGGTCTCGGGAGATATTACTCCCT GAAGTCCATCTCAATTCACCAATTGTAAAGCATAAGCTATACTATTACATTCT ACTTGGAAACCTCCCAAATGAGATCGACCTTGACGATTTAGGTCCATTACATA ATCAAAATTGGAATCAGATAGCACATGAAGAGTCTAACTTAGCTCAACGCTT GGTAAATGTAAGAAATTTTCTAATTACCCACATCCCTGATCTTAGAAAGGGCC ATTGGCAAGAGTATGTCAATGTAATACTGTGGCCGCGAATTCTTCCCTTGATC CCGGATTTTAAAATCAATGACCAATTGCCTCTGCTCAAAAATTGGGACAAGTT AGTTAAAGAATCATGTTCAGTAATCAATGCAGGTACTTCCCAGTGCATTCAGA ATCTCAGCTATGGACTGACAGGTCGTGGGAACCTCTTTACACGATCACGTGAA CTCTCTGGTGACCGCAGGGATATTGATCTTAAGACAGTTGTGGCAGCATGGCA TGACTCAGACTGGAAAAGAATAAGTGATTTTTGGATTATGATCAAATTCCAG ATGAGACAATTAATTGTTAGGCAAACAGATCATAATGATTCTGATTTAATCAC GTATATCGAAAATAGAGAAGGCATAATCATCATAACCCCTGAACTGGTAGCA TTATTTAACACTGAGAATCATACACTAACATACATGACCTTTGAAATTGTACT GATGGTTTCAGATATGTACGAAGGTCGTCACAACATTTTATCACTATGCACAG TTAGCACTTACCTGAATCCTCTGAAGAAAAGAATAACATATTTATTGAGCCTT GTAGATAACTTAGCTTTTCAGATAGGTGATGCTGTATATAACATAATTGCTTTGCTAGAATCCTTTGTATATGCACAGTTGCAAATGTCAGATCCCATCCCAGAAC TCAGAGGACAATTCCATGCATTCGTATGTTCTGAGATTCTTGATGCACTAAGA GGAACTAATAGTTTCACCCAGGATGAATTAAGAACTGTGACAACTAATTTGATATCCCCATTCCAAGATCTGACCCCAGATCTTACGGCTGAATTGCTCTGTATAATGAGGCTTTGGGGACACCCCATGCTCACTGCCAGTCAAGCTGCAGGAAAGGTACGCGAGTCTATGTGTGCTGGAAAAGTATTAGACTTTCCCACCATTATGAAAACACTAGCCTTTTTCCATACTATTCTGATCAATGGATACAGGAGGAAGCATCATGGAGTATGGCCACCCTTAAACTTACCGGGTAATGCTTCAAAGGGTCTCACGGAACTTATGAATGACAATACTGAAATAAGCTATGAATTCACACTTAAGCATTGGAAGGAAGTCTCTCTTATAAAATTCAAGAAATGTTTTGATGCAGACGCAGGTGAGGAACTCAGTATATTTATGAAAGATAAGGCAATTAGTGCCCCAAAACAAGACTGGATGAGTGTGTTTAGAAGAAGCCTAATCAAACAGCGCCATCAGCATCATCAGGTCCCCCTACCAAATCCATTCAATCGACGGCTGTTGCTAAACTTTCTCGGAGATGACAAATTCGACCCGAATGTGGAGCTACAGTATGTAACATCAGGTGAGTATCTACATGATGACACGTTTTGTGCATCATATTCACTAAAAGAGAAGGAAATTAAACCTGATGGTCGAATTTTTGCAAAGTTGACTAAGAGAATGAGATCATGTCAAGTTATAGCAGAATCTCTTTTAGCGAACCATGCTGGGAAGTTAATGAAAGAGAATGGTGTTGTGATGAATCAGCTATCATTAACAAAATCACTATTAACAATGAGTCAGATTGGAATAATATCCGAGAAAGCTAGAAAGTCAACTCGAGATAACATAAATCAACCTGGTTTCCAGAATATCCAGAGAAATAAATCACATCACTCCAAGCAAGTCAATCAGCGAGATCCAAGTGATGACTTTGAATTGGCAGCATCTTTTTTAACTACTGATCTCAAAAAATATTGTTTACAATGGAGGTACCAGACAATTATCCCATTTGCTCAATCATTAAACAGAATGTATGGTTATCCTCATCTCTTTGAGTGGATTCACTTACGGCTAATGCGTAGTACACTTTACGTGGGGGATCCCTTCAACCCACCAGCAGATACCAGTCAATTTGATCTAGATAAAGTAATTAATGGAGATATCTTCATTGTATCACCCAGAGGTGGAATTGAAGGGCTGTGTCAAAAGGCTTGGACAATGATATCTATCGCTGTGATAATTCTATCTGCCACAGAGTCTGGCACACGAGTAATGAGTATGGTGCAGGGAGATAATCAAGCAATTGCTGTCACCACACGAGTACCAAGGAGCCTGCCGACTCTTGAGAAAAAGACTATTGCTTTTAGATCTTGTAATCTATTCTTTGAGAGGTTAAAATGTAATAATTTTGGATTAGGTCACCATTTGAAAGAACAAGAGACTATCATTAGTTCTCACTTCTTTGTTTATAGCAAGAGAATATTCTATCAGGGGAGGATTCTAACGCAAGCCTTAAAAAATGCTAGTAAGCTCTGCTTGACAGCTGATGTCCTAGGAGAATGCACCCAATCATCATGTTCTAATCTTGCAACTACTGTCATGAGGTTAACTGAGAATGGTGTTGAAAAAGATATCTGTTTCTACTTGAATATCTATATGACCATCAAACAGCTCTCCTATGATATCATCTTCCCTCAAGTGTCAATTCCTGGAGATCAGATCACATTAGAATACATAAATAATCCACACCTGGTATCACGATTGGCTCTTTTGCCATCCCAGTTAGGAGGTCTAAACTACCTGTCATGCAGTAGGCTGTTCAATCGAAACATAGGCGACCCGGTGGTTTCCGCAGTTGCAGATCTTAAGAGATTAATTAAATCAGGATGTATGGATTACTGGATCCTTTATAACTTATTAGGGAGAAAACCGGGAAACGGCTCATGGGCTACTTTAGCAGCTGACCCGTACTCAATCAATATAGAGTATCAATACCCTCCAACTACAGCTCTTAAGAGGCACACCCAACAAGCTCTGATGGAACTCAGTACGAATCCAATGTTACGTGGCATATTCTCTGACAATGCACAGGCAGAAGAAAATAACCTTGCTAGGTTTCTCCTGGATAGGGAGGTGATCTTTCCGCGTGTAGCTCACATCATCATTGAGCAAACCAGTGTCGGGAGGAGAAAACAGATTCAAGGATATTTGGATTCAACTAGATCGATAATGAGGAAATCACTAGAAATTAAGCCCTTATCCAATAGGAAGCTTAATGAAATACTGGATTACAACATCAATTACCTAGCTTACAATTTGGCATTACTCAAGAATGCTATTGAACCTCCGACTTATTTGAAGGCAATGACACTTGAAACATGTAGCATCGACATTGCAAGGAACCTCCGGAAGCTCTCCTGGGCCCCACTCTTGGGTGGGAGAAATCTTGAAGGATTAGAGACGCCAGATCCCATTGAAATTACTGCAGGAGCATTAATTGTTGGATCGGGCTACTGTGAACAGTGTGCTGCAGGAGACAATCGATTCACATGGTTTTTCTTGCCATCTGGTATCGAGATAGGAGGGGATCCCCGTGATAATCCTCCTATCCGTGTACCGTACATTGGCTCCAGGACTGATGAGAGGAGGGTAGCCTCAATGGCATACATCAGGGGTGCCTCGAGTAGCTTAAAAGCAGTTCTTAGACTGGCGGGAGTGTACATCTGGGCATTCGGAGATACTCTGGAGAATTGGATAGATGCACTGGATTTGTCTCACACTAGAGTTAACATCACACTTGAACAGCTGCAATCCCTCACCCCACTTCCAACCTCTGCCAATCTAACCCATCGGTTGGATGATGGCACAACTACCCTAAAGTTTACTCCTGCGAGCTCTTACACCTTTTCAAGTTTCACTCATATATCAAATGATGAGCAATACCTGACAATTAATGACAAAACTGCAGATTCAAATATAATCTACCAACAGTTAATGATCACTGGACTCGGAATCTTAGAAACATGGAATAATCCCCCAATCAATAGAACATTCGAAGAATCTACCCTACATTTGCACACTGGTGCATCATGTTGTGTCCGACCTGTGGACTCCTGCATTCTCTCAGAAGCATTAACAGTCAAGCCACATATTACAGTACCGTACAGCAATAAATTTGTATTTGATGAGGACCCGCTATCTGAATATGAAACTGCAAAACTGGAATCGTTATCATTCCAAGCCCAATTAGGCAACATTGATGCTGTAGATATGACAGGTAAATTAACATTATTGTCCCAATTCACTGCAAGGCAGATTATCAATGCAATCACTGGACTCGATGAGTCTGTCTCTCTTACTAATGATGCCATTGTTGCATCAGACTATGTCTCCAATTGGATTAGTGAATGCATGTATACCAAATTAGATGAATTATTTATGTATTGTGGGTGGGAACTACTATTGGAACTATCCTATCAAATGTATTATCTGAGGGTAGTTGGGTGGAGTAATATAGTGGATTATTCTTACATGATCTTGAGAAGAATCCCGGGTGCAGCATTAAACAATCTGGCATCTACATTAAGTCATCCAAAACTTTTCCGACGAGCTATCAACCTAGATATAGTTGCCCCCTTAAATGCTCCTCATTTTGCATCTCTGGACTACATCAAGATGAGTGTGGATGCAATACTCTGGGGCTGTAAAAGAGTCATCAATGTGCTCTCCAATGGAGGGGACTTAGAATTAGTTGTGACATCTGAAGATAGCCTTATTCTCAGTGACCGATCCATGAATCTCATTGCAAGGAAATTAACTTTATTATCACTGATTCACCATAATGGTTTGGAACTACCAAAGATTAAGGGGTTCTCTCCTGATGAGAAGTGTTTCGCTTTGACAGAATTTTTGAGGAAAGTGGTGAACTCAGGGTTGAGTTCAATAGAGAACCTATCAAATTTTATGTACAATGTGGAGAACCCACGGCTTGCAGCATTCGCCAGCAACAATTACTACCTGACCAGAAAATTATTGAATTCAATACGAGATACTGAGTCGGGTCAAGTAGCAGTCACCTCATATTATGAATCATTAGAATATATTGATAGTCTTAAGCTAACCCCACATGTGCCTGGCACCTCATGCATTGAGGATGATAGTCTATGTACAAATGATTACATAATCTGGATCATAGAGTCTAATGCAAACTTGGAGAAGTATCCAATTCCAAATAGCCCTGAGGATGATTCCAATTTCCATAACTTTAAGTTGAATGCTCCATCGCACCATACCTTACGCCCATTAGGGTTGTCATCAACTGCTTGGTATAAGGGTATAAGCTGCTGCAGGTACCTTGAGCGATTAAAGCTACCACAAGGTGATCATTTATATATTGCAGAAGGTAGTGGTGCCAGTATGACAATCATAGAATACCTATTCCCAGGAAGAAAGATATATTACAATTCTTTATTTAGTAGTGGTGACAATCCCCCACAAAGAAATTATGCACCAATGCCTACTCAGTTCATTGAGAGTGTCCCATACAAGCTCTGGCAAGCACACACAGATCAATATCCCGAGATTTTTGAGGACTTCATCCCTCTATGGAACGGAAACGCCGCCATGACTGACATAGGAATGACAGCTTGTGTAGAATTCATCATCAATCGAGTCGGCCCAAGGACTTGCAGTTTAGTACATGTAGATTTGGAATCAAGTGCAAGCTTAAATCAACAATGCCTGTCAAAGCCGATAATTAATGCTATCATCACTGCTACAACTGTTTTGTGCCCTCATGGGGTGCTTATTCTGAAATATAGTTGGTTGCCATTTACTAGATTTAGTACTTTGATCACTTTCTTATGGTGCTACTTTGAGAGAATCACTGTTCTTAGGAGCACATATTCTGATCCAGCTAATCATGAGGTTTATTTAATTTGTATCCTTGCCAACAACTTTGCATTCCAGACTGTCTCGCAGGCAACAGGAATGGCGATGACTTTAACTGATCAAGGGTTTACTTTGATATCACCTGAAAGAATAAATCAGTATTGGGATGGTCACTTGAAGCAAGAACGTATCGTAGCAGAAGCAATTGATAAGGTGGTTCTAGGAGAAAATGCTCTATTTAATTCGAGTGATAATGAATTAATTCTCAAATGTGGAGGGACACCAAATGCACGGAATCTCATCGATATCGAGCCAGTCGCAACTTTCATAGAATTTGAACAATTGATCTGCACAATGTTGACAACCCACTTGAAGGAAATAATTGATATAACAAGGTCTGGAACCCAGGATTATGAAAGTTTATTACTCACTCCTTACAATTTAGGTCTTCTTGGTAAAATCAGTACGATAGTGAGATTATTAACAGAAAGGATTCTAAATCATACTATCAGGAATTGGTTGATCCTCCCACCTTCGCTCCGGATGATCGTGAAGCAGGACTTGGAATTCGGCATATTCAGGATTACTTCCATCCTCAATTCTGATCGGTTCCTGAAGCTTTCTCCAAATAGGAAATACTTGATTGCACAATTAACTGCAGGCTACATTAGGAAATTGATTGAGGGGGATTGCAATATCGATCTAACCAGACCTATCCAAAAGCAAATCTGGAAAGCATTAGGTTGTGTAGTCTATTGTCACGATCCAATGGATCAAAGGGAGTCAACAGAGTTTATTGATATAAATATTAATGAAGAAATAGACCGCGGGATCGATGGCGAGGAAATCTAAACATATCAAGAATCAGAATTAGTTTAAGAAAAAAGAAGAGGATTAATCTTGGTTTTCCCCTTGGTGGGTCGGCATGGCATCTCCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCACTCGGATGGCTAAGGGAGCGGCCGGGGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAGTTGGCTGCTGCCACCGCTGAGCAATAACTAGCATAACCCCTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTGCTGAAAGGAGGAACTATATCCGGATCATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGT (SEQ ID NO: 10). ix. CVL120
