Oncolytic viruses expressing CAR T cell targets and uses thereof
By designing a recombinant chimeric poxvirus, containing a transgene encoding human CD19 and having enhanced oncolyticity, the problem of limited clinical benefits of existing oncolytic viruses in cancer treatment is solved, and a more efficient cancer treatment effect is achieved.
Patent Information
- Application Number
- CN201880064280.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Priority Date
- 2017-08-11
- Filing Date
- 2018-08-10
- Publication Date
- 2025-05-09
- Estimated Expiration
- 2039-06-22
AI Technical Summary
The clinical benefits of existing oncolytic viruses in cancer treatment are limited, and due to safety concerns, the use of highly attenuated viruses mainly limits their anti-tumor efficacy.
A recombinant chimeric poxvirus is designed and tested for a transgene that contains a transgene encoding human CD19 and has enhanced oncolytic properties to improve its effectiveness in cancer treatment.
By causing cancer cells to express CD19, recombinant chimeric poxvirus can be recognized and killed by CAR T cells targeting CD19, thereby improving the effectiveness of cancer treatment.
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Abstract
Description
Background of the Invention
[0002] Cancer is the second leading cause of death in the United States. In recent years, significant progress has been made in cancer immunotherapy, including immune checkpoint inhibitors, T cells with chimeric antigen receptors (CAR T cells), and oncolytic viruses. Oncolytic viruses are naturally occurring or genetically modified viruses that infect cancer cells while leaving healthy cells unharmed, replicate in them, and ultimately kill them.
[0003] Oncolytic viruses are naturally occurring or genetically modified viruses that infect cancer cells while leaving healthy cells unharmed, replicate in cancer cells, and ultimately kill cancer cells (1, 2). A recently completed Phase III clinical trial of the oncolytic herpes simplex virus T-VEC in 436 patients with unresectable stage IIIB, IIIC, or IV melanoma reportedly met its primary endpoint, with a durable response rate of 16.3% in patients receiving T-III compared to 2.1% in patients receiving GM-CSF (3). Based on the results from this trial, the FDA approved T-VEC on October 27, 2015.
[0004] Oncolytic virus constructs from at least 8 different species have been tested in various stages of clinical trials, including adenovirus, herpes simplex virus-1, Newcastle disease virus, reovirus, measles virus, coxsackie virus, Seneca Valley virus and vaccinia virus. It is already clear that oncolytic viruses are well tolerated in cancer patients. However, the clinical benefits of oncolytic viruses as independent therapies are still limited (5). Due to concerns about the safety of oncolytic viruses, only highly attenuated oncolytic viruses (naturally non-toxic or attenuated by genetic engineering) have been used in both preclinical and clinical studies. Since the safety of oncolytic viruses is now fully established, it is time to design and test oncolytic viruses with maximum anti-tumor efficacy. Oncolytic viruses with robust oncolytic effects will release a large amount of tumor antigens, thereby producing a strong immunotherapy effect.
[0005] Vaccinia virus (the prototype member of the Poxviridae family) was used as a smallpox vaccine to eradicate smallpox, which is estimated to have killed 500 million people in the 19th and 20th centuries alone. Therefore, it is undoubtedly the most successful live biological therapeutic agent. The safety of vaccinia virus has been well documented in millions of people worldwide. Vaccinia virus is also the first oncolytic virus to show viral oncolytic effects in the laboratory. Vaccinia virus has been tested as an oncolytic virus in many clinical trials and has been shown to be well tolerated in patients with advanced cancer (2). Several studies have shown that vaccinia virus is superior to adenovirus in terms of oncolytic activity (6), one of the best studied oncolytic virus species and the first oncolytic virus approved for cancer treatment in China (7). In addition to vaccinia virus, other members of the Poxviridae family have also been tested as oncolytic viruses, including raccoon pox virus (8), sheep pox virus (9) and myxoma virus (10). SUMMARY OF THE INVENTION
[0007] Described herein are recombinant chimeric poxviruses comprising a nucleotide sequence having at least 70% (80%, 85%, 90%, 95%, 98%) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2 (or at least 70% (80%, 85%, 90%, 95%, 95%, 98%) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2 modified by TK gene deletion), and further comprising a nucleotide sequence encoding human CD19 or a portion thereof. The recombinant poxvirus is oncolytic and can infect and kill certain cancer cells. It can also cause infected cells to express cell surface CD19 (or a portion of CD19 that can be expressed on the cell surface). The expression of CD19 makes the cells susceptible to being killed by CAR T cells targeting CD19 ("CD19 CAR T cells"). Therefore, various cancers can be treated by administering a recombinant chimeric poxvirus or another oncolytic virus containing a transgene encoding all or part of CD19 (collectively referred to as "CD19-expressing oncolytic virus") and CD19 CAR T cells together or sequentially. In some cases, it is preferred to first treat with an oncolytic virus expressing CD19, and then after a period of time so that the cells can be infected and express CD19 (e.g., 1, 2, 3, 4, 5 or more days), treat with CD19 CAR T cells. One or both treatments can be repeated.
[0008] In one aspect, a recombinant oncolytic virus is provided, comprising a transgene, such as a transgene in an expression cassette, wherein the transgene encodes all or part of human CD19 (UniProt ID P15391). The expressed portion of CD19 is a portion that can be expressed on the cell surface and can be recognized by anti-CD19 antibodies.
[0009] In another aspect, a method of treating cancer in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a chimeric poxvirus as described herein, and simultaneously or subsequently administering a T cell expressing a CAR targeting CD19, thereby treating the subject's cancer. In embodiments, the cancer is, for example, a B cell cancer, ALL, CLL or B-NHL, diffuse large B cell lymphoma, follicular lymphoma, or mantle cell lymphoma.
[0010] In one aspect, a nucleotide sequence having at least 70% (80%, 85%, 90%, 95% or 98%) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2 comprises: (i) nucleic acid fragments from at least two poxvirus strains selected from the group consisting of vaccinia virus strain Brighton, raccoon poxvirus strain Herman, rabbit poxvirus strain Utrecht, vaccinia virus strain WR, vaccinia virus strain IHD, vaccinia virus strain Elstree, vaccinia virus strain CL, vaccinia virus strain Lederle-Chorioallantoic, vaccinia virus strain AS, capripoxvirus strain NZ2, and pseudovaccinia virus strain TJS; (ii) one or more anti-cancer nucleic acid sequences; or (iii) a nucleic acid sequence encoding a detectable portion.
[0011] In another aspect, a nucleotide sequence having at least 70% (80%, 85%, 90%, 95% or 98%) sequence identity to SEQ ID NO: 1 comprises: (i) a nucleic acid segment from vaccinia virus strain Brighton, raccoon poxvirus strain Herman, rabbit poxvirus strain Utrecht, vaccinia virus strain WR, vaccinia virus strain IHD, vaccinia virus strain Elstree, vaccinia virus strain CL, vaccinia virus strain Lederle-Chorioallantoic, and vaccinia virus strain AS; (ii) one or more anti-cancer nucleic acid sequences; or (iii) a nucleic acid sequence encoding a detectable portion.
[0012] In another aspect, the nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 2 comprises: (i) a nucleic acid fragment from capripoxvirus strain NZ2 and pseudovacciniavirus strain TJS; (ii) one or more anti-cancer nucleic acid sequences; or (iii) a nucleic acid sequence encoding a detectable portion.
[0013] In another aspect, a nucleotide sequence having at least 70% (80%, 85%, 90%, 95% or 98%) sequence identity to SEQ ID NO: 3 comprises: (i) a nucleic acid segment from vaccinia virus strain Brighton, raccoon poxvirus strain Herman, rabbitpoxvirus strain Utrecht, vaccinia virus strain WR, vaccinia virus strain IHD, vaccinia virus strain Elstree, vaccinia virus strain CL, vaccinia virus strain Lederle-Chorioallantoic, and vaccinia virus strain AS; (ii) one or more anti-cancer nucleic acid sequences; or (iii) a nucleic acid sequence encoding a detectable portion.
[0014] In one aspect, a nucleotide sequence having at least 70% (80%, 85%, 90%, 95% or 98%) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2 comprises: (i) nucleic acid fragments from at least two poxvirus strains selected from the group consisting of vaccinia virus strain Brighton, raccoon poxvirus strain Herman, rabbit poxvirus strain Utrecht, vaccinia virus strain WR, vaccinia virus strain IHD, vaccinia virus strain Elstree, vaccinia virus strain CL, vaccinia virus strain Lederle-Chorioallantoic, vaccinia virus strain AS, capripoxvirus strain NZ2, and pseudovaccinia virus strain TJS; (ii) one or more anti-cancer nucleic acid sequences; (iii) one or more nucleic acid binding sequences; or (iv) a nucleic acid sequence encoding a detectable portion.
[0015] In another aspect, a nucleotide sequence having at least 70% (80%, 85%, 90%, 95% or 98%) sequence identity to SEQ ID NO: 1 comprises: (i) a nucleic acid segment from vaccinia virus strain Brighton, raccoon poxvirus strain Herman, rabbit poxvirus strain Utrecht, vaccinia virus strain WR, vaccinia virus strain IHD, vaccinia virus strain Elstree, vaccinia virus strain CL, vaccinia virus strain Lederle-Chorioallantoic, and vaccinia virus strain AS; (ii) one or more anti-cancer nucleic acid sequences; (iii) one or more nucleic acid binding sequences; or (iv) a nucleic acid sequence encoding a detectable portion.
[0016] In another aspect, a nucleotide sequence having at least 70% (80%, 85%, 90%, 95% or 98%) (80%, 85%, 90%, 95% or 98%) sequence identity to SEQ ID NO: 2 comprises: (i) a nucleic acid fragment from capripoxvirus strain NZ2 and pseudovacciniavirus strain TJS; (ii) one or more anti-cancer nucleic acid sequences; (iii) one or more nucleic acid binding sequences; or (iv) a nucleic acid sequence encoding a detectable portion.
[0017] In another aspect, a nucleotide sequence having at least 70% (80%, 85%, 90%, 95% or 98%) sequence identity to SEQ ID NO:3 comprises: (i) a nucleic acid segment from vaccinia virus strain Brighton, raccoon poxvirus strain Herman, rabbit poxvirus strain Utrecht, vaccinia virus strain WR, vaccinia virus strain IHD, vaccinia virus strain Elstree, vaccinia virus strain CL, vaccinia virus strain Lederle-Chorioallantoic, and vaccinia virus strain AS; (ii) one or more anti-cancer nucleic acid sequences; (iii) one or more nucleic acid binding sequences; or (iv) a nucleic acid sequence encoding a detectable portion. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Figure 1 Chimeric orthopoxvirus isolates #33 (SEQ ID NO: 1) and #17 showed superior cancer cell killing ability compared to the parental individual wild-type virus strains and the control viruses GLV-1h68 and OncoVEX GFP.
[0020] Figure 2 The chimeric parapoxvirus isolate #189 (SEQ ID NO: 2) showed superior cancer cell killing ability compared to the parental individual wild-type virus strain and the control viruses GLV-1h68 and OncoVEX GFP.
[0021] Figure 3 Chimeric orthopoxvirus isolates #17 and #33 (SEQ ID NO: 1) showed potent cancer cell killing ability in pancreatic cancer cell lines compared to their parental strains and control viruses GLV-1h68 and OncoVEX GFP.
[0022] Figure 4 Chimeric parapoxvirus isolate #189 (SEQ ID NO: 2) showed potent cancer cell killing ability in pancreatic cancer cell lines compared to its parental strain as well as control viruses GLV-1h68 and OncoVEX GFP.
[0023] FIG5. Chimeric virus isolates #33 (SEQ ID NO: 1) and #189 (SEQ ID NO: 2) exhibit excellent cytotoxic activity in gastric cancer cell lines. Cancer cells were infected with each virus at MOIs of 0.01, 0.1, and 1.0. Cell viability 96 hours post-infection is plotted against MOI in MKN-45 (A), OCUM-2M (B), and KATO-3 (C) gastric cell lines.
[0024] Figure 6CD19 expression by MDA-MB-468 parental and CD19t lines as determined by flow cytometry.
[0025] Figure 7 Schematic diagram of the CD19 CAR used in the studies described herein.
[0026] Figure 8 .Truncated EGFR expression, which indicates the presence of CD19 CAR, as determined by flow cytometry.
[0027] Figure 9 MDA-MB-468 tumors, mock or co-cultures of CD19 CAR T cells and 33-CD19t virus were stained and analyzed by flow cytometry to determine CD19t expression on target cells. Top panel: without CD19 CAR T cell treatment. Bottom panel: with CD19 CAR T cell treatment.
[0028] Figure 10 Supernatants collected from a 48-hour long-term killing assay with 33-CD19t virus were assayed for T cell production of IL-2 (bottom) and IFN-γ (top) by enzyme-linked immunosorbent assay (ELISA).
[0029] Figure 11 . Cell culture images (10X) of 24, 48, and 72 hour tumor killing assays comparing mock versus CAR T cell treatment following virus treatment.
[0030] Figure 12. Long-term killing assay of MDA-MB-468 cells. Mock or CD19 CAR T cells and 33-CD19t virus were exposed to cells, and cultures were analyzed to determine CD19t expression and % tumor killing compared to virus control (left) at (A) 24 hours, (B) 48 hours, and (C) 72 hours.
[0031] Figure 13. Oncolytic viruses can effectively deliver CD19t to solid tumors and activate CD19-CAR T cells in vitro. (A) Schematic diagram of vaccinia oncolytic virus [CF33-(SE)hCD19t] showing the incorporation of a synthetic early promoter (P SE) under the control of human truncated CD19 (CD19t), inserted into the J2R locus, replacing the thymidine kinase gene. (B) Immunofluorescence microscopy of MDA-MB-468 cells infected with OV19t at an MOI of 0.025 (left) and an MOI of 1 (center) for 24 hours or cells transduced with lentivirus to stably express CD19t (right). Images are at 10x magnification, and insets are at 40x magnification. (C) FACS plots showing cell surface expression of CD19t and intracellular expression of vaccinia virus on MDA-MB-468 tumor cells measured by flow cytometry 24 hours after infection with OV19t at increasing MOIs. (D) Quantification of CD19t (left), vaccinia (center), and viability (right) of MDA-MB-468 tumor cells after co-culture with the indicated MOIs of OV19t for 24, 48, and 72 hours. (E) Quantification of CD25 (left) and CD137 (right) expression on mock (untransduced) or CD19-CAR T cells after coculture with tumor cells at an effector:tumor (E:T) ratio of 1:2 for 24 hours with or without treatment with OV19t at the indicated MOI.
[0032] Figure 14. OV19t oncolytic virus can force CD19t expression in tumor cells, which redirects CD19-CAR T cell activation and cytotoxicity in vitro. (A) Representative flow cytometry analysis showing CD8 T cells expressed in MDA-MB-468 tumor cells at a 1:1 E:T ratio after 16 hours of coculture with or without treatment with OV19t at the indicated MOI. + CAR + Cell surface CD107a (left) and intracellular IFNγ expression (right) in T cells. (B) IFNγ production measured by ELISA in supernatants collected from co-cultures with or without OV19t treatment at the specified MOI for 24, 48, and 72 hours. (C) Tumor killing assay assessed by flow cytometry, comparing mocks or CD19-CAR T cells after 24, 48, or 72 hours of co-culture with MDA-MB-468 tumor cells treated with OV19t at the specified MOI. (D) Expression of CD19t on tumor cells in the killing assay in c). (E) Viral titers in supernatants collected from co-cultures of T cells and tumor cells treated with OV19t at the specified MOI.
[0033] Figure 15. Antitumor efficacy of combined therapy of OV19t and CD19-CAR T cells in TNBC xenograft model. (A) MDA-MB-468 tumors (5x10 6 cells), and 0, 10 5 , 106 or 10 7 Plaque forming units (pfu) were used for intratumoral treatment and harvested on day 3 (left), 7 (center), or 10 (right) after treatment to quantify CD19t expression by flow cytometry. (+) represents MDA-MB-468 tumors previously transduced with lentiviral vectors to stably express CD19t. (B) MDA-MB-468 tumors bearing subcutaneous (5x10 6 cells) tumors and were treated with OV19t (10 7 Tumor volume (mm) in NSG mice treated with pfu 3 On day 46, mice were treated with mock or CD19-CAR T cells (5x10 6 (C) Mean tumor volume at day 73 of the in vivo experiment described in (B). (D) Schematic diagram of the combination therapy concept using OV to introduce CAR targets into refractory solid tumors. Detailed Description of the Invention
[0035] Described herein are recombinant oncolytic viruses expressing all or part of human CD19. These viruses can be derived from oncolytic chimeric poxvirus compositions or other oncolytic viruses. Suitable recombinant oncolytic viruses can be created by inserting an expression cassette comprising a sequence encoding human CD19 or a portion thereof into a chimeric virus or other oncolytic virus described in PCT / US2017 / 46163, filed August 9, 2017, incorporated herein by reference.
[0036] The term "recombinant" when used in reference to, for example, a cell, nucleic acid, protein or vector, means that the cell, nucleic acid, protein or vector has been modified by the introduction of a heterologous nucleic acid or protein or an alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified.
[0037] The terms "virus" or "virion" are used according to their ordinary meaning within virology and refer to a virion that includes the viral genome (e.g., DNA, RNA, single-stranded, double-stranded), the viral capsid and associated proteins, and in the case of enveloped viruses (e.g., herpes viruses, pox viruses), an envelope comprising lipids and optionally components of the host cell membrane and / or viral proteins.
[0038] The term "poxvirus" is used in accordance with the common sense within virology and refers to a member of the Poxviridae family that is capable of infecting vertebrates and invertebrates and replicating in the cytoplasm of its host cell. In an embodiment, the poxvirus virion has a size of about 200 nm in diameter and about 300 nm in length and has a genome in a single, linear, double-stranded segment of DNA, typically 130-375 kilobases. The term poxvirus includes, but is not limited to, all genera of the Poxviridae family (e.g., betaentomopoxvirus, yatapoxvirus, cervidpox, gammaentomopoxvirus, leporipoxvirus, suipoxvirus, molluscipoxvirus, crocodylidpoxvirus, alphaentomopoxvirus, capripoxvirus, orthopoxvirus, avipoxvirus, and parapoxvirus). In embodiments, the poxvirus is an orthopoxvirus (e.g., smallpox virus, vaccinia virus, cowpox virus, monkeypox virus), a parapoxvirus (e.g., capripox virus, pseudocowpox virus, bovine epidemic stomatitis virus), a yatapoxvirus (e.g., tanapox virus, Yaba monkey tumor virus), or a molluscumpoxvirus (e.g., molluscum contagiosum virus). In embodiments, the poxvirus is an orthopoxvirus (e.g., cowpox virus strain Brighton, raccoonpox virus strain Herman, rabbitpox virus strain Utrecht, vaccinia virus strain WR, vaccinia virus strain IHD, vaccinia virus strain Elstree, vaccinia virus strain CL, vaccinia virus strain Lederle-Chorioallantoic, or vaccinia virus strain AS). In embodiments, the poxvirus is a parapoxvirus (e.g., capripox virus strain NZ2 or pseudocowpox virus strain TJS).
[0039] The term "chimeric" as used in the context of chimeric poxviruses is used according to its ordinary meaning in virology and refers to a hybrid microorganism (e.g., a chimeric poxvirus) created by connecting nucleic acid fragments from two or more different microorganisms (e.g., two viruses from the same subfamily, two viruses from different subfamilies). In an embodiment, each of at least two of the nucleic acid fragments comprises an essential gene necessary for replication. The chimeric poxviruses provided herein (including embodiments thereof) may include one or more transgenes (i.e., non-natural nucleic acid sequences of the viral genome). For example, the chimeric poxviruses provided herein (including embodiments thereof) may include anti-cancer nucleic acid sequences, nucleic acid binding sequences, nucleic acid sequences encoding a detectable portion, or any combination thereof. In an embodiment, the chimeric poxvirus includes a nucleic acid sequence comprising an anti-cancer nucleic acid sequence, a nucleic acid binding sequence, and a nucleic acid sequence encoding a detectable portion. In an embodiment, the chimeric poxvirus includes a nucleic acid sequence comprising an anti-cancer nucleic acid sequence and a nucleic acid sequence encoding a detectable portion. In an embodiment, the chimeric poxvirus includes a nucleic acid sequence comprising a nucleic acid binding sequence and a nucleic acid sequence encoding a detectable portion. In an embodiment, the chimeric poxvirus includes a nucleic acid sequence comprising an anti-cancer nucleic acid sequence and a nucleic acid binding sequence.
[0040] The term "vaccinia virus strain Brighton" is used according to its common ordinary meaning and refers to virus strains with the same or similar names and functional fragments and homologs thereof. The term includes recombinant or naturally occurring forms of vaccinia virus strain Brighton or a variant thereof that maintains vaccinia virus strain Brighton activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%). The term includes recombinant or naturally occurring forms of vaccinia virus strain Brighton or a variant thereof whose genome has sequence identity (e.g., about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identity) to the vaccinia virus strain Brighton genome. Vaccinia virus strain Brighton can refer to a variant having a mutated amino acid residue that modulates (e.g., increases or decreases when compared to vaccinia virus strain Brighton) vaccinia virus strain Brighton activity, expression, cell targeting or infectivity. Vaccinia virus strain Brighton can be modified as described herein. In the embodiment, the vaccinia virus strain Brighton is referred to by ATCC (American Type Culture Collection) reference number ATCC VR-302 TM Identified viral strain, variant or homolog thereof.
[0041] The term "raccoon poxvirus strain Herman" is used according to its common ordinary meaning and refers to virus strains of the same or similar name and functional fragments and homologs thereof. The term includes recombinant or naturally occurring forms of raccoon poxvirus strain Herman or variants thereof that maintain raccoon poxvirus strain Herman activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%). The term includes recombinant or naturally occurring forms of raccoon poxvirus strain Herman or variants thereof whose genome has sequence identity (e.g., about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identity) to the raccoon poxvirus strain Herman genome. Raccoon poxvirus strain Herman can refer to a variant having a mutated amino acid residue that modulates (e.g., increases or decreases when compared to raccoon poxvirus strain Herman) raccoon poxvirus strain Herman activity, expression, cellular targeting or infectivity. The raccoon poxvirus strain Herman can be modified as described herein. In embodiments, the raccoon poxvirus strain Herman is referred to by ATCC reference number ATCC VR-838 TM Identified viral strain, variant or homolog thereof.
[0042] The term "rabbitpoxvirus strain Utrecht" is used according to its common ordinary meaning and refers to virus strains with the same or similar names and their functional fragments and homologs. The term includes recombinant or naturally occurring forms of rabbitpoxvirus strain Utrecht or variants thereof that maintain rabbitpoxvirus strain Utrecht activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%). The term includes recombinant or naturally occurring forms of rabbitpoxvirus strain Utrecht or variants thereof whose genome has sequence identity (e.g., about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100%) to the rabbitpoxvirus strain Utrecht genome. Rabbitpoxvirus strain Utrecht may refer to a variant having a mutated amino acid residue that modulates (e.g., increases or decreases when compared to rabbitpoxvirus strain Utrecht) rabbitpoxvirus strain Utrecht activity, expression, cell targeting or infectivity. Rabbitpoxvirus strain Utrecht may be modified as described herein. In the embodiment, the rabbitpox virus strain Utrecht is referred to by ATCC reference number ATCC VR-1591 TM Identified viral strain, variant or homolog thereof.
[0043] The term "vaccinia virus strain WR" is used according to its common ordinary meaning and refers to a virus strain of the same or similar name and its functional fragments and homologs. The term includes recombinant or naturally occurring forms of vaccinia virus strain WR or a variant thereof that maintains vaccinia virus strain WR activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%). The term includes recombinant or naturally occurring forms of vaccinia virus strain WR or a variant thereof whose genome has sequence identity (e.g., about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identity) to the vaccinia virus strain WR genome. Vaccinia virus strain WR can refer to a variant having a mutated amino acid residue that modulates (e.g., increases or decreases when compared to vaccinia virus strain WR) vaccinia virus strain WR activity, expression, cell targeting or infectivity. Vaccinia virus strain WR can be modified as described herein. In embodiments, vaccinia virus strain WR is referred to by ATCC reference number ATCC VR-1354 TM Identified viral strain, variant or homolog thereof.
[0044] The term "vaccinia virus IHD" is used according to its common ordinary meaning and refers to a virus strain of the same or similar name, and functional fragments and homologs thereof. The term includes recombinant or naturally occurring forms of vaccinia virus IHD or variants thereof that maintain vaccinia virus IHD activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%). The term includes recombinant or naturally occurring forms of vaccinia virus IHD or variants thereof whose genome has sequence identity (e.g., about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% identity) to a vaccinia virus IHD genome. Vaccinia virus IHD may refer to a variant having a mutated amino acid residue that modulates (e.g., increases or decreases when compared to vaccinia virus IHD) vaccinia virus IHD activity, expression, cellular targeting, or infectivity. Vaccinia virus IHD may be modified as described herein. In the embodiment, vaccinia virus strain IHD is referred to by ATCC reference number ATCC VR-156 TM Identified viral strain, variant or homolog thereof.
[0045] The term "vaccinia virus strain Elstre" is used according to its common ordinary meaning and refers to virus strains with the same or similar names and their functional fragments and homologs. The term includes recombinant or naturally occurring forms of vaccinia virus strain Elstre or variants thereof that maintain vaccinia virus strain Elstre activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%). The term includes recombinant or naturally occurring forms of vaccinia virus strain Elstre or variants thereof whose genome has sequence identity (e.g., about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identity) to the vaccinia virus strain Elstre genome. Vaccinia virus strain Elstre may refer to a variant having a mutated amino acid residue that modulates (e.g., increases or decreases when compared to vaccinia virus strain Elstre) vaccinia virus strain Elstre activity, expression, cell targeting or infectivity. Vaccinia virus strain Elstre can be modified as described herein. In the embodiment, vaccinia virus strain Elstre is referred to by ATCC reference number ATCC VR-1549 TM Identified viral strain, variant or homolog thereof.
[0046] The term "vaccinia virus strain CL" is used according to its common ordinary meaning and refers to a virus strain with the same or similar name and its functional fragments and homologs. The term includes recombinant or naturally occurring forms of vaccinia virus strain CL or a variant thereof that maintains vaccinia virus strain CL activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%). The term includes recombinant or naturally occurring forms of vaccinia virus strain CL or a variant thereof whose genome has sequence identity (e.g., about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identity) to the vaccinia virus strain CL genome. Vaccinia virus strain CL may refer to a variant having a mutated amino acid residue that modulates (e.g., increases or decreases when compared to vaccinia virus strain CL) vaccinia virus strain CL activity, expression, cell targeting or infectivity. Vaccinia virus strain CL can be modified as described herein. In embodiments, vaccinia virus strain CL is referred to by ATCC reference number ATCC VR-1774 TM Identified viral strain, variant or homolog thereof.
[0047] The term "vaccinia virus strain Lederle-Chorioallantoic" is used according to its common ordinary meaning and refers to virus strains of the same or similar name and functional fragments and homologs thereof. The term includes recombinant or naturally occurring forms of vaccinia virus strain Lederle-Chorioallantoic or variants thereof that maintain vaccinia virus strain Lederle-Chorioallantoic activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%). The term includes recombinant or naturally occurring forms of vaccinia virus strain Lederle-Chorioallantoic or variants thereof whose genome has sequence identity (e.g., about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identity) to the vaccinia virus strain Lederle-Chorioallantoic genome. Vaccinia virus strain Lederle-Chorioallantoic can refer to a variant having a mutated amino acid residue that modulates (e.g., increases or decreases when compared to vaccinia virus strain Lederle-Chorioallantoic) the activity, expression, cellular targeting, or infectivity of vaccinia virus strain Lederle-Chorioallantoic. Vaccinia virus strain Lederle-Chorioallantoic can be modified as described herein. In embodiments, vaccinia virus strain Lederle-Chorioallantoic refers to a variant of vaccinia virus strain Lederle-Chorioallantoic identified by ATCC reference number ATCC VR-118. TM Identified viral strain, variant or homolog thereof.
[0048] The term "vaccinia virus strain AS" is used according to its common ordinary meaning and refers to virus strains with the same or similar names and their functional fragments and homologs. The term includes recombinant or naturally occurring forms of vaccinia virus strain AS or variants thereof that maintain vaccinia virus strain AS activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%). The term includes recombinant or naturally occurring forms of vaccinia virus strain AS or variants thereof whose genome has sequence identity (e.g., about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identity) to the vaccinia virus strain AS genome. Vaccinia virus strain AS may refer to a variant having a mutated amino acid residue that modulates (e.g., increases or decreases when compared to vaccinia virus strain AS) vaccinia virus strain AS activity, expression, cell targeting or infectivity. Vaccinia virus strain AS may be modified as described herein. In the embodiment, vaccinia virus strain AS is referred to by ATCC reference number ATCC VR-2010 TM Identified viral strain, variant or homolog thereof.
[0049] The term "capripoxvirus strain NZ2" is used according to its common ordinary meaning and refers to a virus strain having the same or similar name and its functional fragments and homologs. The term includes recombinant or naturally occurring forms of capripoxvirus strain NZ2 or a variant thereof that maintains capripoxvirus strain NZ2 activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%). The term includes recombinant or naturally occurring forms of capripoxvirus strain NZ2 or a variant thereof whose genome has sequence identity (e.g., about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100%) to the capripoxvirus strain NZ2 genome. Capripoxvirus strain NZ2 may refer to a variant having a mutated amino acid residue that modulates (e.g., increases or decreases when compared to capripoxvirus strain NZ2) capripoxvirus strain NZ2 activity, expression, cell targeting or infectivity. Capripoxvirus strain NZ2 may be modified as described herein. In embodiments, capripox virus strain NZ2 is referred to by ATCC reference number ATCC VR-1548 TM Identified viral strain, variant or homolog thereof.
[0050] The term "pseudopoxvirus TJS" is used according to its common ordinary meaning and refers to a virus strain having the same or similar name and its functional fragments and homologs. The term includes recombinant or naturally occurring pseudopoxvirus TJS or a variant thereof that maintains pseudopoxvirus TJS activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%). The term includes recombinant or naturally occurring pseudopoxvirus TJS or a variant thereof that has a genome with sequence identity (e.g., about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100%) to the pseudopoxvirus TJS genome. Pseudopoxvirus TJS may refer to a variant having a mutated amino acid residue that modulates (e.g., increases or decreases when compared to pseudopoxvirus TJS) pseudopoxvirus TJS activity, expression, cell targeting or infectivity. Pseudopoxvirus TJS may be modified as described herein. In the embodiment, pseudopox virus strain TJS is referred to by ATCC reference number ATCC VR-634 TM Identified viral strain, variant or homolog thereof.