[0169] The nucleic acid sequence for CVL120 isGCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCTAATACGACTCACTATAGGGACCAAGGGGAAAATGAAGTGGTGACTCAAATCATCGAAGACCCTCGAGATTACATAGGTCCGGAACCTATGGCCTTCGTGACCGACCTCGAGTCAGAGTAGTTCAATAAGGACCTATCAAGTTTGGGCAATTTTTCGTCCCCGACACAAAAATGTCATCCGTGCTTAAAGCATATGAGCGATTCACGCTCACTCAAGAACTGCAAGATCAGAGTGAGGAAGGTACAATCCCACCTACAACACTAAAACCGGTAATCAGGGTATTTATACTAACCTCTAATAACCCAGAGCTAAGATCCCGGCTTCTTCTATTCTGCCTACGGATTGTTCTCAGTAATGGTGCAAGGGATTCCCATCGCTTTGGAGCATTACTCACAATGTTTTCGCTACCATCAGCCACAATGCTCAATCATGTCAAATTAGCTGACCAGTCACCAGAAGCTGATATCGAAAGGGTAGAGATCGATGGCTTTGAGGAGGGATCATTCCGCTTAATCCCCAATGCTCGTTCAGGTATGAGCCGTGGAGAGATCAATGCCTATGCTGCACTTGCAGAAGATCTACCTGACACACTAAACCATGCAACACCTTTCGTTGATTCCGAAGTCGAGGGAACTGCATGGGATGAGATTGAGACTTTCTTAGATATGTGTTACAGTGTCCTAATGCAGGCATGGATAGTGACTTGCAAGTGCATGACTGCGCCAGACCAACCTGCTGCTTCTATTGAGAAACGCCTGCAAAAATATCGTCAGCAAGGCAGGATCAACCCGAGATATCTCCTGCAACCGGAGGCTCGACGAATAATCCAGAATGTAATCCGGAAGGGAATGGTGGTCAGACATTTCCTCACCTTTGAACTGCAGCTTGCCCGAGCACAAAGCCTTGTATCAAATAGGTATTATGCTATGGTAGGGGATGTTGGAAAGTATATAGAGAATTGTGGAATGGGAGGCTTCTTTTTGACACTAAAATATGCATTAGGAACTAGATGGCCCACACTTGCTTTAGCTGCATTTTCAGGAGAGCTAACAAAGCTAAAGTCCCTCATGGCATTATACCAGACCCTTGGTGAGCAGGCCCGATATTTGGCCCTATTGGAGTCACCACATTTGATGGATTTTGCTGCAGCAAACTACCCACTGCTATATAGCTATGCTATGGGAATAGGCTATGTGTTAGATGTCAACATGAGGAACTACGCTTTCTCCAGATCATACATGAACAAGACATATTTCCAATTGGGAATGGAAACTGCAAGAAAACAACAGGGTGCAGTTGACATGAGGATGGCAGAAGATCTCGGTCTAACTCAAGCCGAACGCACCGAGATGGCAAATACACTTGCCAAATTGACCACAGCAAATCGAGGGGCAGACACCAGGGGAGGAGTCAACCCGTTCTCATCTGTCACTGGGACAACTCAGGTGCCCGCTGCAGCAACAGGTGACACACTCGAGAGTTACATGGCAGCGGATCGACTGAGGCAGAGATATGCTGATGCAGGCACCCATGATGATGAGATGCCACCATTGGAAGAGGAGGAAGAGGACGACACATCTGCAGGTCCACGCACTGGACCAACTCTTGAACAAGTGGCCTTGGACATCCAGAACGCAGCAGTTGGAGCTCCCATCCATACAGATGACCTGAATGCCGCACTGGGTGATCTTGACATCTAGACAATTCAGATCCCAATCTAAAATTGACATACCTAATTGATTAGTTAGATGGAACTACAGTGGATTCCATAAGGTTCCTGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACAAGCGACTGCCGGTGCCAACAGCGCAATCCACAATCTACAATGGATCCCACTGATCTGAGCTTCTCCCCAGATGAGATCAATAAGCTCATAGAGACAGGCCTGAATACTGTAGAGTATTTTACTTCCCAACAAGTCACAGGAACATCCTCTCTTGGAAAGAATACAATACCACCAGGGGTCACAGGACTACTAACCAATGCTGCAGAGGCAAAGATCCAAGAGTCAACTAACCATCAGAAGGGCTCAGTTGGTGGGGGTGCAAAACCAAAGAAACCGCGACCAAAAATTGCCATTGTGCCAGCAGATGACAAAACAGTGCCCGGAAAGCCGATCCCAAACCCTCTATTAGGTCTGGACTCCACCCCGAGCACCCAAACTGTGCTTGATCTAAGTGGGAAAACATTACCATCAGGATCCTATAAGGGGGTTAAGCTTGCGAAATTTGGAAAAGAAAATCTGATGACACGGTTCATCGAGGAACCCAGAGAGAATCCTATCGCAACCAGTTtCCCCATCGATTTTAAGAGGGGCAGGGATACCGGCGGGTTCCATAGAAGGGAGTACTCAATCGGATGGGTGGGAGATGAAGTCAAGGTCACTGAGTGGTGCAATCCATCCTGTTCTCCAATCACCGCTGCAGCAAGGCGATTTGAATGCACTTGTCACCAGTGTCCAGTCACTTGCTCTGAATGTGAACGAGATACTTAATACAGTGAGAAATTTGGACTCTCGGATGAATCAACTGGAGACAAAAGTAGATCGCATTCTCTCATCTCAGTCTCTAATCCAGACCATCAAGAATGACATAGTTGGACTTAAAGCAGGGATGGCTACTTTAGAAGGAATGATTACAACTGTGAAAATCATGGACCCGGGAGTTCCCAGTAATGTTACTGTGGAAGATGTACGCAAGACACTAAGTAACCATGCTGTTGTTGTGCCAGAATCATTCAATGATAGTTTCTTGACTCAATCTGAAGATGTAATTTCACTTGATGAGTTGGCTCGACCAACTGCAACAAGTGTTAAGAAGATTGTCAGGAAGGTTCCTCCTCAGAAGGATCTGACTGGATTGAAGATTACACTAGAGCAATTGGCAAAGGATTGCATCAGCAAACCGAAGATGAGGGAAGAGTATCTCCTCAAAATCAACCAGGCTTCCAGTGAGGCTCAGCTAATTGACCTCAAGAAAGCAATCATCCGCAGTGCAATTTGATCAAGAAACACCCAATTACACTACACTGGTATGACACTGTACTAACCCTGAGGGTTTTAGAAAAAACGATTAACGATAAATAAGCCCGAACACTACACACTACCTGAGGCAGCCATGCCATCCATCAGCATTCCCGCAGACCCCACCAATCCACGTCAATCAATAAAAGCGTTCCCAATTGTGATCAACAGTGATGGGGGTGAGAAAGGCCGCTTGGTTAAACAACTACGCACAACCTACTTGAATGACCTAGATACTCATGAGCCACTGGTGACATTCATAAATACCTATGGATTCATCTACGAACAGGATCGGGGGAATACCATTGTCGGAGAGGATCAACTTGGGAAGAAAAGAGAGGCTGTGACCGCTGCAATGGTTACCCTTGGATGTGGGCCTAATCTACCATCATTAGGGAATGTCCTGGGACAACTGAGGGAATTCCAGGTCACTGTTAGGAAGACATCCAGCAAAGCGGAAGAGATGGTCTTTGAAATTGTTAAGTATCCGAGAATATTTCGGGGTCATACATTAATCCAGAAAGGACTAGTCTGTGTCTCCGCAGAAAAATTTGTTAAGTCACCAGGGAAAATACAATCTGGAATGGACTATCTCTTCATTCCGACATTTCTGTCAGTGACTTACTGTCCAGCTGCAATCAAATTTCAGGTACCTGGCCCCATGTTGAAAATGAGATCAAGATACACTCAGAGCTTACAACTTGAACTAATGATAAGAATCCTGTGTAAGCCCGATTCGCCACTTATGAAGGTCCATACCCCTGACAAGGAGGGAAGAGGATGTCTTGTATCAGTATGGCTGCATGTATGCAACATCTTCAAATCAGGAAACAAGAATGGCAGTGAGTGGCAGGAATACTGGATGAGAAAGTGTGCTAACATGCAACTTGAAGTGTCGATTGCAGATATGTGGGGACCAACTATCATAATTCATGCCAGAGGTCACATTCCCAAAAGTGCTAAGTTGTTTTTTGGAAAGGGTGGATGGAGCTGCCATCCACTTCACGAAGTTGTTCCAAGTGTCACTAAAACACTATGGTCCGTGGGCTGTGAGATTACAAAGGCGAAGGCAATAATACAAGAGAGTAGCATCTCTCTTCTCGTGGAGACTACTGACATCATAAGTCCAAAAGTCAAAATTTCATCTAAGCATCGCCGCTTTGGGAAATCAAATTGGGGTCTGTTCAAGAAAACTAAATCACTGCCTAACCTGACGGAGCTGGAATGACTGACCTCTAATCGAGACTACACCGCCGCAAACTATAGGTGGGTGGTACCTCAGTGATTAATCTTGTAAGCACTGATCGTAGGCTACAACACACTAATATTATCCAGATTAGAGAGCTTAATTAGCTCTGTATTAATAATAACACTACTATTCCAATAACTGGAATCACCAGCTTGATTTATCTCCAAAATGATTCAAAGAAAACAAATCATATTAAGACTATCCTAAGCACGAACCCATATCGTCCTTCAAATCATGGGTACTATAATTCAATTTCTGGTGGTCTCCTGTCTATTGGCAGGAGCAGGCAGCCTTGATCCAGCAGCCCTCATGCAAATCGGTGTCATTCCAACAAATGTCCGGCAACTTATGTATTATACTGAAGCTTCATCAGCATTCATTGTTGTGAAGTTAATGCCTACAATTGACTCGCCGATTAGTGGATGTAATATAACATCAATTTCAAGCTATAATGCAACAGTGACAAAACTCCTACAGCCGATCGGTGAGAATTTGGAGACGATTAGGAACCAGTTGATTCCAACTCGGAGGAGACGCCGGTTTGCAGGGGTGGTGATTGGATTAGCTGCATTAGGAGTAGCTACTGCCGCACAGGTCACTGCCGCAGTGGCACTAGTAAAGGCAAATGAAAATGCTGCGGCTATACTCAATCTCAAAAATGCAATCCAAAAAACAAATGCAGCAGTTGCAGATGTGGTCCAGGCCACACAATCACTAGGAACGGCAGTTCAAGCAGTTCAAGATCACATAAACAGTGTGGTAAGTCCAGCAATTACAGCAGCCAATTGTAAGGCCCAAGATGCTATCATTGGCTCAATCCTCAATCTCTATTTGACCGAGTTGACAACCATCTTCCACAATCAAATTACAAACCCTGCATTGAGTCCCATTACAATTCAAGCTTTAAGGATCCTACTGGGGAGTACCTTGCCGACTGTGGTCGAAAAATCTTTCAATACCCAGATAAGTGCAGCTGAGCTTCTCTCATCAGGGTTATTGACAGGCCAGATTGTGGGATTAGATTTGACCTATATGCAGATGGTCATAAAAATTGAGCTGCCAACTTTAACTGTACAACCTGCAACCCAGATCATAGATCTGGCCACCATTTCTGCATTCATTAACAATCAAGAAGTCATGGCCCAATTACCAACACGTGTTATGGTGACTGGCAGCTTGATCCAAGCCTATCCCGCATCGCAATGCACCATTACACCCAACACTGTGTACTGTAGGTATAATGATGCCCAAGTACTCTCAGATGATACTATGGCTTGCCTCCAAGGTAACTTGACAAGATGCACCTTCTCTCCAGTGGTTGGGAGCTTTCTCACTCGATTCGTGCTGTTCGATGGAATAGTTTATGCAAATTGCAGGTCGATGTTGTGCAAGTGCATGCAACCTGCTGCTGTGATCCTACAGCCGAGTTCATCCCCTGTAACTGTCATTGACATGTACAAATGTGTGAGTCTGCAGCTTGACAATCTCAGATTCACCATCACTCAATTGGCCAATGTAACCTACAATAGCACCATCAAGCTTGAATCATCCCAGATCTTGTCTATTGATCCGTTGGATATATCCCAGAATCTAGCTGCGGTGAATAAGAGTCTAAGTGATGCACTACAACACTTAGCACAAAGTGACACATATCTTTCTGCAATCACATCAGCTACGACTACAAGTGTATTATCCATAATAGCAATCTGTCTTG GATCGTTAGGTTTAATATTAATAATCTTGCTCAGTGTAGTTGTGTGGAAGTTA TTGACCATTGTCGTTGCTAATCGAAATAGAATGGAGAATTTTGTTTATCATAA ATAAGCATTCCACCACTCACGATCTGATCTCAGTGAGAAAAATCAACCTGCA ACTCTTGGAACAAGATAAGACAGTCATCCATTAGTAATTTTTAAGAAAAAAA CGATAGGACCGAACCTAGTATTGAAAGAACCGTCTCGGTCAATCTAGGTAAT CGAGCTGATACCGTCTCGGAAAGCTCAAATCGCGCGCCACCaZggccgatogcaacgg caccatcaccgtggaagagcttaaaaagctgctcgagcagtggaacctggttatcggctttctgttcctgacctggatctgcct gctccagttcgcttatgccaaccggaacaggttcctgtacatcatcaagctgatcttcctgtggctgctgtggcctgtgacactg gcctgcttcgtgctggccgctgtgtaccggattaactggatcaccggcggaatcgccatcgccatggcctgtctggtcggcctg atgtggctgtcttacttcatcgccagcttcagactgtttgccagaaccagaagcatgtggtccttcaaccccgagacaaacatc ctgctgaatgtgccactgcacggcaccatcctgacaagacctctgctggaaagcgagctggtgattggagccgtgatcctga gaggccatctgcggatcgctggccaccacctgggaagatgcgacatcaaggacctgcctaaggaaatcacagtggctaca tctcggaccctgagctactacaaactgggcgcctctcaaagagtggccggcgacagcggcttcgccgcctacagcagatac agaatcggcaactacaagctgaataccgatcacagcagctccagcgacaacatcgccctgctggtgcagtgd GACG TACGACCTGCTATAGGCTATCCACTGCATCATCTCTCCTGCCATACTTCCTACT CACATCATATCTATTTTAAAGAAAAAATAGGCCCGAACACTAATCGTGCCGG CAGTGCCACTGCACACACAACACTACACATACAATACACTACAATGGTTGCA GAAGATGCCCCTGTTAGGGCCACTTGCCGAGTATTATTTCGAACAACAACTTT AATCTTTCTATGCACACTACTAGCATTAAGCATCTCTATCCTTTATGAGAGTTT AATAACCCAAAAGCAAATCATGAGCCAAGCAGGCTCAACTGGATCTAATTCT GGATTAGGAAGTATCACTGATCTTCTTAATAATATTCTCTCTGTCGCAAATCA GATTATATATAACTCTGCAGTCGCTCTACCTCTACAATTGGACACTCTTGAAT CAACACTCCTTACAGCCATTAAGTCTCTTCAAACCAGTGACAAGCTAGAACA GAACTGCTCGTGGAGTGCTGCACTGATTAATGATAATAGATACATTAATGGC ATCAATCAGTTCTATTTTTCAATTGCTGAGGGTCGCAATCTGACACTTGGCCC ACTTCTTAATATGCCTAGTTTCATTCCAACTGCCACGACACCAGAGGGCTGCA CCAGGATCCCATCATTCTCGCTCACTAAGACACACTGGTGTTATACACACAATGTTATCCTGAATGGATGCCAGGATCATGTATCCTCAAATCAATTTGTTTCTAT GGGAATCATTGAACCCACTTCTGCCGGGTTTCCATTCTTTCGAACCCTAAAGA CTCTATATCTCAGCGATGGGGTCAATCGTAAGAGCTGCTCTATCAGTACAGTT CCGGGGGGTTGTATGATGTACTGTTTTGTTTCTACTCAACCAGAGAGGGATGA CTACTTTTCTGCCGCTCCTCCAGAACAACGAATTATTATAATGTACTATAATG ATACAATCGTGGAGCGCATAATTAATCCACCCGGGGTACTAGATGTATGGGCAACATTGAACCCAGGAACAGGAAGCGGGGTATATTATTTAGGTTGGGTGCTC TTTCCAATATATGGCGGCGTGATTAAAGGTACGAGTTTATGGAATAATCAAGC AAATAAATACTTTATCCCCCAGATGGTTGCTGCTCTCTGCTCACAAAACCAGG