[0051] In an embodiment, the vaccinia virus strain Brighton is vaccinia virus strain Brighton ATCC VR-302 TM In an embodiment, the raccoon poxvirus strain Herman is raccoon poxvirus strain Herman ATCC VR-838 TM In an embodiment, the rabbitpox virus strain Utrecht is the rabbitpox virus strain Utrecht ATCC VR-1591 TM In an embodiment, the vaccinia virus strain WR is vaccinia virus strain WR ATCC VR-1354 TM In an embodiment, the vaccinia virus strain IHD is vaccinia virus strain IHD ATCC VR-156 TM In an embodiment, the vaccinia virus strain Elstree is vaccinia virus strain Elstree ATCC VR-1549 TM In an embodiment, the vaccinia virus strain CL is vaccinia virus strain CL ATCC VR-1774 TM In an embodiment, the vaccinia virus strain Lederle-Chorioaltotol is vaccinia virus strain Lederle-Chorioallantoic ATCC VR-118 TM In an embodiment, the vaccinia virus strain AS is vaccinia virus strain AS ATCC VR-2010 TM In an embodiment, the capripox virus strain NZ2 is capripox virus strain NZ2 ATCC VR-1548TM In an embodiment, the pseudovaccinia virus strain TJS is the pseudovaccinia virus strain TJS ATCC VR-634 TM .
[0052] I. Chimeric Poxvirus Compositions
[0053] In one aspect, a chimeric poxvirus expressible on the surface of a cell is provided, comprising a nucleotide sequence having at least 70% (75%, 80%, 85%, 90%, 92%, 94%, 96%, 98%, or 99%) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2 and a nucleotide sequence encoding human CD 19 or a portion thereof. In some embodiments, the sequence having at least 70% identity to SEQ ID NO: 1 or 2 comprises nucleotide sequences ("nucleic acid fragments") from at least two poxvirus strains selected from the group consisting of: cowpox virus strain Brighton, raccoonpox virus strain Herman, rabbitpox virus strain Utrecht, vaccinia virus strain WR, vaccinia virus strain IHD, vaccinia virus strain Elstree, vaccinia virus strain CL, vaccinia virus strain Lederle-Chorioallantoic, vaccinia virus strain AS, capripoxvirus strain NZ2, and pseudovaccinia virus strain TJS, e.g., a nucleotide sequence of at least 100 consecutive nucleotides.
[0054] The chimeric oncolytic poxviruses described herein include a transgene encoding a human truncated human CD19 (CD19t), which lacks a functional signaling domain but includes an extracellular domain and a transmembrane domain. The truncated human CD19 comprises the following amino acid sequence (or a sequence at least 95%, 97%, 98% or 99% identical thereto) MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEPPCVPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVTLAYLIFCLCSLVGILHLQRALVLRRKR (SEQ ID NO: C). In some cases, CD19t comprises amino acids 22-323 of SEQ ID NO: C or consists of amino acids 22-323 of SEQ ID NO: C. Amino acids 1-21 of SEQ ID NO: 3 are signaling domains and can be replaced with different signaling domains. Thus, the oncolytic virus comprises a sequence comprising a nucleotide sequence encoding a truncated human CD19 operably linked to an expression control sequence (e.g., an early promoter).
[0055] In embodiments, the nucleic acid fragment is from vaccinia virus strain Brighton, raccoon pox virus strain Herman, rabbit pox virus strain Utrecht, vaccinia virus strain WR, vaccinia virus strain IHD, vaccinia virus strain Elstree, vaccinia virus strain CL, vaccinia virus strain Lederle-Chorioallantoic, and vaccinia virus strain AS.
[0056] In embodiments, the nucleic acid sequence comprises a nucleic acid segment from the vaccinia virus strain Brighton and the raccoon pox virus strain Herman. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from the vaccinia virus strain Brighton and the rabbitpox virus strain Utrecht. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from the vaccinia virus strain Brighton and the vaccinia virus strain WR. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from the vaccinia virus strain Brighton and the vaccinia virus strain IHD. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from the vaccinia virus strain Brighton and the vaccinia virus strain Elstree. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from the vaccinia virus strain Brighton and the vaccinia virus strain CL. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from the vaccinia virus strain Brighton and the vaccinia virus strain Lederle-Chorioallantoic. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from the vaccinia virus strain Brighton and the vaccinia virus strain AS. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from the vaccinia virus strain Brighton and the capripox virus strain NZ2. In an embodiment, the nucleic acid sequence includes nucleic acid segments from the vaccinia virus strain Brighton and the pseudovaccinia virus strain TJS.
[0057] In embodiments, the nucleic acid sequence comprises a nucleic acid fragment from the rabbitpox virus strain Utrecht and the vaccinia virus strain WR. In embodiments, the nucleic acid sequence comprises a nucleic acid fragment from the rabbitpox virus strain Utrecht and the vaccinia virus strain IHD. In embodiments, the nucleic acid sequence comprises a nucleic acid fragment from the rabbitpox virus strain Utrecht and the vaccinia virus strain Elstree. In embodiments, the nucleic acid sequence comprises a nucleic acid fragment from the rabbitpox virus strain Utrecht and the vaccinia virus strain CL. In embodiments, the nucleic acid sequence comprises a nucleic acid fragment from the rabbitpox virus strain Utrecht and the cowpox virus strain Lederle-Chorioallantoic. In embodiments, the nucleic acid sequence comprises a nucleic acid fragment from the rabbitpox virus strain Utrecht and the vaccinia virus strain AS. In embodiments, the nucleic acid sequence comprises a nucleic acid fragment from the rabbitpox virus strain Utrecht and the sheeppox virus strain NZ2. In embodiments, the nucleic acid sequence comprises a nucleic acid fragment from the rabbitpox virus strain Utrecht and the pseudocowpox virus strain TJS.
[0058] In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain WR and vaccinia virus strain IHD. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain WR and vaccinia virus strain Elstree. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain WR and vaccinia virus strain CL. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain WR and vaccinia virus strain Lederle-Chorioaltototolic. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain WR and vaccinia virus strain AS. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain WR and capripox virus strain NZ2. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain WR and pseudovaccinia virus strain TJS.
[0059] In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain IHD and vaccinia virus strain Elstree. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain IHD and vaccinia virus strain CL. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain IHD and vaccinia virus strain Lederle-Chorioaltototolic. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain IHD and vaccinia virus strain AS. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain IHD and capripox virus strain NZ2. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain IHD and pseudovaccinia virus strain TJS.
[0060] In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain Elstree and vaccinia virus strain CL. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain Elstree and vaccinia virus strain Lederle-Chorioallantoic. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain Elstree and vaccinia virus strain AS. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain Elstree and capripox virus strain NZ2. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain Elstree and pseudovaccinia virus strain TJS.
[0061] In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain CL and vaccinia virus strain Lederle-Chorioallantoic. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain CL and vaccinia virus strain AS. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain CL and capripox virus strain NZ2. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain CL and pseudovaccinia virus strain TJS.
[0062] In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain Lederle-Chorioallantoic and vaccinia virus strain AS. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain Lederle-Chorioallantoic and capripox virus strain NZ2. In embodiments, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain Lederle-Chorioallantoic and pseudovaccinia virus strain TJS.
[0063] In an embodiment, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain AS and capripox virus strain NZ2. In an embodiment, the nucleic acid sequence comprises a nucleic acid segment from vaccinia virus strain AS and pseudovaccinia virus strain TJS. In an embodiment, the nucleic acid sequence comprises a nucleic acid segment from capripox virus strain NZ2 and pseudovaccinia virus strain TJS.
[0064] II. Chimeric Antigen Receptor (CAR) Targeting CD19
[0065] A variety of CD19 CARs have been described and can be used, including those described in US 7,446,179 and Park et al. 2016 Blood 128: 4035. CD19 CARs can include scFvs that bind to CD19, such as FMC63 (Zola et al. 1991 Immunol Cell Biol 69: 411) or SJ25C1 (Bejcek et al. 1995 Cancer Research 55: 2346), both of which are commercially available.
[0066] This text describes nucleic acid molecules encoding a CAR, the CAR comprising: a scFv targeting CD19 (e.g., Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr ValSer Ser (SEQ ID NO: D) or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions); a transmembrane domain selected from the group consisting of: a CD4 transmembrane domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions), a CD8 transmembrane domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions), a CD28 transmembrane domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions), and a CD3ζ transmembrane domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions); a costimulatory domain (e.g., a CD28 costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions); or 4-1L BB costimulatory domain, or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions); or both the CD28 costimulatory domain, or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions) and the 4-1 BB costimulatory domain, or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions); and the CD3ζ signaling domain, or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications.
[0067] In various embodiments: the costimulatory domain is selected from the group consisting of a CD28 costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications, a 4-1BB costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications, and an OX40 costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications. In certain embodiments, a 4-1BB costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications is present. In some embodiments, there are two costimulatory domains, e.g., a CD28 costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions) and a 4-1BB costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions). In various embodiments, 1-5 (e.g., 1 or 2) amino acid modifications are substitutions.
[0068] In some cases, a short sequence of 1-6 amino acids (eg, GGG) is present between the costimulatory domain and the CD3ζ signaling domain and / or between the two costimulatory domains.
[0069] Additional embodiments of the CAR include: a scFv targeting CD19; and two different costimulatory domains selected from the group consisting of a CD28 costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications, a 4-1 BB costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications, and an OX40 costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications; two different costimulatory domains selected from the group consisting of a CD28 costimulatory domain or a variant thereof having 1-2 amino acid modifications, a 4-1 BB costimulatory domain or a variant thereof having 1-2 amino acid modifications, and an OX40 costimulatory domain or a variant thereof having 1-2 amino acid modifications; CD19 scFv or a variant thereof having 1-2 amino acid modifications; a transmembrane domain selected from the group consisting of: a CD4 transmembrane domain or a variant thereof having 1-2 amino acid modifications, a CD8 transmembrane domain or a variant thereof having 1-2 amino acid modifications, a CD28 transmembrane domain or a variant thereof having 1-2 amino acid modifications, and a CD3ζ transmembrane domain or a variant thereof having 1-2 amino acid modifications; a costimulatory domain (e.g., a CD28 costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions); or a 4-1L BB costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions); or both a CD28 costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions) and a 4-1 BB costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions); and a CD3ζ signaling domain or a variant thereof having 1-2 amino acid modifications; located on a CD19 A spacer between the scFv or variant thereof and the transmembrane domain (e.g., a spacer comprising an amino acid sequence selected from SEQ ID NOs: 2-12 and 42 (Table 3) or variants thereof having 1-5 (e.g., 1 or 2) amino acid modifications); a spacer comprising an IgG hinge region; a spacer comprising 1-150 amino acids; no spacer; a 4-1 BB signaling domain comprising the amino acid sequence of SEQ ID NO: 24, a CD3 ζ signaling domain comprising the amino acid sequence of SEQ ID NO: 21, and a linker of 3 to 15 amino acids positioned between the costimulatory domain and the CD3 ζ signaling domain or variant thereof. In certain embodiments in which two costimulatory domains are present, one is a 4-1 L BB costimulatory domain and the other is a costimulatory domain selected from CD28 and CD28gg. In various embodiments, 1-5 (e.g., 1 or 2) amino acid modifications are substitutions, e.g., conservative substitutions.
[0070] Also disclosed are a population of human T cells transduced by a vector comprising an expression cassette encoding a chimeric antigen receptor, wherein the chimeric antigen receptor comprises: a scFv targeting CD19; a transmembrane domain selected from the group consisting of a CD4 transmembrane domain or a variant thereof having 1-5 amino acid modifications (e.g., 1 or 2) amino acid modifications (e.g., substitutions), a CD8 transmembrane domain or a variant thereof having 1-5 amino acid modifications (e.g., 1 or 2) amino acid modifications (e.g., substitutions), a CD28 transmembrane domain or a variant thereof having 1-5 amino acid modifications (e.g., 1 or 2) amino acid modifications (e.g., substitutions), and a CD3ζ transmembrane domain or a variant thereof having 1-5 amino acid modifications (e.g., 1 or 2) amino acid modifications (e.g., substitutions); a costimulatory domain (e.g., a CD28 costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions); or a 4-1L BB costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions); or a CD28 costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions) and a 4-lBB costimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions); and a CD3ζ signaling domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions). In various embodiments, the human T cell population includes central memory T cells (TCM cells), for example, at least 20%, 30%, 40%, 50% 60%, 70%, 80% of the cells are TCM cells, or the T cell population includes central memory T cells, naive T cells, and stem central memory cells (T CM / SCM / N cells), such as at least 20%, 30%, 40%, 50%, 60%, 70%, 80% of the cells are T CM / SCM / N In either case, the T cell population includes both CD4+ cells and CD8+ cells (e.g., at least 20% of CD3+ T cells are CD4+, and at least 3% of CD3+ T cells are CD8+, and at least 70, 80, or 90% are CD4+ or CD8+; at least 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60% of cells are CD3+ cells, and at least 4%, 5%, 8%, 10%, 20% of CD3+ cells are CD8+ cells).
[0071] Also described is a method of treating cancer in a patient comprising administering a population of autologous or allogeneic human T cells (e.g., autologous or allogeneic T cells comprising central memory T cells (TCM cells) or a combination of central memory T cells, naive T cells, and stem central memory cells (i.e., T cells that are TCM / SCM / N cells), at least 20%, 30%, 40%, 50%, 60%, 70%, 80% of the cells are TCM / SCM / N cells. In either case, the T cell population comprises a TCM / SCM / N cell comprising a chimeric antibody encoding a chimeric antibody. A vector containing an expression cassette for the primary receptor transduces both CD4+ cells and CD8+ cells (e.g., at least 20% of the CD3+ T cells are CD4+, and at least 3% of the CD3+ T cells are CD8+, and at least 70%, 80% or 90% are CD4+ or CD8+; at least 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60% of the CD3+ cells are CD4+, and at least 4%, 5%, 8%, 10%, 20% of the CD3+ cells are CD8+ cells).
[0072] CD19 CAR may include a spacer between a CD19 binding domain (e.g., CD19 scFv) and a transmembrane domain. A variety of different spacers can be used. Some of them include at least a portion of a human Fc region, such as a hinge portion or CH3 domains or variants thereof in a human Fc region. Table 1 below provides various spacers that can be used in CAR as described herein.
[0073] Table 1: Examples of spacers
[0074]
[0075]
[0076] Some spacers include all or part of an immunoglobulin (e.g., IgG1, IgG2, IgG3, IgG4) hinge region, i.e., a sequence falling between the CH1 and CH2 domains of an immunoglobulin, such as an IgG4 Fc hinge or a CD8 hinge. Some spacers include an immunoglobulin CH3 domain or both a CH3 domain and a CH2 domain. The immunoglobulin-derived sequence may include one or more amino acid modifications, such as 1, 2, 3, 4, or 5 substitutions, for example, substitutions that reduce off-target binding.
[0077] "Amino acid modification" refers to amino acid replacement, insertion and / or deletion in a protein or peptide sequence. "Amino acid replacement" or "substitution" refers to the replacement of an amino acid at a specific position in a parent peptide or protein sequence with another amino acid. Substitution can be performed to change the amino acid in the resulting protein in a non-conservative manner (i.e., by changing a codon from an amino acid grouping with a specific size or characteristic to an amino acid belonging to another grouping) or in a conservative manner (i.e., by changing a codon from an amino acid grouping with a specific size or characteristic to an amino acid belonging to the same grouping). Such conservative changes typically result in fewer changes in the structure and function of the resulting protein. The following are examples of various amino acid groupings: 1) amino acids with non-polar R groups: alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine; 2) amino acids with uncharged polar R groups: glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine; 3) amino acids with charged polar R groups (negatively charged at pH 6.0): aspartic acid, glutamic acid; 4) basic amino acids (positively charged at pH 6.0): lysine, arginine, histidine (at pH 6.0). Another grouping would be those amino acids with a phenyl group: phenylalanine, tryptophan, and tyrosine.
[0078] For amino acid positions in immunoglobulins discussed herein, numbering is according to the EU index or EU numbering scheme (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., United States Public Health Service, National Institutes of Health, Bethesda, hereby incorporated by reference in its entirety). The EU index or EU index or EU numbering scheme as in Kabat refers to the EU numbering of antibodies (Edelman et al., 1969 Proc Natl Acad Sci USA 63:78-85).
[0079] A variety of transmembrane domains can be used. Table 2 includes examples of suitable transmembrane domains. Where a spacer domain is present, the transmembrane domain is located at the carboxyl terminus of the spacer domain.
[0080] Table 2: Examples of transmembrane domains
[0081]
[0082] Many CARs described herein include one or more (e.g., two) costimulatory domains. The costimulatory domain is located between the transmembrane domain and the CD3ξ signaling domain. Table 3 includes examples of suitable costimulatory domains and sequences of CD3ξ signaling domains.
[0083] Table 3: Examples of CD3 zeta domains and co-stimulatory domains
[0084] Example
[0085] Example 1. New potent chimeric poxviruses for oncolytic immunotherapy of cancer
[0086] Oncolytic chimeric poxviruses are described below and can be used to prepare recombinant chimeric poxviruses that express human CD19 in cells infected with the recombinant virus. Because the recombinant virus infects cancer cells and causes them to express CD19, the infected cells can be targeted by a CAR targeting CD19.
[0087] Chimeric poxviruses used to create recombinant poxviruses have the potential to combine advantageous features from different virus species and, therefore, be superior to wild-type viruses alone. Because orthopoxviruses and parapoxviruses are antigenically distinct, the potent chimeric orthopoxviruses and potent chimeric parapoxviruses generated in this study can potentially be combined into the same treatment regimen to achieve maximum therapeutic efficacy. As explained in more detail in PCT / US2017 / 46163, filed August 9, 2017, chimeric poxviruses, including isolates #33 (SEQ ID NO: 1) and #189 (SEQ ID NO: 2), were generated from a pool of chimeric orthopoxviruses and chimeric parapoxviruses. Several chimeric orthopoxvirus and parapoxvirus isolates, including isolates #33 and #189, demonstrated superior killing ability to their parental wild-type viruses alone on the NCI 60 panel of cancer cell lines.
[0088] Generation of chimeric virus pools and isolation of individual chimeric viruses.
[0089] Pools of chimeric orthopoxviruses were generated by co-infecting CV-1 cells with vaccinia virus strain Brighton, raccoonpox virus strain Herman, rabbitpox virus strain Utrecht, and vaccinia virus strains WR, IHD, Elstree, CL, Lederle-Chorioaltotoic, and AS at a multiplicity of infection (MOI) of 0.01 for each virus. To generate pools of chimeric parapoxviruses, MDBK cells were co-infected with capripox virus strain NZ2 and pseudovaccinia virus strain TJS at an MOI of 0.1. Pilot experiments by the applicant indicated that CV-1 cells were susceptible to all orthopoxviruses used in this study, and both capripox virus and pseudovaccinia virus infected and formed plaques in MDBK cells.
[0090] 100 chimeric orthopoxvirus plaques and 100 chimeric parapoxvirus plaques were selected from CV-1 cells infected with the chimeric orthopoxvirus pool and MDBK cells infected with the chimeric parapoxvirus pool, respectively. These 200 plaques were plaque purified twice more in the corresponding cells to generate 200 clonally purified individual chimeric virus isolates. Virus #14-113 is a chimeric orthopoxvirus isolate, while virus #114-213 is a chimeric parapoxvirus isolate.
[0091] New and powerful chimeric poxvirus isolates were identified by high-throughput screening in NCI-60 cell lines. The tumor cell killing activity of 200 chimeric orthopoxviruses and chimeric parapoxvirus isolates, as well as 11 parental virus strains and 2 control oncolytic viruses (GLV-1h68 and OncoVEX GFP) was evaluated and compared in a group of NCI-60 cell lines (Table 4). GLV-1h68 is one of the best-studied oncolytic vaccinia viruses and is currently in clinical development. OncoVEX GFP has the same backbone as T-VEC, which is an oncolytic herpes simplex virus-1 and the first oncolytic virus approved by the FDA. Each cell line was infected with each virus at an MOI of 0.01. Cell viability was measured 96 hours after infection using the MTS assay. The amount of virus used in this high-throughput screening experiment (MOI 0.01) was intentionally kept low and optimized to compare cell killing in adherent cell lines (most cell lines in the NCI-60 panel are adherent cells) so that potent new virus isolates could stand out. However, this amount of virus was too low to see any significant and consistent cell killing in suspension cell lines. Therefore, for the purpose of virus comparison, results from six leukemia cell lines were not included in the analysis.
[0092] Table 4. List of NCI-60 cell lines
[0093]
[0094]
[0095] Among the 100 new chimeric OPV isolates, isolates #17 (SEQ ID NO: 3) and #33 (SEQ ID NO: 1) demonstrated significantly better cell killing in the NCI-60 solid tumor cell line than the nine parental OPV strains and two control viruses ( Figure 1 Among the 100 new parapoxvirus isolates, isolate 189 (SEQ ID NO: 2) stood out, showing significantly better cell killing than the two parental parapoxvirus strains and the control virus ( Figure 2 The three new chimeric virus isolates (#17, #33, and #189) caused significant cell death in most NCI-60 solid cancer cell lines even at an MOI of 0.01. In general, at a low MOI of 0.01, orthopoxviruses and chimeric orthopoxviruses killed cancer cells more potently than parapoxviruses and chimeric parapoxvirus isolates.
[0096] The genomic DNA of the new poxvirus isolates #33 and #189 was isolated from the purified virions and subjected to next generation sequencing using an Illumina Hiseq 2500 with a coverage of more than 1000 times. The gaps were PCR amplified and sequenced by Sanger sequencing. 189,415 base pairs (bps) of the #33 genome were completely sequenced, while 138,203bps of the 189 genome were obtained. Initial BLAST to GenBank indicated that the genomic sequences of both #33 and #189 were not identical to any genomic sequence in GenBank. Compared to any other orthopoxvirus, #33 is closer to the vaccinia virus strain. #189 is very close to the capripoxvirus NZ2 strain, one of the parental parapoxviruses. The nucleotide sequences of all ORFs identified in the capripoxvirus NZ2 strain were identical to those of all ORFs in #189. Compared to the capripoxvirus NZ2, there is a "G" insertion at position 6755 in the #189 genome. In the inverted terminal repeat region, there is one copy of the repetitive element that is deleted in the #189 genome and one copy of another repetitive element that is inserted. Overall, both #33 and #189 represent new and unique poxvirus isolates.
[0097] All cancer cell lines were cultured in RPMI-1640 (Mediatech, Manassas, VA). African green monkey kidney fibroblasts (CV-1) and bovine kidney epithelial cells (MDBK) were obtained from the American Type Culture Collection (ATCC; Rockville, MD, USA) and cultured in Dulbecco's Modified Eagle's Medium (DMEM) (Mediatech, Manassas, VA). All culture media were supplemented with 10% FBS (Mediatech, Manassas, VA) and 1% penicillin-streptomycin solution (Mediatech, Manassas, VA). Cells were cultured at 37°C, 5% CO2.
[0098] Viruses: Cowpox virus (Brighton), raccoonpox virus (Herman), rabbitpox virus (Utrecht), vaccinia virus (WR, IHD, Elstree, CL, Lederle-Chorioallantoic, and AS), capripox virus (NZ2), and pseudovaccinia virus (TJS) were purchased from ATCC. All orthopoxvirus strains were grown and titered in CV-1 cells, and parapoxvirus strains were grown and titered in MDBK cells.
[0099] Generation of Chimeric Orthopoxvirus and Chimeric Parapoxvirus Pools and Isolation of Individual Clonal Chimeric Virus Isolates: Chimeric orthopoxvirus pools were generated by co-infecting CV-1 cells with vaccinia virus strain Brighton, raccoon pox virus strain Herman, rabbit pox virus strain Utrecht, and vaccinia virus strains WR, IHD, Elstree, CL, Lederle-Chorioaltototolic, and AS at a multiplicity of infection (MOI) of 0.01 for each virus. To generate chimeric parapoxvirus pools, MDBK cells were co-infected with capripox virus strain NZ2 and pseudovaccinia virus strain TJS at an MOI of 0.1. Infected cells were harvested 3 days after infection. The initial chimeric orthopoxvirus pool was further passaged 3 times in CV-1 cells at an MOI of 0.1, and the initial chimeric parapoxvirus pool was further passaged 3 times in MDBK cells at an MOI of 0.1. 100 chimeric orthopoxvirus plaques and 100 chimeric parapoxvirus plaques were selected from CV-1 cells infected with the final chimeric orthopoxvirus pool and MDBK cells infected with the final chimeric parapoxvirus pool, respectively. These 200 plaques were further plaque purified twice in the corresponding cells to generate 200 clonally purified individual chimeric virus isolates.
[0100] NCI-60 cancer cell lines and a panel of pancreatic cancer cell lines, including PANC-1, MIA-PaCa2, BxPC3, FG, Capan-2, and Su.86.86, were distributed into 96-well plates (3000 cells / well for solid tumor cell lines and 5000 / well for leukemia cell lines) using an epMotion 5075 liquid handler (Eppendorf) under sterile conditions and incubated overnight at 37°C under 5% (v / v) CO2. Cells were then infected with 200 chimeric orthopoxvirus and chimeric parapoxvirus isolates, as well as 11 parental virus strains and 2 control oncolytic viruses GLV-1h68 and OncoVEX GFP at an MOI of 0.01. Cell viability was determined 96 hours after infection using the MTS assay (Promega). The absorbance at 490 nm was measured using an automatic BMG PHERAstar plate reader (BMG Labtech). Each experiment was performed in duplicate. The cell viability of mock-infected cells was set as 100%.
[0101] MKN-45, OCUM-2M, and KATO-3 cells were seeded into 96-well plates at a concentration of 3,000 cells per well and incubated overnight at 37°C under 5% (v / v) CO2. Cells were infected with #33, #189, GLV-1h68, and OncoVEX GFP at MOIs of 0.01, 0.1, and 1, respectively. Cell viability was monitored daily for 4 days at 37°C under 5% (v / v) CO2 using the MTS assay.
[0102] Genomic DNA of #33 and #189 was extracted from purified virions using the Wizard genomic DNA purification kit (Promega) and disrupted by sonication. Libraries were prepared using the KAPA LTP library preparation kit. Sequencing was performed using an Illumina HiSeq 2500.
[0103] Example 2. High-throughput screening in pancreatic cancer cell lines
[0104] The NCI-60 cancer cell line contains only solid cancers from 8 different organs (see Table 4). In order to investigate whether the results from the NCI-60 cancer cell line will be reproduced in solid cancers from other organs. Six pancreatic cancer cell lines (BxPC3, FG, MIA PaCa-2, Capan-2, PANC-1 and SU.86.86) were infected with the same virus used for high throughput screening in the NCI-60 cancer cell line at an MOI of 0.1. Cell viability was again measured using the MTS assay 96 hours after infection. Chimeric orthopoxvirus isolates #17 and #33 showed the best cell killing among all chimeric orthopoxvirus isolates, while chimeric parapoxvirus isolate #189 showed the best cell killing among all chimeric parapoxvirus isolates. As shown in Table 5 and Figure 3 and Figure 4 As shown in Figure 3, they were better than their respective parental virus strains and the control viruses GLV-1h68 and OncoVEXGFP in killing pancreatic cancer cell lines. Thus, the results from the NCI-60 cancer cell lines were reproduced very well in a panel of pancreatic cancer cell lines.
[0105] Table 5. Survival of pancreatic cancer cells.
[0106]
[0107]
[0108] Example 3. Novel chimeric orthopoxvirus isolate 33 and chimeric parapoxvirus isolate #189 show potent cell killing in gastric cancer cell lines.
[0109] Based on the results of high-throughput screening of NCI-60 cancer cell lines and a panel of pancreatic cancer cell lines, the new chimeric orthopoxvirus isolate #33 and chimeric parapoxvirus isolate #189 were selected for further characterization. The tumor cell killing activity of isolates #33 and #189 was further studied in three gastric cancer cell lines. MKN-45, OCUM-2M, and KATO-3 cells were infected with #33, #189, GLV-1h68, and OncoVEX GFP at MOIs of 0.01, 0.1, and 1. Cell viability was monitored daily for 4 days using the MTS assay. MKN-45 and OCUM-2M cell lines were most sensitive to #33, moderately sensitive to OncoVEX GFP, and least sensitive to GLV-1h68. KATO-3 cells were most sensitive to OncoVEX GFP at a low MOI of 0.01, while #33, #189, and OncoVEX GFP killed KATO-3 cells equally well at higher MOIs (0.1 and 1). KATO-3 cells were least sensitive to GLV-1h68. Overall, #33 was the most effective at killing gastric cancer cell lines, while GLV-1h68 was the least effective at killing gastric cancer cell lines ( Figures 5A-5C ).
[0110] As reported in Table 6, the 90 genes present in all sequenced ChPVs and their functions (when known) are listed (abbreviations: IMV, intracellular mature virus; IEV, intracellular enveloped virus; EEV, extracellular enveloped virus). Genes are named after their VACV-COP counterparts. Asterisks * indicate genes that are also present in both EnPVs. Table 3 is adapted from Gubser et al. (Gubser, C., Hue, S., Kellam, P., and Smith, GL (2004). Poxvirus genomes: a phylogenetic analysis. J Gen Virol 85, 105-117), which is incorporated herein by reference in its entirety and for all purposes.
[0111] Table 6. Minimal genetic complements of Chordopoxviruses.
[0112]
[0113]
[0114]
[0115] Example 4. Construction of recombinant chimeric poxvirus
[0116] Construction of a shuttle vector for inserting exogenous gene expression cassettes into the genome of the #33 chimeric poxvirus
[0117] To construct the thymidine kinase (TK) shuttle vector, the left and right flank sequences of the TK gene of the #33 chimeric poxvirus were PCR amplified from #33 genomic DNA using Q5 High Fidelity 2X Master Mix (New England Biolabs Inc., Ipswich, MA) and the following primers: 5'-GCGCATATGATCTATGGATTACCATGGATGACAACTC-3' and 5'-CGTTTAACTCGTCTAATTAATTCTGTAC-3' (left flank), 5'-CAGGTAAAAGTACAGAATTAATTAGACGAGTTAAACGAGCTCGTCGACGGATCCGCTAGCGGCCGCGGAGGTAATGATATGTATCAATCGGTGTGTAG-3' and 5'-GCGGAATTCGTAATTACTTAGTAAATCCGCCGTACTAGG-3' (right flank). The two fragments were joined using a gene splicing method by overlap extension, digested with NdeI and EcoRI, and cloned into the identically cut plasmid pGPT to generate p33NC-TK. The flanking sequences of TK in the shuttle vector were confirmed by sequencing. p33NC-TK contains the left and right flanking sequences of TK separated by SacI, SalI, BamHI, NheI, and NotI, and the Escherichia coli guanine phosphoribosyltransferase (gpt) gene driven by the vaccinia virus (VACV) early promoter p7.5E as a transient dominant gene selection marker.