CAACTCAAGTCCAAAATGCTAAGTCATCATACTATAGCAGCTGGTTTGGCAAT CGAATGATTCAGTCTGGGATCCTGGCATGTCCTCTTCGACAGGATCTAACCAA TGAGTGTTTAGTTCTGCCCTTTTCTAATGATCAGGTGCTTATGGGTGCTGAAG GGAGATTATACATGTATGGTGACTCGGTGTATTACTATCAAAGAAGCAATAG TTGGTGGCCTATGACCATGCTGTATAAGGTAACCATAACATTCACTAATGGTC AGCCATCTGCTATATCAGCTCAGAATGTGCCCACACAGCAGGTCCCTAGACCT GGGACAGGAGACTGCTCTGCAACCAATAGATGTCCCGGTTTTTGCTTGACAG GAGTGTATGCCGATGCCTGGTTACTGACCAACCCTTCGTCTACCAGTACATTT GGATCAGAAGCAACCTTCACTGGTTCTTATCTCAACACAGCAACTCAGCGTAT CAATCCGACGATGTATATCGCGAACAACACACAGATCATAAGCTCACAGCAA TTTGGATCAAGCGGTCAAGAAGCAGCATATGGCCACACAACTTGTTTTAGGG ACACAGGCTCTGTTATGGTATACTGTATCTATATTATTGAATTGTCCTCATCTC TCTTAGGACAATTTCAGATTGTCCCATTTATCCGTCAGGTGACACTATCCTAA AGGCAGAAGCCTTCAGGTCTGACCCAGCCAATCAAAGCATTATACCAGACCA TGGCCTACCATCGGCTTTAAAGAAAAAAATAGGCCCGGACGGGTTAGCAACA AGCGGCGGCCGCCGCCACCatgttcgtcttcctggtcctgctgcctctggtctcctcacagtgcgtcaatctgaca actcggactcagctgccacctgcttatactaatagcttcaccagaggcgtgtactatcctgacaaggtgtttagaagctccgtgctg cactctacacaggatctgtttctgccattctttagcaacgtgacctggttccacgccatccacgtgagcggcaccaatggcacaaa gcggttcgacaatcccgtgctgccttttaacgatggcgtgtacttcgcctctaccgagaagagcaacatcatcagaggctggatct ttggcaccacactggactccaagacacagtctctgctgatcgtgaacaatgccaccaacgtggtcatcaaggtgtgcgagttcca gttttgtaatgatcccttcctgggcgtgtactatcacaagaacaataagagctggatggagtccgagtttagagtgtattctagcgcc aacaactgcacatttgagtacgtgagccagcctttcctgatggacctggagggcaagcagggcaatttcaagaacctgagggag ttcgtgtttaagaatatcgacggctacttcaaaatctactctaagcacacccccatcaacctggtgcgcgacctgcctcagggcttc agcgccctggagcccctggtggatctgcctatcggcatcaacatcacccggtttcagacactgctggccctgcacagaagctac ctgacacccggcgactcctctagcggatggaccgccggcgctgccgcctactatgtgggctacctccagccccggaccttcctg ctgaagtacaacgagaatggcaccatcacagacgcagtggattgcgccctggaccccctgagcgagacaaagtgtacactgaa gtcctttaccgtggagaagggcatctatcagacatccaatttcagggtgcagccaaccgagtctatcgtgcgctttcctaatatcac aaacctgtgcccatttggcgaggtgttcaacgcaacccgcttcgccagcgtgtacgcctggaataggaagcggatcagcaactg cgtggccgactatagcgtgctgtacaactccgcctctttcagcacctttaagtgctatggcgtgtcccccacaaagctgaatgacct gtgctttaccaacgtctacgccgattctttcgtgatcaggggcgacgaggtgcgccagatcgcccccggccagacaggcaagat cgcagactacaattataagctgccagacgatttcaccggctgcgtgatcgcctggaacagcaacaatctggattccaaagtgggcggcaactacaattatctgtaccggctgtttagaaagagcaatctgaagcccttcgagagggacatctctacagaaatctaccaggc cggcagcaccccttgcaatggcgtggagggctttaactgttatttcccactccagtcctacggcttccagcccacaaacggcgtg ggctatcagccttaccgcgtggtggtgctgagctttgagctgctgcacgccccagcaacagtgtgcggccccaagaagtccacc aatctggtgaagaacaagtgcgtgaacttcaacttcaacggcctgaccggcacaggcgtgctgaccgagtccaacaagaagttc ctgccatttcagcagttcggcagggacatcgcagataccacagacgccgtgcgcgacccacagaccctggagatcctggacat cacaccctgctctttcggcggcgtgagcgtgatcacacccggcaccaatacaagcaaccaggtggccgtgctgtatcaggacgt gaattgtaccgaggtgcccgtggctatccacgccgatcagctgaccccaacatggcgggtgtacagcaccggctccaacgtctt ccagacaagagccggatgcctgatcggagcagagcacgtgaacaattcctatgagtgcgacatcccaatcggcgccggcatct gtgcctcttaccagacccagacaaactctcccagaagagcccggagcgtggcctcccagtctatcatcgcctataccatgtccct gggcgccgagaacagcgtggcctactctaacaatagcatcgccatcccaaccaacttcacaatctctgtgaccacagagatcct gcccgtgtccatgaccaagacatctgtggactgcacaatgtatatctgtggcgattctaccgagtgcagcaacctgctgctccagt acggcagcttttgtacccagctgaatagagccctgacaggcatcgccgtggagcaggataagaacacacaggaggtgttcgcc caggtgaagcaaatctacaagaccccccctatcaaggactttggcggcttcaatttttcccagatcctgcctgatccatccaagcct tctaagcggagctttatcgaggacctgctgttcaacaaggtgaccctggccgatgccggcttcatcaagcagtatggcgattgcct gggcgacatcgcagccagggacctgatctgcgcccagaagtttaatggcctgaccgtgctgccacccctgctgacagatgaga tgatcgcacagtacacaagcgccctgctggccggcaccatcacatccggatggaccttcggcgcaggagccgccctccagatc ccctttgccatgcagatggcctataggttcaacggcatcggcgtgacccagaatgtgctgtacgagaaccagaagctgatcgcc aatcagtttaactccgccatcggcaagatccaggacagcctgtcctctacagccagcgccctgggcaagctccaggatgtggtg aatcagaacgcccaggccctgaataccctggtgaagcagctgagcagcaacttcggcgccatctctagcgtgctgaatgacatc ctgagccggctggacaaggtggaggcagaggtgcagatcgaccggctgatcaccggccggctccagagcctccagacctat