[0118] The F14.5L shuttle vector was constructed similarly. The left and right flank sequences of the #33 chimeric poxvirus F14.5L gene were amplified by PCR from #33 genomic DNA using Q5 High Fidelity 2X Master Mix (New England Biolabs Inc., Ipswich, MA) and the following primers: 5'-GCGCATATGTAGAAGAATTGATAAATATGAAACCTTTTAAG-3' and 5'-CCTCTCTAGCTTTCACTTAAACTGTATCG-3' (left flank), 5'-GAATAATCGATACAGTTTAAGTGAAAGCTAGAGAGGAAGCTTGAGCTCGAGGATCCGCTAGCGGCCGCTGAAGAGGATGCTAGAATCAAGGAGGAGCAAG-3' and 5'-GCGGAATTCTCCGGGCAGTGACTTTGTAGCTCTCCCAG-3' (right flank). The two fragments were ligated using a gene splicing method by overlap extension. The resulting fragment was digested with NdeI and EcoRI and cloned into the identically cut plasmid pGPT, generating p33NC-F14.5L. The flanking sequences of F14.5L in the shuttle vector were confirmed by sequencing. p33NC-F14.5L contains the left and right flanking sequences of F14.5L separated by HindIII, Sad, XhoI, BamHI, NheI, and NotI, and an E. coli gpt transient dominant gene selection marker driven by the VACV early promoter p7.5E.
[0119] Example 5. Recombinant chimeric poxvirus expressing CD19t provides a target for CAR targeting CD19
[0120] Two breast cancer cell lines, MDA-MB-468wt (triple negative breast cancer cell line) (parental line) and an MDA-MB-468 variant modified to express a truncated human CD19 lacking the signaling domain (MDA-MB-468-CD19t), were used in the following studies. Figure 6 As shown, MDA-MB-468-CD19t represents CD19t. T cells modified to express a CAR targeting CD19 as described in more detail below were also used. The CARs expressed by these T cells were Figure 7 The schematic diagram is shown in FIG and includes: a scFv targeting CD19 and an IgG4 spacer, a CD28 transmembrane domain, a CD28 co-stimulatory domain, and CD3zeta. The sequence encoding this CAR and the truncated EGFR is inserted into a lentiviral vector, and this recombinant vector is used to transduce PBMCs. The truncated EGFR can be used as a marker for CAR expression. Figure 8As shown, EGFR expression was compared between mock-transfected PBMCs and PBMCs transfected with recombinant lentivirus expressing CD19 CAR and truncated EGFR, showing that the transfected cells efficiently expressed the transgene.
[0121] Chimeric poxvirus #33 was engineered to express a truncated CD19 recombinant oncolytic virus (33-CD19t). MDA-MB-48 tumor cells that do not express CD19 were exposed to various MOIs of recombinant oncolytic virus 33-CD19t and mock-transfected T cells. Figure 9 As shown in the upper panel, increasing levels of the recombinant oncolytic virus 33-CD19t increased CD19 expression and reduced cell number. Figure 9 The figure below depicts the results when MDA-MB-468 tumor cells were exposed to various MOIs of recombinant oncolytic virus 33-CD19t and transfected T cells expressing CD19-targeting CAR. As can be seen, the number of MDA-MB-468 cells expressing CD19t was greatly reduced.
[0122] Figure 10 Depicted are the results of a study measuring IL-2 (lower panel) and IFN-gamma (upper panel) levels in a long-term killing assay. In this study, MDA-MB-468 cells were exposed to recombinant oncolytic virus 33-CD19t alone; recombinant oncolytic virus 33-CD19t and mock-transfected T cells; or recombinant oncolytic virus 33-CD19t and transfected T cells expressing a CD19-targeting CAR.
[0123] Figure 11 is a series of cell culture images from a cell killing assay. In this study, MDA-MB-468 cells were exposed to recombinant oncolytic virus 33-CD19t at an MOI of 1 in the presence of mock-transfected T cells or transfected T cells expressing a CD19-targeting CAR. The upper series of images are MDA-MB-468 cells cultured in the absence of recombinant oncolytic virus 33-CD19t or transfected T cells expressing a CD19-targeting CAR.
[0124] Figure 12 depicts the results of long-term cell killing assays, in which MDA-MB-468 cells or MMDA-MB-231 cells are cultured with the following: only recombinant oncolytic virus 33-CD19t (various MOIs);Recombinant oncolytic virus 33-CD19t (various MOIs) and analog transfected T cells;Or recombinant oncolytic virus 33-CD19t (various MOIs) and transfected T cells expressing CD19 targeting CAR.Tumor cell killing and CD19t expression were measured.
[0125] The studies in this example collectively demonstrate that: 1) in MDA-MB-48 cells exposed to recombinant oncolytic virus 33-CD19t, the expression of CD19t increased with increasing MOI; 2) in MDA-MB-48 cells exposed to recombinant oncolytic virus 33-CD19t in the presence of CD19-CAR T cells, T cells produced higher levels of IL-2 and IFN-gamma as the MOI increased; and 3) CD19 CAR T cells showed efficacy in MDA-MB-48 cells exposed to recombinant oncolytic virus 33-CD19t.
[0126] Example 6. Recombinant chimeric poxvirus expressing CD19t and CD19 CAR is effective in a TNBC xenograft model.
[0127] As shown in Figure 13, oncolytic viruses can effectively deliver CD19t to solid tumors and activate CD19-CART cells in vitro. Figure 13, Figure A is a schematic diagram of vaccinia oncolytic virus [CF33-(SE)hCD19t], showing the incorporation of the synthetic early promoter (P SE ) under the control of human truncated CD19 (CD19t), inserted into the J2R locus, replacing the thymidine kinase gene. Figure 13, Panel B depicts immunofluorescence microscopy of MDA-MB-468 cells infected with OV19t at an MOI of 0.025 (left) and an MOI of 1 (center) for 24 hours, or cells transduced with lentivirus to stably express CD19t (right). Images are at 10x magnification, and insets are at 40x magnification. Figure 13, Panel C is a set of FACS graphs showing cell surface expression of CD19t on MDA-MB-468 tumor cells and intracellular expression of vaccinia virus measured by flow cytometry 24 hours after infection with OV19t at increasing MOIs. Figure 13, D shows the quantification of CD19t (left), vaccinia (middle) and viability (right) of MDA-MB-468 tumor cells after co-culture with OV19t of the specified MOI for 24, 48 and 72 hours. Figure 13, E shows the quantification of CD25 (left) and CD137 (right) expression on mock (untransduced) or CD19-CART cells after co-culture with tumor cells at an effector: tumor (E: T) ratio of 1: 2 for 24 hours with or without OV19t treatment of the specified MOI.
[0128] As shown in Figure 14, OV19t oncolytic virus can force CD19t expression in tumor cells, which redirects the activation and cytotoxicity of CD19-CAR T cells in vitro. Figure 14, Panel A is a representative flow cytometry analysis showing CD8 T cells expressed in MDA-MB-468 tumor cells at a 1:1 E:T ratio after 16 hours of co-culture with or without treatment with OV19t at the indicated MOI.+ CAR + Cell surface CD107a (left) and intracellular IFNγ expression (right) in T cells. Figure 14, B shows IFNγ production measured by ELISA in supernatants collected from co-cultures with or without OV19t treatment for 24 hours, 48 hours, and 72 hours at a specified MOI. Figure 14, C shows a tumor killing assay assessed by flow cytometry, comparing mocks or CD19-CAR T cells co-cultured with MDA-MB-468 tumor cells treated with OV19t at a specified MOI for 24, 48, or 72 hours. Figure 14, D shows viral titers in supernatants collected from co-cultures of T cells and tumor cells treated with OV19t at a specified MOI.
[0129] As shown in Figure 15, the combination therapy with OV19t and CD19-CAR T cells was effective in the TNBC xenograft model. Figure 15, Panel A shows the effect of OV19t and CD19-CAR T cells on the TNBC xenograft model in mice implanted with subcutaneous MDA-MB-468 tumors (5x10 6 cells), and 0, 10 5 , 10 6 or 10 7 Plaque forming units (pfu) were used for intratumoral treatment and harvested on day 3 (left), 7 (center), or 10 (right) after treatment to quantify CD19t expression by flow cytometry. (+) represents MDA-MB-468 tumors that were previously lentivirally transduced to stably express CD19t. Figure 15, Panel B shows a sample of MDA-MB-468 tumors bearing subcutaneous MDA-MB-468 (5x10 6 cells) tumors and were treated with OV19t (10 7 Tumor volume (mm) in NSG mice treated with pfu 3 On day 46, mice were treated with mock or CD19-CAR T cells (5x10 6 Figure 15, Panel C shows the average tumor volume on day 73 of the in vivo experiment described in Panel B. Figure 15, Panel D is a schematic diagram of the concept of combined therapy using OV to introduce CAR targets into refractory solid tumors.
[0130] References
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[0132] 2.Chen NG&Szalay AA(2010)Oncolytic vaccinia virus:a theranostic agentfor cancer.Future Virol.5(6):763-784.
[0133] 3.Andtbacka RH,et al.(2015)Talimogene Laherparepvec Improves DurableResponse Rate in Patients With Advanced Melanoma.J Clin Oncol33(25):2780-2788.
[0134] 4.Anonymous(2015)First Oncolytic Viral Therapy for Melanoma.Cancerdiscovery.
[0135] 5.Russell SJ,Peng KW,&Bell JC(2012)Oncolytic virotherapy.NatBiotechnol30(7):658-670.
[0136] 6.Thorne SH,et al.(2007)Rational strain selection and engineeringcreates a broad-spectrum,systemically effective oncolytic poxvirus,JX-963.JClin Invest117(11):3350-3358.
[0137] 7.Yu W&Fang H(2007)Clinical trials with oncolytic adenovirus inChina.Curr Cancer Drug Targets 7(2):141-148.
[0138] 8.Evgin L,et al.(2010)Potent Oncolytic Activity of Raccoonpox Virusin the Absence of Natural Pathogenicity.Mol Ther.
[0139] 9. Rintoul JL, et al. (2012) ORFV: a novel oncolytic and immunestimulating parapoxvirus therapeutic. Mol Ther 20(6):1148-1157.
[0140] 10.Chan WM&McFadden G(2014)Oncolytic Poxviruses.Annu Rev Virol1(1):119-141. Sequence Listing <110> City of Hope <120> Oncolytic viruses expressing CAR T cell targets and their uses <130> 40056-0034WO1 <150> 62 / 544,707 <151> 2018-08-11 <160> 2 <170> PatentIn version 3.5 <210> 1 <211> 189415 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 1 gagaaagaga taaaactttt ttacgactcc atcagaaaga ggtttaatat ttttgtgaga 60 ccatcgaaga gagaaagaga aagagatagt tagtctagat attttctta gtacaaaagt 120 caatgtttta aaaatattgg acaagaattt gtctgtataa aaacttgtgt gaaattttgt 180 accaaagaaa aaatgtgagc agtatcccct acatggattt tactagatca tttatatacc 240 aaaaaatatt atacgatcta cgttttatta tatgatttta acgtgtaaat tataaacatt 300 attttatgat atacaattgt ctggtaacct agatgggcat aggggatgtt gataagctcg 360 acgagtatat gttgttggac gttatgttt aagaaatagt tgatgcatca gaaaagagaat 420 aaaaaatatt ttagtgagac catcgaagag agaaagagat aaaacttttt tacgactcca 480 tcagaaagag gtttaatatt tttgtgagac catcgaagag agaaagaagaa taaaaatatt 540 ttatgactcc attgaagaga gaagaagaaa atgagaatga gaataaaaat attttagtga 600 caccatcaga aagaggttta atatttttgt gagaccatcg aagagagaaa gagaataaaa 660 atattttatg actccattga agaagaaag agaaaatgag aatgagaata aaaatatttt 720 agtgacacca tcagaaagag gtttaatatt tttatgaga ccatcaaaga gagaaagaga 780 ataaaaatat ttttgtaaaa ctttttttat gagaccatca aagagagaaa gagaataaaa 840 atatttttgt aaaacttttt ttatgagacc atcaaagaga gaaaagagaat aaaaatattt 900 ttgtaaaact ttttttatga gaccatcaaa gagagaaaga gaataaaaat attttgtaa 960 aacttttttt atgagaccat caaagagaga aagagaataa aaatattttt gtaaaacttt 1020 ttttatgaga ccatcaaaga gagaaagaga ataaaaaaat attttgtaa aacttttttt 1080 atgagaccat cagaaagagg tttaatattt ttgtgatacc ctgaaaggaa ataggaatag 1140 gaatagtgtc ataatcgtat cacactattg agacagaaaa agaagaagtc gcgagaggta 1200 actttttgtt ttgcaaaccg gaatatagtg tccggtacac ttttttaatt cgtggtgtgc 1260 ctgaatcgtt cgattaaccc tactcatcca atttcagatg aatagagtta tcgattcaga 1320 cacacgcttt gagttttgtt gaatcgatga gtgaagtatc atcggttgca ccttcagatg 1380 ccgatccgtc gacatacttg acctcaagtt cagatgattc cttgcacatg tctccgatac 1440 gaacgctaaaa ctctagattc ttgacacatt ttgtatcgac gatcgttgaa ccgatgatat 1500 cttcgtaact cactttctta tgagagatgt tagacccgag tactggatgg gtcttgatgt 1560 cgctgtcttt ctcttcttcg ctacatctga tgtcgataga cacctcacag tctttccatc 1620 agcggattct gagatggatt taatctgagg acatttggtg aatccaaagt tcattctcag 1680 acctccaccg atgatggagt aataagtggt aggaggatct acatcctcga ctgattccac 1740 ctcgggatct ggatctgact cggactctgt aatttccgtt acggattggc aaatcttatc 1800 atcggtcggt gtttggtctt gctttgtgac tttgataata acatcgattc ccatatgatg 1860 tttgttttct tcttccgtac acgatgagga tgattgctga agactggcag gcacatgcat 1920 gccagtacga tatattgttt catgattgct attgattgag tactgttctt tatgattcta 1980 cttccttacc gtgcaataaa ttagaatata ttttctactt ttacgagaaa ttaattattg 2040 tatttatggg tgaaaaactt actataaaaa gcgggtgggt ttggaattag tgatcagttt 2100 atgtatatcg caactaccgg gcatatggct acattaccca catgataaga gattgtatca 2160 gtttcgtagt cttgagtatt ggtattacta tatagtatat agatgtcgac gctagagtta 2220 ctgtctccga atgcggcatg atagtatcat tctttgctt cgttaactgt tggaggag 2280 aatctttgtt attgcattta atctcgaat tcagagtgca caccttctc ctgtaagaa 2340 tcctgaagtt gctaccttat tagaacgga gaagtatcca tcacgaaaga cgggattaca 2400 gtctttatga ttcatagtaa tagttagttc cgacgttgag atggattcgc tgagaccggt 2460 agtggtcgtc cgagtacacg atgtgtcgtt gacgggatac agattaattt ccacatcgat 2520 atagttaaag gtatttctgg gtacggtttt gagatcgtcg tacatgggaa atgaatgtg 2580 actgtctgaa tgtatggctt taagatagct gtgataccgt atacaggtcg gtgtcggaga 2640 ttcgaatctc tttaggcga cttatgtcac gatgatggaa tctatcttat cgaatgatat 2700 atttttcata atacacttt tatagtccctc gtttaacag atttactat gtagttccgc 2760 gatgactcg tcccttaata ggcagtaggc tagtatcttt tttacgtagt aatcgtcgta 2820 gggagagaca tcttgtagaa caacgattta atcataggta gagatacttt cagtctgtgg 2880 tggatgatgt cattcacac atccgccttg tatatgatgt ttctgttttc aaacaccaag 2940 tcgaataccg tctttagtcg gaaggttgat gtcgtatccg atgtatgagg caacattgtt 3000 gttacaattt tgaaaggcgg tattatagta ttcgtctttc tgaatgtcga acctatctag 3060 tagataccgt agtatattga gagtgtatcc ttgattatgt tttatgaata gataaagtag 3120 atgttgtcct tcttcctttt gttcgtgcca attgagtaac attatgagaa tatgacctgt 3180 tgcacaatcg ttccatgatg ggtgtacaat caagattatt acgtatcctc gtatcggctc 3240 ctcgagataa aagagcatac accacacgag gactatgttt ggtatactgt tgaaggtaag 3300 tgtgtaaccg cgttaatgtt tgctccataa tctattatcg cgtagatgaa tcgcttctcg 3360 gctcgcatct tagtgtgact taacttgtaa taattgcttt tgtagaacgt ggatatgtgt 3420 ttacagtagt aatgaagaga agtgagtcca tcctcgtcga cgcaattagg gtcggatcct 3480 ttgtacagaa cgtaatagtt tagactccca ttgaatttat atctaagata acacagcaat 3540 agatcggatg attactaaa gtcatcaatg gtgtccgtta gtatatcaaa gatcttgtta 3600 tcgattgata gtgaatgaat cagatagtgg tgtagaggaa tatgtccttt ttcatccttg 3660 ctatcaaagt tacgcatgcc gtggtgtaac aatatcttta atacagatgg attaaatcgt 3720 gtattcatcg tatagcaatg taatggagag ttacctcgtt tattcagatc gcagtgttta 3780 ataactagct taaacagatg agacgatgta tccacatcaa agaacgtaaa atacatatga 3840 caaacattgt tgacagaaac gtgaccttca ttcttaccgt cgtccataaa tacgttaggt 3900 atgtaccaca tactgtcgcg aacgatgcgt acaatctcgt ccatctcata atgatttact 3960 ttttcataat taaagatgtg aaagaaaaac agaacaatat atttttttag taatgttat 4020 gcgagacata taaaataaac tccgtgttta tgatcatttt taacagcaac acattcaata 4080 ttgtattgtt atttttatat tatttacaca attaacaata tattattagt ttatattact 4140 gaattaataa tataaaattc ccaatcttgt cataaacaca cactgagaaa cagcataaac 4200 acaaaatcca tcaaaaatgt cgatgaaata tctgatgttg ttgttcgctg ctatgataat 4260 cagatcattc gccgatagtg gtaacgctat cgaaacgaca tcgccagaaa ttacaaacgc 4320 tacaacagat attccagcta tcagattatg cggtccagag ggagatggat attgtttaca 4380 cggtgactgt atccacgcta gagatattga cggtatgtat tgtagatgct ctcatggtta 4440 tacaggcatt agatgtcagc atgtagtatt agtagactat caacgttcag aaaacccaaa 4500 cactacaacg tcatatatcc catctcccgg tattatgctt gtattagtag gcattattat 4560 tattacgtgt tgtctattat ctgtttatag gttcactcga cgaactaaac tacctataca 4620 agatatggtt gtgccataat ttttataaat ttttttatga gtatttttac aaaaaaaatg 4680 tataaagtgt atgtcttatg tatatttata aaaatgctaa gtatgcgatg tatctatgtt 4740 atttgtattt atctaaacaa tacctctacc tctagatatt atacaaaaat tttttatttc 4800 ggcatattaa agtaaaatct agttaccttg aaaatgaata cagtgggtgg ttccgtatca 4860 ccagtaagaa cataatagtc gaatacagta tccgattgag attttgcata caatactagt 4920 ctagaaagaa atttgtaatc atcttctgtg acgggagtcc atatatctgt atcatcgtct 4980 agtttatcag tgtcccatgc tatattcctg ttatcatcat tagttaatga aaataactct 5040 cgtgcttcag aaaagtcaaa tattgtatcc atacatacat ctccaaaact atcgcttata 5100 cgtttatctt taacgatacc tatacctaga tggttattta ctaacagaca ttttccagat 5160 ctattgacta taactcctat agttccaca tcaccaagt atgatcatc tattgttata 5220 taacaataac atactcttt tccatttta tcagtatgta tatctatac aacgtcgtcg 5280 ttgtagtgaa tagtagtcat tgatctatta tatgaaacgg atatgtctag aacggcaatt 5340 gttttacgtc cagttaacac tttctttgat ttaaagtcta gagtctttgc aaacataata 5400 tccttatccg actttatatt tcctgtaggg tggtataatt ttattttgcc tccacatatc 5460 ggtgtttcca atattac tagacatat tccatatagt tattagttaa gggtacccaa 5520 ttagaacacg tacgcttatt atcatcattt ggatcgtatt tcataaagt tattgtacta 5580 tcgatgtcaa cacattctac atttttaat cgtctatata gtatttttct gatattttct 5640 atatatcag aattgtcttc catcagt tgtatactt cggaatcag tacatgttta 5700 aaatttctc tgatgtcatt ccttatacaa tcaattcat tattaacag tttaagtc 5760 tgtagacctt tatcgtcgta atatccatt gtcttattag ttacgcttat ttttatgtgt 5820 tttacgttgc tttattatat tttatagaa tgattgttg acgaatcacg agaactatta 5880 agacacatta ttaggtatat attataaaaa agttttgat tacgatgtta taagaggaaa 5940 gaggacacat windowcata helpcattaa ctacattctt atacatcgt atcaaaga 6000 attgcaattt tgatgtataa caactgtcaa tgggttatgg aattgtatat tacatattat 6060 acggtatgtt ggtaacgaca ataccgatc ggtaattgtc tgccggtgta atagaattat 6120 atatatctat ctattacacc ggctgagtat gcataataat aagttgtggt agtatgatct 6180 ccatatttat atttaggac ttgtattca gtatttttgg aatcataaa aaaaaaaa 6240 agttttacta atttaaaattt taaaaagtat ttacatttt ttcactgttt agtcgcggat 6300 atggaattcg atcctgccaa atcaataca tcatctatag atcatgtaac atattaca 6360 tacatagatg aaccaatga tataagacta acagtagca tattaccgaaa tattaataac 6420 attacatatt attacaat cacaaaata atacacatt tggctaatca atttcggggct 6480 tggaaaaaac gtatcgccgg aagggactat atgactact tatctagaga tacaggata 6540 caacaatcaa aacttactga aactatacgt aactgtcaaa aaaatagaaa catatatggt 6600 ctatatatac actacaattt agttattaat gtggttattg attggataac cgatgtgatt 6660 gttcaatcaa tattaagagg gttggtaaat tggtacatag ctaataatac ctatactcca 6720 aatacaccca samaaacaac aaccatttct gagttggata tcatcaaaat actggataaa 6780 tacgaggacg tgtatagagt aagtaaagaa aaagaatgtg gaatttgcta tgaagttgtt 6840 tactcaaaac gatagatact ttggtttatt ggattcgtgt actcatatat tttgcataac 6900 atgcatcaat atatggcata aaacacgaag agaaaccggt gcgtcggata attgtcctat 6960 atgtcgtacc cgttttagaa acataacaat gagcaagttc tataagctag ttaactaata 7020 aataaaaagt ttaatttgtt gacgacgtat gtcgttattt ttctcgtatg aaagattaaa 7080 ttcaattcaa ttcgttgttt ctaatataat ctgccgtatt ggatggattc tcaagacaat 7140 tgcatttaga ttatattatc atgaataaaa atagtagcac gcactacttc agccaaatat 7200 tcttttttga aacgccatct atcgtagtga ggacacaagt gaacctataa ttatcaaatt 7260 tattagtatc agtcacatga aggactttct gtagagtgac gattctacca tctatggtac 7320 taacggttc atcctccttg ataccctcac ccaaatgttc tataaattta gcatcctcgt 7380 ccgatctcat atcctttgcc aaccaataca tgtagctaaa attaggcata aatttcacac 7440 atccagtgca acgaaattct ccagaagatg ttacgatgtt taggttagga catttgattt 7500 cgtcggcatt aacatatggg tgaacacacc catacatgaa agcgatgaga aataggattc 7560 tcatcttgcc aaaatatcac tagaaaaaat ttatttatca atttaaagg tataaaaat 7620 acttattgtt gctcgaatat tttgtatttg atggtatacg gaagattaga aatgtaggta 7680 ttcatcaa ctgattctat ggttttatgt attctatcat gtttcactat tgcgtcggaa 7740 atatatcat atgcttccac atatatttta ttttgtttta actcataata ctcacgtaat 7800 tctggattat tggcatatct atgaataatt ttagctccat gatcagtaaa tattaatgag 7860 aacatagtat taccacctac cattatttt ttcatttcgt tcaattcttg attgcaaaga 7920 tctatatat cattatagcg ttgacttatg gactctggaa tcttagacga tgtacagtca 7980 tctataatca tggcatattt atacattgt ttatagcat agtagttatc tacgatgtta 8040 gatatttctc tcaatgaatc atcacacaa tctaatgtag gtttatgaca window 8100 ttcagcagtt caatgtttct agattcgttg atggcaatgg ctatacatgt atatccgtta 8160 tttgatctaa tgttgacatc tgaccggat tcagcagta aagatactag agattgttta 8220 ttatatctaa cagccttgtg agaagtgtt tctcctcgtt tgtcaatcat gttaatgtct 8280 ttaagataag gtaggcaaat gtttatagta ctaagaattg ggcaagcata agacatgtca 8340 caaagaccct tttgtagt ataagtgtaa aaattataac attcatagtt ggatttacat 8400 aggtgtccaa tcggtctc tccatcatcg agatattga tggcatctcc cttccttttt 8460 tagtagatat ttcatcgtgt aagaatcaat attatattt ctaaagtatt cgtgtatagc 8520 ctctttattt accacagttc catattccac tagaggata tcgccgaatg tcatatactc 8580 aattagtata tgttggagga catccgagtt cattgttttc atatcaaa agatggttttc 8640 cttatcattt ctccatagtg gtacaatact acacattatt ccgtgcggct ttccatttc 8700 caaaaacaat ttgaccaat ctaaatctac atctttattg tatctataat cactattag 8760 ataatcagcc atattactc gagtgcaaca tgttagatcg tctatatatg ataagcagt 8820 gttatctatt cctttcatta acaatttaac gatgtctata tctatatgg atgacttaat 8880 ataatattga agagctgtac atagttttt atctatagaa gacggcttga ttccgtgatt 8940 aattagacat ttacaactt ccggacgcac atatgctc gtatccgact ttgaatacag 9000 atgagagatg atacagat gcaatacggt accgcaattt cgtagttgat aatcatcata 9060 cgcgtatcag tactcgtccct cataaagaac actgcagcca tttctatga acaaatcaat 9120 aattttagga acaggatcat tgtcattaca taatttcta taactgaacg atggttttca 9180 catttaacac tcaagtcaa tccatgttct accacacct ttatcagtc aacgtctaca 9240 tttttggatt tcatatagct gatatatta aagtcattta tgttgctaaa tccagtggct 9300 tctagtagag ccatcgctat atcctttaac ttcatgt ctactatttg tgtattcttc 9360 taatggggta gctgtctcca atttttgcgt aatggattag tgccactgtc tagtagtagt 9420 ttgacgacct cgacattatt acatgctca ttaaaaaggt atgcgtgtaa agcattattc 9480 ttgaattggt tcctggtatc attaggatct ctgtctctca acatctgttt aagttcatcg 9540 agagccacct cctcattttc cagatagtca aacattttga ctgaatgagc tactgtgaac 9600 tctatacacc cacacaacta atgtcattaa atattatttt tttgaatgta ttataccat 9660 gtcaaaaact tgtacaatta ttataaaaa taatttagtg tttaaatttt accagttcca 9720 gattttacac ctccgttaac cccactttt acaccactgg acgatcctcc tcccacatt 9780 ccaccgccac cagatgtata agttttagat cctttattac taccatcatg tccatggata 9840 aagacactcc acatgccgcc actaccccc cctttagaag acatattaat agacttaag 9900 cavaagttta acataaaat taatcacgag tacctacta ccactaca ctattatatg 9960 attatagttt ctatttttac agtaccttaa ctaaagtctc tagtcacaag agcaatacta 10020 ccaacctaca ctattatatg attatagttt ctatttttat aggaacgcgt acgagaaaat 10080 caaatgtcta atttctaacg gtagtgttga taaacgatta tcgtcaatgg attackcctc 10140 10200. 10200. 10200. 10200. 10200. 10200. 10200. 10200. 10200 attataaac ttatattgct tattagccca atctgtaaat atcggattat taacatatcg tttctttgta ggtttattta acatgtacat cactgtaagc atgtccgtac catttatttt aatttgacgc atatccgcaa tttctttttc gcagtcggtt ataattcta tatatgatgg attackcatgcta catgtgtact fatherfather fatherfather attack attack atattttcag 10500. 10500. gtacctgtga tcgtctaggt aatcaactgt 10560. 10560. 10560. 10560. 10560. 10560. 10560. 