gtgacacagcagctgatcagggccgccgagatcagggccagcgccaatctggcagcaaccaagatgtccgagtgcgtgctg ggccagtctaagagagtggacttttgtggcaagggctatcacctgatgtccttccctcagtctgccccacacggcgtggtgtttctg cacgtgacctacgtgcccgcccaggagaagaacttcaccacagcccctgccatctgccacgatggcaaggcccactttccaag ggagggcgtgttcgtgtccaacggcacccactggtttgtgacacagcgcaatttctacgagccccagatcatcaccacagacaa caccttcgtgagcggcaactgtgacgtggtcatcggcatcgtgaacaataccgtgtatgatccactccagcccgagctggacag ctttaaggaggagctggataagtatttcaagaatcacacctcccctgacgtggatctgggcgacatcagcggcatcaatgcctcc gtggtgaacatccagaaggagatcgaccgcctgaacgaggtggctaagaatctgaacgagagcctgatcgacctccaggagc tgggcaagtatgagcagtacatcaagtggccctggtacatctggctgggcttcatcgccggcctgatcgccatcgtgatggtgac catcatgctgtgctgtatgacatcctgctgttcttgcctgaagggctgctgtagctgtggctcctgctgtaagtttgacgaggatgac tctgaacctgtgctgaagggcgtgaagctgcattacacctaaT A AGGT C GACTC AT GGA AT GC AT AC C AAACATTATTGACACTAATGACACACAAAATTGGTTTTAAGAAAAACCAAGAG AACAATAGGCCAGAATGGCTGGGTCTCGGGAGATATTACTCCCTGAAGTCCA TCTCAATTCACCAATTGTAAAGCATAAGCTATACTATTACATTCTACTTGGAA ACCTCCCAAATGAGATCGACCTTGACGATTTAGGTCCATTACATAATCAAAATTGGAATCAGATAGCACATGAAGAGTCTAACTTAGCTCAACGCTTGGTAAATGTAAGAAATTTTCTAATTACCCACATCCCTGATCTTAGAAAGGGCCATTGGCAAGAGTATGTCAATGTAATACTGTGGCCGCGAATTCTTCCCTTGATCCCGGATTTTAAAATCAATGACCAATTGCCTCTGCTCAAAAATTGGGACAAGTTAGTTAAAGAATCATGTTCAGTAATCAATGCAGGTACTTCCCAGTGCATTCAGAATCTCAGCTATGGACTGACAGGTCGTGGGAACCTCTTTACACGATCACGTGAACTCTCTGGTGACCGCAGGGATATTGATCTTAAGACAGTTGTGGCAGCATGGCATGACTCAGACTGGAAAAGAATAAGTGATTTTTGGATTATGATCAAATTCCAGATGAGACAATTAATTGTTAGGCAAACAGATCATAATGATTCTGATTTAATCACGTATATCGAAAATAGAGAAGGCATAATCATCATAACCCCTGAACTGGTAGCATTATTTAACACTGAGAATCATACACTAACATACATGACCTTTGAAATTGTACTGATGGTTTCAGATATGTACGAAGGTCGTCACAACATTTTATCACTATGCACAGTTAGCACTTACCTGAATCCTCTGAAGAAAAGAATAACATATTTATTGAGCCTTGTAGATAACTTAGCTTTTCAGATAGGTGATGCTGTATATAACATAATTGCTTTGCTAGAATCCTTTGTATATGCACAGTTGCAAATGTCAGATCCCATCCCAGAACTCAGAGGACAATTCCATGCATTCGTATGTTCTGAGATTCTTGATGCACTAAGAGGAACTAATAGTTTCACCCAGGATGAATTAAGAACTGTGACAACTAATTTGATATCCCCATTCCAAGATCTGACCCCAGATCTTACGGCTGAATTGCTCTGTATAATGAGGCTTTGGGGACACCCCATGCTCACTGCCAGTCAAGCTGCAGGAAAGGTACGCGAGTCTATGTGTGCTGGAAAAGTATTAGACTTTCCCACCATTATGAAAACACTAGCCTTTTTCCATACTATTCTGATCAATGGATACAGGAGGAAGCATCATGGAGTATGGCCACCCTTAAACTTACCGGGTAATGCTTCAAAGGGTCTCACGGAACTTATGAATGACAATACTGAAATAAGCTATGAATTCACACTTAAGCATTGGAAGGAAGTCTCTCTTATAAAATTCAAGAAATGTTTTGATGCAGACGCAGGTGAGGAACTCAGTATATTTATGAAAGATAAGGCAATTAGTGCCCCAAAACAAGACTGGATGAGTGTGTTTAGAAGAAGCCTAATCAAACAGCGCCATCAGCATCATCAGGTCCCCCTACCAAATCCATTCAATCGACGGCTGTTGCTAAACTTTCTCGGAGATGACAAATTCGACCCGAATGTGGAGCTACAGTATGTAACATCAGGTGAGTATCTACATGATGACACGTTTTGTGCATCATATTCACTAAAAGAGAAGGAAATTAAACCTGATGGTCGAATTTTTGCAAAGTTGACTAAGAGAATGAGATCATGTCAAGTTATAGCAGAATCTCTTTTAGCGAACCATGCTGGGAAGTTAATGAAAGAGAATGGTGTTGTGATGAATCAGCTATCATTAACAAAATCACTATTAACAATGAGTCAGATTGGAATAATATCCGAGAAAGCTAGAAAGTCAACTCGAGATAACATAAATCAACCTGGTTTCCAGAATATCCAGAGAAATAAATCACATCACTCCAAGCAAGTCAATCAGCGAGATCCAAGTGATGACTTTGAATTGGCAGCATCTTTTTTAACTACTGATCTCAAAAAATATTGTTTACAATGGAGGTACCAGACAATTATCCCATTTGCTCAATCATTAAACAGAATGTATGGTTATCCTCATCTCTTTGAGTGGATTCACTTACGGCTAATGCGTAGTACACTTTACGTGGGGGATCCCTTCAACCCACCAGCAGATACCAGTCAATTTGATCTAGATAAAGTAATTAATGGAGATATCTTCATTGTATCACCCAGAGGTGGAATTGAAGGGCTGTGTCAAAAGGCTTGGACAATGATATCTATCGCTGTGATAATTCTATCTGCCACAGAGTCTGGCACACGAGTAATGAGTATGGTGCAGGGAGATAATCAAGCAATTGCTGTCACCACACGAGTACCAAGGAGCCTGCCGACTCTTGAGAAAAAGACTATTGCTTTTAGATCTTGTAATCTATTCTTTGAGAGGTTAAAATGTAATAATTTTGGATTAGGTCACCATTTGAAAGAACAAGAGACTATCATTAGTTCTCACTTCTTTGTTTATAGCAAGAGAATATTCTATCAGGGGAGGATTCTAACGCAAGCCTTAAAAAATGCTAGTAAGCTCTGCTTGACAGCTGATGTCCTAGGAGAATGCACCCAATCATCATGTTCTAATCTTGCAACTACTGTCATGAGGTTAACTGAGAATGGTGTTGAAAAAGATATCTGTTTCTACTTGAATATCTATATGACCATCAAACAGCTCTCCTATGATATCATCTTCCCTCAAGTGTCAATTCCTGGAGATCAGATCACATTAGAATACATAAATAATCCACACCTGGTATCACGATTGGCTCTTTTGCCATCCCAGTTAGGAGGTCTAAACTACCTGTCATGCAGTAGGCTGTTCAATCGAAACATAGGCGACCCGGTGGTTTCCGCAGTTGCAGATCTTAAGAGATTAATTAAATCAGGATGTATGGATTACTGGATCCTTTATAACTTATTAGGGAGAAAACCGGGAAACGGCTCATGGGCTACTTTAGCAGCTGACCCGTACTCAATCAATATAGAGTATCAATACCCTCCAACTACAGCTCTTAAGAGGCACACCCAACAAGCTCTGATGGAACTCAGTACGAATCCAATGTTACGTGGCATATTCTCTGACAATGCACAGGCAGAAGAAAATAACCTTGCTAGGTTTCTCCTGGATAGGGAGGTGATCTTTCCGCGTGTAGCTCACATCATCATTGAGCAAACCAGTGTCGGGAGGAGAAAACAGATTCAAGGATATTTGGATTCAACTAGATCGATAATGAGGAAATCACTAGAAATTAAGCCCTTATCCAATAGGAAGCTTAATGAAATACTGGATTACAACATCAATTACCTAGCTTACAATTTGGCATTACTCAAGAATGCTATTGAACCTCCGACTTATTTGAAGGCAATGACACTTGAAACATGTAGCATCGACATTGCAAGGAACCTCCGGAAGCTCTCCTGGGCCCCACTCTTGGGTGGGAGAAATCTTGAAGGATTAGAGACGCCAGATCCCATTGAAATTACTGCAGGAGCATTAATTGTTGGATCGGGCTACTGTGAACAGTGTGCTGCAGGAGACAATCGATTCACATGGTTTTTCTTGCCATCTGGTATCGAGATAGGAGGGGATCCCCGTGATAATCCTCCTATCCGTGTACCGTACATTGGCTCCAGGACTGATGAGAGGAGGGTAGCCTCAATGGCATACATCAGGGGTGCCTCGAGTAGCTTAAAAGCAGTTCTTAGACTGGCGGGAGTGTACATCTGGGCATTCGGAGATACTCTGGAGAATTGGATAGATGCACTGGATTTGTCTCACACTAGAGTTAACATCACACTTGAACAGCTGCAATCCCTCACCCCACTTCCAACCTCTGCCAATCTAACCCATCGGTTGGATGATGGCACAACTACCCTAAAGTTTACTCCTGCGAGCTCTTACACCTTTTCAAGTTTCACTCATATATCAAATGATGAGCAATACCTGACAATTAATGACAAAACTGCAGATTCAAATATAATCTACCAACAGTTAATGATCACTGGACTCGGAATCTTAGAAACATGGAATAATCCCCCAATCAATAGAACATTCGAAGAATCTACCCTACATTTGCACACTGGTGCATCATGTTGTGTCCGACCTGTGGACTCCTGCATTCTCTCAGAAGCATTAACAGTCAAGCCACATATTACAGTACCGTACAGCAATAAATTTGTATTTGATGAGGACCCGCTATCTGAATATGAAACTGCAAAACTGGAATCGTTATCATTCCAAGCCCAATTAGGCAACATTGATGCTGTAGATATGACAGGTAAATTAACATTATTGTCCCAATTCACTGCAAGGCAGATTATCAATGCAATCACTGGACTCGATGAGTCTGTCTCTCTTACTAATGATGCCATTGTTGCATCAGACTATGTCTCCAATTGGATTAGTGAATGCATGTATACCAAATTAGATGAATTATTTATGTATTGTGGGTGGGAACTACTATTGGAACTATCCTATCAAATGTATTATCTGAGGGTAGTTGGGTGGAGTAATATAGTGGATTATTCTTACATGATCTTGAGAAGAATCCCGGGTGCAGCATTAAACAATCTGGCATCTACATTAAGTCATCCAAAACTTTTCCGACGAGCTATCAACCTAGATATAGTTGCCCCCTTAAATGCTCCTCATTTTGCATCTCTGGACTACATCAAGATGAGTGTGGATGCAATACTCTGGGGCTGTAAAAGAGTCATCAATGTGCTCTCCAATGGAGGGGACTTAGAATTAGTTGTGACATCTGAAGATAGCCTTATTCTCAGTGACCGATCCATGAATCTCATTGCAAGGAAATTAACTTTATTATCACTGATTCACCATAATGGTTTGGAACTACCAAAGATTAAGGGGTTCTCTCCTGATGAGAAGTGTTTCGCTTTGACAGAATTTTTGAGGAAAGTGGTGAACTCAGGGTTGAGTTCAATAGAGAACCTATCAAATTTTATGTACAATGTGGAGAACCCACGGCTTGCAGCATTCGCCAGCAACAATTACTACCTGACCAGAAAATTATTGAATTCAATACGAGATACTGAGTCGGGTCAAGTAGCAGTCACCTCATATTATGAATCATTAGAATATATTGATAGTCTTAAGCTAACCCCACATGTGCCTGGCACCTCATGCATTGAGGATGATAGTCTATGTACAAATGATTACATAATCTGGATCATAGAGTCTAATGCAAACTTGGAGAAGTATCCAATTCCAAATAGCCCTGAGGATGATTCCAATTTCCATAACTTTAAGTTGAATGCTCCATCGCACCATACCTTACGCCCATTAGGGTTGTCATCAACTGCTTGGTATAAGGGTATAAGCTGCTGCAGGTACCTTGAGCGATTAAAGCTACCACAAGGTGATCATTTATATATTGCAGAAGGTAGTGGTGCCAGTATGACAATCATAGAATACCTATTCCCAGGAAGAAAGATATATTACAATTCTTTATTTAGTAGTGGTGACAATCCCCCACAAAGAAATTATGCACCAATGCCTACTCAGTTCATTGAGAGTGTCCCATACAAGCTCTGGCAAGCACACACAGATCAATATCCCGAGATTTTTGAGGACTTCATCCCTCTATGGAACGGAAACGCCGCCATGACTGACATAGGAATGACAGCTTGTGTAGAATTCATCATCAATCGAGTCGGCCCAAGGACTTGCAGTTTAGTACATGTAGATTTGGAATCAAGTGCAAGCTTAAATCAACAATGCCTGTCAAAGCCGATAATTAATGCTATCATCACTGCTACAACTGTTTTGTGCCCTCATGGGGTGCTTATTCTGAAATATAGTTGGTTGCCATTTACTAGATTTAGTACTTTGATCACTTTCTTATGGTGCTACTTTGAGAGAATCACTGTTCTTAGGAGCACATATTCTGATCCAGCTAATCATGAGGTTTATTTAATTTGTATCCTTGCCAACAACTTTGCATTCCAGACTGTCTCGCAGGCAACAGGAATGGCGATGACTTTAACTGATCAAGGGTTTACTTTGATATCACCTGAAAGAATAAATCAGTATTGGGATGGTCACTTGAAGCAAGAACGTATCGTAGCAGAAGCAATTGATAAGGTGGTTCTAGGAGAAAATGCTCTATTTAATTCGAGTGATAATGAATTAATTCTCAAATGTGGAGGGACACCAAATGCACGGAATCTCATCGATATCGAGCCAGTCGCAACTTTCATAGAATTTGAACAATTGATCTGCACAATGTTGACAACCCACTTGAAGGAAATAATTGATATAACAAGGTCTGGAACCCAGGATTATGAAAGTTTATTACTCACTCCTTACAATTTAGGTCTTCTTGGTAAAATCAGTACGATAGTGAGATTATTAACAGAAAGGATTCTAAATCATACTATCAGGAATTGGTTGATCCTCCCACCTTCGCTCCGGATGATCGTGAAGCAGGACTTGGAATTCGGCATATTCAGGATTACTTCCATCCTCAATTCTGATCGGTTCCTGAAGCTTTCTCCAAATAGGAAATACTTGATTGCACAATTAACTGCAGGCTACATTAGGAAATTGATTGAGGGGGATTGCAATATCGATCTAACCAGACCTATCCAAAAGCAAATCTGGAAAGCATTAGGTTGTGTAGTCTATTGTCACGATCCAATGGATCAAAGGGAGTCAACAGAGTTTATTGATATAAATATTAATGAAGAAATAGACCGCGGGATCGATGGCGAGGAAATCTAAACATATCAAGAATCAGAATTAGTTTAAGAAAAAAGAAGAGGATTAATCTTGGTTTTCCCCTTGGTGGGTCGGCATGGCATCTCCACCTCCTCGC...
Claims
What is claimed is:
1. A composition comprising a modified PIV5 CVB viral expression vector having at least 98% sequence identity to SEQ ID NO: 1, wherein the CVB viral expression vector comprises mutations of a PIV5 viral genome at amino acid residue S157 or S156 of the P / V gene resulting in the removal of a phosphorylation site and higher transcription activities thereby improving virus titer in cell culture, and wherein the CVB viral expression vector is highly immunogenic and can be used as an effective vaccine platform.
2. The composition of claim 1, wherein the mutation at amino acid residue SI 57 or SI 56 comprises the substitution of serine (S) with an amino acid residue selected from a group consisting of alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), selenocysteine (U), valine (V), tryptophan (W), and tyrosine (Y).
3. The composition of claim 1, wherein the mutation at amino acid residue SI 57 or SI 56 comprises the substitution of the serine (S) amino acid residue SI 57 to phenylalanine (F) or the substitution of the serine (S) amino acid residue SI 56 to asparagine (N).
4. The composition of claim 1, wherein the CVB viral expression vector expresses a heterologous polypeptide comprising a viral antigen selected from a group consisting of SARS-CoV-2, RSV or viral or bacterial antigens.
5. The composition of claim 1, wherein the PIV5 genome has a heterologous nucleic acid sequence with at least 98% sequence identity to SEQ ID NOs: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 and wherein the viral expression vector expresses a heterologous polypeptide comprising a coronavirus spike (S) and / or nucleocapsid (N) proteins or the RSV-F protein.
6. The composition of claim 5, wherein the coronavirus spike (S) and / or nucleocapsid (N) proteins are S or N proteins of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a SARS-CoV-2 Wuhan strain, or a variant of SARS-CoV- 2, where the variant of SARS-CoV-2 is a SARS-CoV-2 beta variant, a SARS-CoV-2 gamma variant, a SARS-CoV-2 delta variant, a SARS-CoV-2 omicron variant, a SARS- CoV-2 Omicron BA.l, a SARS-CoV-2 Omicron BA.5, BQ1 or XBB1 or any future emerging variants.
7. The composition of claim 5, wherein the coronavirus S gene comprises the coronavirus S gene of SARS-CoV-2 and wherein a cytoplasmic tail of the coronavirus S gene has been replaced with a cytoplasmic tail of the fusion (F) gene of the CVB or a CPI vector.
8. The composition of claim 5, wherein the PIV5 genome with S157F or S156N in the P / V gene of the PIV5 viral genome (CVB) further comprises an open reading frame deletion mutations of a SH gene, and wherein the N gene of the SARS-CoV-2 Wuhan strain is inserted to replace the SH gene of PIV5 and the S gene of SARS-CoV-2 Wuhan strain or other variant strains is inserted between a PIV5 hemagglutinin (HN) gene and a polymerase (L) gene of CVB.
9. The composition of claim 5, wherein an entire SH gene transcript unit of a PIV5 viral genome is deleted and the S gene of the SARS-CoV-2 Wuhan strain or other variant strains is placed between a HN gene and a L gene of CVB.
10. The composition of claim 5, wherein the S gene of the SARS-CoV-2 variant is inserted to replace the S gene of the SARS-CoV-2 Wuhan strain and the N gene of the SARS-CoV-2 Wuhan strain is inserted in the place of the SH gene of PIV5.
11. The composition of claim 5, wherein the S gene of the SARS-CoV-2 Omicron BA.5 variant is inserted between the HN and L genes of PIV5 to replace the S gene of Wuhan strain.
12. The composition of claim 5, wherein the S gene of the SARS-CoV-2 Omicron BA.5 variant is inserted to replace the S gene of the SARS-CoV-2 Wuhan strain and the N gene of SARS-CoV-2 Wuhan strain is inserted to replace the SH gene of CVB.
13. The composition of claim 5, wherein the PIV5 F and HN genes are deleted and wherein the S gene of SARS-CoV-2 Wuhan strain is between HN and L genes of CVB.
14. The composition of claim 5, wherein the N gene of the SARS-CoV-2 Wuhan strain is inserted between F and HN, and the S gene of the SARS-CoV-2 Wuhan strain is inserted between the HN and L genes of CVB.
15. The composition of claim 5, wherein the M gene from the SARS-CoV-2 Wuhan strain is inserted between F and HN, and the S gene of the SARS-CoV-2 Wuhan strain is inserted between HN and L of CVB.
16. The composition of claim 5, wherein the M gene from the SARS-CoV-2 Wuhan strain is inserted after F of PIV5, the E gene from the SARS-CoV-2 Wuhan strain inserted between the M gene of SARS-CoV-2 and HN, and the S gene of SARS-CoV-2 Wuhan strain is inserted between HN and L of CVB.
17. The composition of claim 5, wherein the M gene from the SARS-CoV-2 Wuhan strain is inserted after F of PIV5, the N gene from the SARS-CoV-2 Wuhan strain is inserted between the M gene and the E gene of SARS-CoV-2, the E gene from the SARS- CoV-2 Wuhan strain inserted between the N gene of SARS-CoV-2 and HN, and the S gene of SARS-CoV-2 Wuhan strain is inserted between HN and L of CVB.
18. The composition of claim 5, wherein the RSV-F protein in inserted in place of PIV5 SH gene (ASH) or inserted between PIV5 SH and NH (SH-NH) or between HN and L (HN-L).
19. A method of inducing an immune response in a subject having or at risk of having SARS-COV-2, RSV or other viral or bacterial infections, the method comprising administering the composition of claim 1 to the subject as a primary vaccine or a booster vaccine, wherein the immune response comprises a humoral immune response and / or a cellular immune response.
20. The method of claim 19, wherein the composition is administered intranasally, intramuscularly, topically, or orally.
Citation Information
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