10560 fatherctgct atttctggga fathertttatc tgccagtata acacaaatag fathercatgt aaacccatat tttgttatta tattaatgtc tgcgccatta tctattaacc attctactag gctgacacta tgcgacttaa tacaatgata aagtatacta catccatgtt tatctatttt gtttatatca tcaatatacg gcttacaaag ttttagtatc gataacacat ccaactcacg catagagaag gtagggaata atggcataat atttattagg ttatcatcat tgtcattatc tacaactaag tttccattt ttaaaata ctcgacaact ttaggatc tattgccaaa 10920 ttttgaaaa tatttattta tatgcttaaa tctatataat gtagctcctt catcaatcat 10980 accattaata acatgatgt atactgtatg atagataca tattctaa atagatcttg 11040 tagaatct gtatatcttt tagaattgt gattattagg attattac gtaaactatt 11100 acacaatct aaaatataaa acgtatcacg gtcgaataat agttgatcaa ctatatatt 11160 atcgatttg tgatttttct tcctaactg tttacgtaaa tagttagata gatatttcat 11220 tagttcatga ccactatagt tactatcgaa taacgcgtca atattttccc gtttaatatc 11280 gcatttgtca agataatat aagtgtggt atgttcacga taagtataat aacgcatctc 11340 ttttttgtgt gaaattaaat agtttatcac gtccaagat gtagcataac catcttgtga 11400 cctagtataata atataataat agagaactgt tttacccatt ctatcatcat atcagtggt 11460 gtagtcgtaa tcgtaatcgt ctaattcatc atcccaatta taatattcac cagcacgtct 11520 aatctgttct atttgatct tgtatccata ctgtatgttg ctacatgtag gtattccttt 11580 atccaataat agtttaaaca catctacatt gggatttgat gttgtagcgt atttctctac 11640 aatattaata ccatttttga tactatttat ttctatacct ttcgaaatta gtaatttcaa 11700 taagtctata tcgatgttat cagaacatag atattcgaat atatcaaaat cattgatatt 11760 tttatagtcg actgacgaca ataacaaaat cacaacatcg tttttgatat tattattttt 11820 cttggtaacg tatgccttta atggagtttc accatcatac tcatataatg gatttgcacc 11880 actttctatc aatgattgtg cactgctggc atcgatgtta aatgttttac aactatcata 11940 gagtatctta tcgttaacca tgattggttg ttgatgctat cgcatttttt ggtttctttc 12000 atttcagtta tgtatggatt tagcacgttt gggaagcatg agctcatatg atttcagtac 12060 tgtagtgtca gtactattag tttcgatcag atcaatgtct agatctatag aatcaaaaca 12120 cgataggtca gaagataatg aatatctgta cgcttctttt tgtactgtaa cttctggtttt 12180 tgttagatgg ttgcatcgtg cttaacatc aatggtacaa attttatcct cgctttgtgt 12240 atcatattcg tctctagtat aaaattctat attcagatta tcatgcgatg tgtatacgct 12300 aacggtatca ataaacggag cacaccattt agtcataaca gtaatccaaa atttttaaa 12360 gtatatctta acgaaagaag ttgtgtcatt gtctacggtg tatggtacta gatcctcata 12420 agtgtatata tctagagtaa tgtttaattt attaaatggt tgataatatg gatcctcatg 12480 acaatttccg aagatggaaa tgagatatag acatgcaata aatctaatcg aagacatggt 12540 tactccttaa aaaaatacga ataatcacct tggctattta gtaagtgtca tttaacacta 12600 tactcatatt aatccatgga ctcataatct ctatacggga ttaacggatg ttctatatac 12660 ggggatgagt agttttctt tttaacttta tactttttac taatcatatt tagactgatg 12720 tatgggtaat agtgtttaaa gagttcgttc tcatcatcag aataaatcaa tatctctgtt 12780 tttttgttat acagatgtat tacagcctca tatattacgt aatagaacgt gtcatctacc 12840 ttattaactt tcaccgcata gttgtttgca aatacggtta atcctttgac ctcgtcgatt 12900 tccgaccaat ctgggcgtat aatgaatcta aactttaatt tcttgtaatc attcgaaata 12960 atttttagtt tgcatccgta gttatcccct ttatgtaact gtaaatttct caacgcgata 13020 tctccattaa taatgatgtc gaattcgtgc tgtataccca tactgaatgg atgaactaac 13080 gaatatcaac ggcgttaata gtaatttact ttttcatctt tacatattgg gtactagtttt 13140 tactatcata agtttataaa ttccacaagc tactatggaa taagccaacc atcttagtat 13200 accacacatg tcttaaagtt tattaattaa ttacatgttg ttttatatat atcgctacga 13260 attaaagag aaatcagttt aggaagaaaa aaattcta tctacatcat cacgtctctg 13320 tattctacga tagagtgcta ctttaagatg agacatatcc gtgtcatcaa aatatactc 13380 cattaaaatg attattccgg cagcgaactt gatattggat atatcacaac ctttgttaat 13440 atctacgaca atagacagca gtcccatggt tccataaaca gtgagttat ctttctttga 13500 agcgatagtt tgtagagatc ttataaaacc gtcaaacgac atcgcattta tatctttagc 13560 taattcatat atgttaccat cgtaatatct aaccgcgtct atcttaaacg tttccatcgc 13620 tttaaagacg tttccgatag atggtctcat ttcatcagtc atactgagcc aacaatata 13680 atcgtgtata acatctttga tagaatcaga ctctaaagaa aacgaatcgg ctttattata 13740 cgcattcatg ataaacttaa tgaaaaatgt ttttcgttgt ttaagttgga tgaatagtat 13800 gtcttaataa ttgttattat ttcattaatt aatatttagt aacgagtaca ctctataaaa 13860 acgagaatga cataactagt tatcaaagtg tctaggacgc gtaattttca tatggtatag 13920 atcctgtaag cattgtctgt attctggagc tattttcttt atcgcattag taagttcaga 13980 atatgttata aatttaaatc gaataacgaa catgacttta gtaaagtcgt ctatattaac 14040 tcttttattt tctagccatc gtaataccat gtttaagata gtatattctc tagttactac 14100 gatctcatcg ttgtctagaa tatcacatac tgaatctaca tccaatttta gaaattggtc 14160 tgtgttacat atctcttcta tattattgtt gatgtattgt cgtagaaaac tattacgtag 14220 accattttct ttataaaacg aatatatagt actccaatta tctttaccga tatatttgca 14280 cacataatcc attctctcaa tcactacatc tttaagattt tcgttgttaa gatatttggc 14340 taaactatat aattctatta gatcatcaac agaatcagta tatattttc tagatccaaa 14400 gacgaactct ttggcgtcct ctataatatt cccagaaaag atattttcgt gttttagttt 14460 atcgagatct gatctgttca tatacgccat gattgtacgg tacgttatga taaccgcata 14520 aaataaaaat ccattttcat ttttaaccaa tactattcat aattgagatt gatgtaatac 14580 tttgttactt tgaacgtaaaa gacagtacac ggatccgtat ctccaacaag cacgtagtaa 14640 tcaaatttgg tgttgttaaa cttcgcaata ttcatcaatt tagatagaaa cttatactca 14700 tcatctgttt taggaatcca tgtattatta ccactttcca acttatcatt atcccaggct 14760 atgtttcgtc catcatcgtt gcgcagagtg aataattcttt ttgtattcgg tagttcaaat 14820 atatgatcca tgcatagatc ggcaaagcta ttgtagatgt gatttttcct aaatctaata 14880 taaactcgt ttactagcaa acactttcct gatttatcga ccaagacaca tatggtttct 14940 aaatctatca agtggtgggg atccatagtt atgacgcagt aacatagatt attacattct 15000 tgactgtcgc taatatctaa atatttattg ttatcgtatt ggattctgca tatagatggc 15060 ttgtatgtca agatataga acacataacc aatttatagt cgcgctttac attctcgaat 15120 ctaaagttaa gagatttaga aacattata tcctcggatg atgttatcac tgttttctgga 15180 gtaggatata ttaaagtctt tacagatttc gtccgattca aaaatcac taaatatat 15240 cccacattat catctgttag agtagtatca ttaatctat tattttat gaagatata 15300 tcactgctca cctctatatt tcgtacattt ttaactgtt tgtataatat ctctctgata 15360 caatcagata tatctattgt gtcggtagac gataccgtta catttgaatt aatggtgttc 15420 cattttacaa cttttacaa gttgaccaat tcattctaa tagtatcaa ctctccatga 15480 ttaatatttt taatagtatc cattttatat cacacaggac aaagtagc tgacataac 15540 cattgtataa ttttatgtt ttatgtttat tagcgtacac attttggaag ttccggcttc 15600 catgtatttc ctggagagca agtagatgat gaggaaccag atagttatta tccgtacttg 15660 cacttaaagt ctacattgtc gttgtatgag tatgatcttt taaacccgct agacaagtat 15720 ccgtttgata ttgtaggatg tggacattta acaatctgac acgtgggtgg atcggaccat 15780 tctcctcctg aacacaggac accagagtta ccaatcaacg aatatccact attgcaacta 15840 taagttacaa cgctcccatc ggtataaaaa tcctcgtatc cgttatgtct tccgttggat 15900 atagatggag gggattggca tttaacagat tcacaaatag gtgcctcggg attccatacc 15960 atagatccag tagatcctaa ttcacaatac gatttagatt caccgatcaa ctgatatccg 16020 ctattacaag agtacgttat actagagcca aagtctactc cgccaatatc aagttggcca 16080 ttatcgatat ctcgaggcga tgggcatctc cgtttaatac attgattaaa gagtgtccat 16140 ccagtacctg tacatttagc atatataggt cccatttttt gctttctgta tccaggtaga 16200 catagatatt ctatagtgtc tcctatgttg taattagcat tagttccac actattctta 16260 aattttatat taatgggacg tgaaggaata ggacagtatg atagaacgca tcctattccc 16320 aacaatgtca ggaacgtcac gctctccacc ttcatattta tttatccgta aaaatgttat 16380 cctggacatc gtacaataa taaaaaagcc catatatgtt tgctattgta gaaattgttt 16440 ttcacagttg ctcaaaacg atggcagtga cttatgagtt tcatcttg taaacatatc 16500 ataatattcg atattacgag ttgacatatc gacaaatttc caagtatttg attttggata 16560 atattcgtat ttgcatctg ctataattta gatataatca ccgcaagaac acacgaacat 16620 ctttcctaca tggttaaagt acatgtataa ttctatccat ttgtctcct aactatata 16680 tttgtataga taattacgag tctcataagt aattccagta attgcataga tgtcaccatc 16740 gtactctaca gcataaacta tactatgatg tctaggcatg ggagacttt ttatccaacg 16800 atttttagtg aacattcta catcgtttaa tactacatat ttctcatacg tggtataaac 16860 tccacccatt acatatatat catcgtttac gatacgac gcgcctgaat atctaggagt 16920 aattaagtttt ggaagtctta tccattcga agtgccgtgt ttcaatatt ctgccacacc 16980 cgttgaaata gaaaattcta atcctcctat tacatataac tttccatcgt taacacaagt 17040 actaacttct gattttaacg acgacatatt agtaaccgtt ttccatttt tcgttttaag 17100 atctacccgc gatacggaat aaacatgtct attgttaatc atgccgccaa taatgtatag 17160 acaattatgt aaaacatttg cattatagaa ttgtctatct gtattaccga ctatcgtcca 17220 atattctgtt ctaggagt aatgggttat tgtggatata taatcagt ttttaatgac 17280 tactatatta tgttttac catttcgtgt cactggcttt gtagatttgg atatagttaa 17340 tcccacaat gatatagcat tgcgcatagt attagtcata aacttgggat gtaaaatgtt 17400 gatgatatct acatcgtttg gatttttg tatccacttt ataatatca tagctgtaac 17460 atcctcatga tttacgttaa cgtcttcgtg ggataagata gttgtcagtt catcctttga 17520 taatttcca aattctggat cggatgtcac cgcagtaata ttgttgatta ttctacat 17580 cgacgcatta tatagtttt taattccata ttgtttagaa aagttaaaca tccttataca 17640 atttgtggaa ttaatattat gatcatagt ttttacacat agattacta caggcgtaac 17700 atcaattatt acggcagcaa ctagtatcat ttctacattg tttatggtga tgtttatctt 17760 cttccagcgc atagtcta atagcgattc aaacgcgtga tagtttatac cattcaat 17820 aatcacttca tcatttatat gtgctcctg atgcgttta aaaaaattat acggagacgc 17880 cgtaataatt tccttattca cttgtataat ttccccattg atagaaaata tcacgctttc 17940 cattcttgaa gtactataag taattatagt atatgtaaa cgtttatata ttcaatattt 18000 tttaaaaat cattttgaca ttaattcctt ttataatttc cgtctatcat ctatagaaac 18060 gtattctatg aatttataaa atgctttac gtgtcctatc gtaggcgata gaaccgctaa 18120 aaagcctatc gatttctac aaagaatct atttaatggt atagggag tataaaacat 18180 taaatgcccg tacttattaa agtattcagt agccaatcct aactctttcg atacttatt 18240 aatggctctt gttctgtacg aatctatttt ttgacaac ggacctagtg gtatatcttg 18300 ttctatgtat ctaaaataat gtctgactag atccgttagt ttatatcct cagtcatctt 18360 gtctagaatg gcaatctaa ctgcggtttt aggctttagt ttagtttta tatctacatc 18420 tatgtcttta tctaacacca aaatataat agctaatatt ttattacaat catccggata 18480 ttcttctacg atctcactaa ctaatgtttc tttggttata ctagtatagt cacgatcaga 18540 caaataaaga aaatcagatg atcgatgaat aatacattta aattcatcat ctgtaagatt 18600 tttgagatgt ctcattaaaa tattattagg gttagtactc attatcattc ggcagctatt 18660 acttatttta ttattttca ccatatagat caatcattag atcatcaaaa tatgtttcaa 18720 tcatcctaaa gagtatggtg aatgactctt cccatctaat ttctgaacgt tcaccaatgt 18780 ctctagccac tttggcacta atagcgatca ttcgcttagc gtcttctata ttattaactg 18840 gttgattcaa tctatctagc aatggaccgt cggacagcgt cattctcatg ttcttaatca 18900 atgtacatac atcgccgtca tctaccaatt catccaacaa cataagcttt ttaaaatcat 18960 cattataata ggtttgatcg ttgtcatttc tccaaagaat atatctaata agtagagtcc 19020 tcatgattag ttaacaacta tttttatgt taaatcaatt agtacaccgc tatgtttaat 19080 acttattcat atttagttt ttaggattga gaatcaatac aaaaattaa tgcatcatta 19140 attttagaaa tacttagttt ccacgtagtc atgaaacat ttgaaccat cgtacaggac 19200 gttctcgtac aggactaac tataaaccgg tttatattg ttcaagatag atacaatcc 19260 gataactttt tttacgaatt ctacgggatc cactttaaaa gtgtcatacc gggttctttt 19320 tattcttta aacagatcaa tggtgtgatg ttgattaggt cttttacgaa tttgatatag 19380 atagcgttc acatactcctc cataatggtc aatcgccatt tgttcgtatg tcataaattc 19440 tttaattata tgacactgtg tattattag ttcatccttg ttcatcatta ggaatctatc 19500 caaaatggca attatactag aactataggt gcgttgtata cacatattga tgtgtctgtt 19560 tatacaatcc atgatatttg gatccatgct actaccttcg ggtaaaattg tagcatcata 19620 taccattct agtactttag gttcattatt atccattgca gaggacgtca tgatcgaatc 19680 aaaaaaaat atattatttt tatgttatt tgttaaaaat atcatcgaa tactcgtaa 19740 gatactcctt catgaacata atcagttaca aaacgtttat atgagtaaa gtatctacga 19800 tttttacaaa agtccggatg cataagtaca aagtacgcga taaacggaat aataatagat 19860 ttatctagtc tatctttttc tatagctttc atagttagat acatggtctc agaagtagga 19920 tttgtaaca tcagcttcga taaaatgact gggttattta gtcttacaca ttcgctcata 19980 catgtatgac cgttaactac agagtctaca ctaaaatgat tgaacaatag atagtctacc 20040 attgttcgt attcagatag tacagcgtag tacatggcat cttcacaaat tatatcattg 20100 tctaatagat atttgacgca tcttatggat cccacttcaa cagccatctt aaaatcggta 20160 aaatcatatt gctttccttt atcattaata atttctaaaa catcatctct atcataaaag 20220 atacaaatat taactgtttg atccgtaata acattgctag tcgatagcaa tttgttaata 20280 agatgcgctg ggctcaatgt cttaataaga agtgtaagag gactatctcc gaatttgttt 20340 tgtttattaa catccgttga tggaagtaaa agatctataa tgtctacatt cttgactgtt 20400 ttagagcata caatatggag aggtgtattt ccatcatgat ctggttttga gggactaatt 20460 cctagtttca tcatccatga gattgtagaa gctttttggat tgtctgacat aagatgtcta 20520 tgaatatgat tttgccaaa tttatccact atcctggctt cgaatccgat ggacattatt 20580 ttttaaaca ctctttctga aggatctgta cacgccaaca acggaccaca tccttcttca 20640 tcaaccgagt tgttaatctt ggctccatac tgtaccaata aatttattct ctctatgact 20700 tcatcatctg ttcccgagag aatatataga ggtgttttat tatgtttatc acacgcgttt 20760 ggatctgcgc cgtgcgtcag cagcatcgcg actattctat tattattaat tttagaagct 20820 atatgcaatg gataatttcc atcatcatcc gtctcatttg gagagtatcc tctatgaaga 20880 agttcttcga caaatcgttc atctagtcct ttaattccac aatacgcatg tagaatgtga 20940 taattattc cagaaggttc gatagcttgt agcatattcc taaatacatc taaattttta 21000 ctattatatt tggcataaag agatagataa tactcggccg acataatgtt gtccattgta 21060 gtataaaaat tatatttct atttctattt ctgtatatttt gcaacaattt actctctata 21120 acaaatatca taacttagtt cttttatgtc aagaaggcac tggtttagtt catctataaa 21180 tgtcacgcca taactaccac gcatgccata ctcagaatta tgataagat atttatcctt 21240 ggggtgtagg taatggggat taatctttgt tggatcagtc tctaagttaa cacatgtcac 21300 acatgatcca tttatagtta tatcacacga tgatgattta tgaattgatt ccggagatc 21360 gctatcgtat ttgtggttc cacaattcat ttcatacat gttattgtca cactaatatt 21420 atgatgaact tattactagcc gctgagtggt aaaacaga acatagtt tattacttt 21480 accacaccc tcagccgctg ccacaatct ctgatccgta tccatgatg tcatgtttat 21540 ttctagtccg tatccagtca acactagtt agcattctg tcgatatagc ttcactcat 21600 atgacactca ccaatatag tagattaat gtcgtaattt acaccatag tgagttcggc 21660 ggcaaagtac caataccggt aatcttgtcg aggaggacat atagtattct tgtattctac 21720 tgaatacccg agagatgcga tacaaagag windowactaat tgtaacca tcttactca 21780 atatgtaac atagtacga tgcaatgagt aagacaatag gaatctatc ttatatacac 21840 atattattc tatcatttt accaattagt tagtgtaatg ttaacaaaa tgtgggagaa 21900 tctaattagt ttttctttac acaattgacg tacatgagtc tgagttcctt gtttttgcta 21960 attatttcat ccaatttatt attcttgact atatcgagat cttttgtata ggagtcagac 22020 ttgtattcaa catgcttttc tataatcatt ttagctattt cggcatcatc caatagtaca 22080 ttttccagat tagcagaata gatattaatg tcgtatttga acagagcctg taacatctca 22140 atgtctttat tatctatagc caatttaatg tccggaatga agagaaggga attattggtg 22200 tttgtcgacg tcatatagtc gagcaagaga atcatcatat ccacgtgtcc attttttata 22260 gtggtgtgaa tacaactaag gagaatagcc agatcaaaag tagatggtat ctctgaaaga 22320 aagtaggaaa caatacttac atcattaagc atgacggcat gataaaatga agttttccat 22380 ccagttttcc catagaacat cagtctccaa tttttcttaa caaacagttt taccgtttgc 22440 atgttaccac tatcaaccgc ataatacaat gcggtgtttc ccttgtcatc aaattgtgaa 22500 tcatccagtc cactgaatag caaaatcttt actattttgg tatcttccaa tgtggctgcc 22560 tgatgtaatg gaattcatt cttagaga tttcaatg ctccagcgtt cacaacgta 22620 catactagac gcacgttatt atcagctatt gcataataca agcactatg tccatggaca 22680 tccgccttaa atgcatcttt gctagagaga aagctttca gctgcttaga cttccaagta 22740 ttaattcgtg acgatccat gtctgaaacg agacgctaat tagtgtatat tttcattt 22800 tttataattt tgtcatattg caccagaatt ctaatagatc tgattagtag 22860 atacatggct atcgcaaac aacatataca cattataa aaataattt tattagaaa 22920 attcagattt cacgtaccca tcaataaa taaaataatg attccttaca ccgtacccat 22980 attaaggaga ttccacctta cccataaca atataaatcc agtataatca tgtctgatga 23040 tgaacacaaa tggtgtatta aattccagtt ttcaggaga tgatctcgcc gtagctacca 23100 tgagtaga tgcctctgct acagttcctt gttcgtcgac atctatctt gcattctgaa 23160 acattttata atatatat gggtccctag tcatatgttt aaacaacgca ttatctggat 23220 taaacatact aggagccatc atttcggcta tcgacttaat atccctctta ttttcgatag 23280 aaaatttagg gagtttaaga ttgtacactt tattccctaa ttgaaacgac caatagtcta 23340 atttgcagc cgtaatagaa tctgtgaaat gggtcatatt atcacctatt gccaggtaca 23400 tactaatatt agcatcctta tacggaaggc gtaccatatc atattcttcg tcatcgattg 23460 tgattgtatt tccttgcaat ttagtaacta cgttcatcat gggaaccgtt ttcgtaccgt 23520 acttattagt aaaactagca ttgcgtgttt tagtgatatc aaacggatat tgccatatac 23580 ctttaaaata tatagtatta atgattgccc atagagtatt attgtcgagc atattagaat 23640 ctactacatt agacataccg gatctacgtt ctactataga attaatttta ttaaccgcat 23700 ctcgtctaaa gtttaatcta tataggccga atctatgata ttgttgataa tacgacggtt 23760 taatgcacac agtattatct acgaaacttt gataagttag atcagtgtac gtatatttag 23820 atgttttcag cttagctaat cctgatatta attctgtaaa tgctggaccc agatctcttt 23880 ttctcaaatc catagtcttc aataattcta ttctagtatt acctgatgca ggcaatagcg 23940 acataaacat agaaaacgaa taaccaaacg gtgagaagac aatattatca tcttgaatat 24000 ttttatacgc tactataccg gcattggtaa atccttgcag acgataggta gacactgaac 24060 acgttaacga tagtatcaat aacgcaatca tgattttatg gtattaataa ttaaccttat 24120 tttatgttc ggtataaaaa ttattgatgt ctacacatcc ttttgtaatt gacatctata 24180 tatccttttg tataatcaac tctaatcact ttaactttta cagttttccc taccagttta 24240 tccctatatt caacatatct atccatatgc atcttaacac tctctgccaa gatagcttca 24300 aagtgaggat agtcaaaaag ataaatatat agagcataat cattctcgta tactctgccc 24360 tttattacat cacccgcatt gggcaacgaa taacaaaatg caagcatctt gttaacgggc 24420 tcgtaaattg ggataaaaat tatgttttta tatctatttt attcaagaga atattcagga 24480 atttcttttt ccggttgtat ctcatcgcag tatatatcat ttgtacattg tttcatattt 24540 tttaatagtc tacacctttt agtaggacta gtatcgtaca attcatagct gtattttgaa 24600 ttccaatcac gcataaaaat atcttccaat tgttgacgaa gacctaatcc atcatccggt 24660 gtaatattaa tagatgctcc acatgtatcc gtaaagtaat ttcctgtcca atttgaggta 24720 cctatatacg ccgttttatc ggttaccata tattttggcat ggtttaccct agaatacgga 24780 atgggaggat cagcatctgg tacataaat agctttactt ctatattat gtttttagat 24840 tttagcatag cgatagatct taaaaagttt ctcatgataa acgaagatcg ttgccagca 24900 ctaatcaata gcttaacgga tactgtctg tctatagcgg ctctttta ttcatcttct 24960 atataaggcc aaaaaaaaat attgcctgcc ttcgataaa taataggt aaagttcata 25020 acagatacat aaacgaattt actcgcattt ctaatacatg acataagc ggttaatca 25080 ttggttcttt ccatagtaca tagttgttgc ggtgcagaag cataaatac agagtgtgga 25140 acaccactta cgttaatact aagaggatga tctgtattat atacgacgg aaaagtttt 25200 ttccaattat atggtagatt gttaaccca agataccagt atacccaaa aatttgagtg 25260 agatccgctg ccaagttcct attattgaag atcgcaatac ccaatcttt gacctgagtt 25320 agtgatctcc aatccatgtt agcgcttcct aaataaatat gtgtattatc agatatccaa 25380 aattttgtat gaagaactcc tcctaggata tttgtaatat ctatgtatcg tacttcaact 25440 ccggccattt gtagtctttc aacatcctttt aatggtttgt tagatttatt gacggctact 25500 ctaactctta ctcctctttt gggtaattgt acaatctcgt ttaatattat cgtgccgaaa 25560 ttcgtaccca cttcatccga taaactccaa taaaaagatg atatatctag tgtttttgtg 25620 gtattggata gaatttccct ccacatgtta aatgtagaca aatacttt atcaaattgc 25680 atacctatag gaatagtctc tgtaatcact gcgattgtat tatccggatt cattttattt 25740 gttaaaaaat aatcctatat cacttcactc tattaaaaat ccaagttttct atttctttca 25800 tgactgattt tttaacttca tccgtttcct tatgaagatg atgtttggca ccttcataaa 25860 tttttatttc tctattacaa tttgcatgtt gcatgaaata atatgcacct aaaacatcgc 25920 taatctcatt gtttgttccc tggagtatga gagtcggggg gtgttaatct tgggaattat 25980 ttttctaacc ttgttggtag ccttcaagac ctgactagca aatccagcct taattttttc 26040 atgattgatt aatgggtcgt attggtattt ataaacttta tccatatctc tagatactga 26100 ttctggacat agctttccga ctggcgcatt tggtgtgatg gttcccataa gtttggcagc 26160 tagcagattc agttttgaaa cagcatctgc attaactaga ggagacatta gaatcattgc 26220 tgtaaacaag tttggattat cgtaagaggc tagtatagaa attgttgctc ccatggaatg 26280 cccaataaga agactggaac tcctaaataa gtagatttaa tagttaccac gtgctgtacc 26340 acatctctaa catacgtacc aaagtcatca atcatcattt tttcaccatt acttcttcca 26400 tgtccaatat gatcatgtga gaatactaaa attcctaacg atgatatgtt ttcagctagt 26460 tcgtcataac gtccagaatg tttaccagct ccatgactta tgaatactaa tgccttagga 26520 tatgtaatag gtttccaata tatgtaatca ttgtccagat tgaacataca gtttgcactc 26580 atgattcacg ttatataact atcaatatta acagttcgtt tgatgatcat attattttta 26640 tgttttattg ataattgtaa aaacatacaa ttaaatcaat atagaggaag gagacggcta 26700 ctgtctttg tgagatagtc atggcgacta aattagatta tgaggatgct gttttttact 26760 ttgtggatga tgataaaata tgtagtcgcg actccatcat cgatctata gatgaatata 26820 ttacgtggag aaatcatgtt atagtttta aaagatat taccagttgt ggaagactgt 26880 aaaggaatt gatgaagttc gatgatgtcg ctatacggta ctatggtatt gataaaatta 26940 atgagattgt cgaagctatg agcgaggg accactacat cattttaca aaagtccatg 27000 atcaggaaag tctattcgct accataggaa tatgtgctaa atcactgaa cattgggat 27060 aaaaagat ttcagaatct agatccaat cattgggaaa cattacagat ctgatgaccg 27120 acgatataat aaacatcttg atactttc tagaaaaaaa attgaattga tgatataggg 27180 gtcttcataa cgcataatta ttacgttagc attctatatc cgtgttaaaa aaaattatcc 27240 tatcatgtat ttgagagttt tattgtagc aaacatgata gctgtgatgc caataagctt 27300 tagatattca cgcgtgctag tgttaggt ggtattatct ggtggtgaaa tgtccgttat 27360 ataatctaca aacaatcat cgcatatagt atgcgatagt agagtaaca ttttatagt 27420 ttttactgga ttcatacatc gtctacccaa tttggttata aatgaaattg tcgccaatct 27480 tacacccaac cccttgttat ccattagtat agtattaact tcgttattta tgtcataaac 27540 tgtaaatgat tttgtagatg ccatatcata catgatattc atgtccctat tataatcatt 27600 actaacttta tcacaatata tgttgataat atctatatat gatctagtct ttgtgggcaa 27660 ctgtctatac aagtcgcta aacgttgttt actcatatag tatcgaacag ccatcattac 27720 atggtcccgt tccgttgata gataatcgag tatgttagtg gacttgtcaa atctatatac 27780 catattttct ggaagtggat atacatagtc gtgatcaaca ttattgctag cctcatcttc 27840 tatatcatgt actataccat tatctatatc atctacataa tctacgatat tattacacat 27900 aaacatcgac aacatactat tgtttattat ctaagtcctg ttgatccaaa cccttgatct 27960 cctctatttg tactatctag agattgtact tcttccagtt ctggataata tatacgttga 28020 tagattagct gagctattct atctccagta tttacattaa acgtacattt tccattatta 28080 ataagaatga ctcctatgtt tcccctataa tctcgtcta ttacaccacc tcctatatca 28140 atgcctttta gtgacagacc agacctagga gctattctac catagcaat cttaggcatg 28200 gabatactaa tatctgtctt aattaactgt ctttctcctg gagggatagt ataatcgtaa 28260 gcgctataca aatcatatcc ggcagcaccc ggcgattgcc tagtaggaga tttagctctg 28320 ttagttttcct taacaatct aactggtgag ttatattca tgttgaacat aaactaata 28380 ttttattca aaattattta ccatcccata tattccatga ataagtgtga tgattgtaca 28440 cttctatagt atctatatac gattcacgat aaatcctcc tatcaatagc agtttattat 28500 ccactatgat caattctgga ttatccctcg gataaatagg atcatctatc agagtccatg 28560 tattgctgga ttcacataa aattccgcat ttctaccac caataac cttctaccga 28620 acactaacgc gcatgattta taatgaggat ataagtgga tggtccaac tgccactgat 28680 catgattggg tagcaatat tctgtagttg tatcagttc agaatgtcct cccattacgt 28740 atacatt gtttatagat gccactgctg gattacatct agttttcaga agactcggca 28800 fathers ccgtggaacc aacgctcaac agatgtggga tttggtagac ctcctactac gtataattta ttgttagcgg gtatcccgct agcatacagt ctggggctat tcatcggagg aattggaatc caattgtttg father tacagctata gcattgttat gtatttcatt gttcatccat ccaccgatga gatatactac ttctccaaca tgagtacttg 29100. 10100. 1000. 1000. 1000. 1000. 1000. 1000 acttgtatga tttgcgtggt tgtttatcac aatgaaatat tttggtacag tctagtatcc attttacatt atttatacct ctggggagaaa gataattga cctgattaca tttttgataa 29280. ttttcttc gctttatata ccacttaatg acaaaatcaa ctacataatc ctcatctgga acatttagtt catcgctttc tagatagt ttcatagata gataatcaaa attgtctatg atgtcatctt ccagttccaa aaagtgtttg gcaataagt ttttagtatg acataagaga ttggatagtc cgtattctat acccatcatg taacactcga caaatattc ctttctaaaa tctcgtaaga taaagtttat aaagtgtag atgataaatt 29520 ctacagaggt taatatagaa gcagtaata aattgacgac gttatgacta tctatatata 29580 cctttccagt atacgagtaa ataatatag aagttaaact gtgaatgtca aggtctagac 29640 aaaccctcgt aactggatct ttatttttcg tgttttttg acgtaaatgt gtgcgaaagt 29700 aaaggataa cttttcaat atcgtagaat tgactattat attgccacct atagcatcaa 29760 taattgtttt gaatttctta gtcatagaca atgctaatat attcttacag tacacagtat 29820 taaaatat cggcatttat gtttctttaa aagtcaacat ctagagaaaa atgattatct 29880 ttttgagaca taactcccat tttttggtat tcacccacac gtttttcgaa aaaattagtt 29940 tttccttcca atgatatatt ttccatgaaa tcaaacggat tggtaacatt ataaattttt 30000 ttaaatccca attcagaaat caatctatcc gcgacgaatt ctatatatgt tttcatcatt 30060 tcacaattca ttcctataag tttaactgga agagccgcag taagaaattc ttgttcaatg 30120 gatactgcat ctgttataat agatctaacg gtttcttcac tcggtggata caataaatgt 30180 ttaaacatca aacatgcgaa gtcgcagtgt agaccctcgt ctctactaat tagttcgttg 30240 gaaaacgtga gtccgggcat taggccacgc ttttaagcc aaaatatgga agcgaatgat 30300 ccggaaaaga agattccttc tactgcagca aaggcaataa gtctctctcc ataaccggcg 30360 ctgtcatgta tccacttttg agcccaatcg gccttctttt ttacacaagg catcgtttct 30420 atggcattaa agagatagtt ttttcatta ctatctttaa cataagtatc gatcaaaaga 30480 ctatacattt ccgaatgaat gttttcaatg gccatctgaa atccgtagaa acatctagcc 30540 tcggtaatct gtacttctgt acaaaatcgt tccgccaaat tttcattcac tattccgtca 30600 ctggctgcaa aaaacgccaa tacatgtttt ataaaatatt ttcgtctgg tgttagttta 30660 ttccaatcat tgatatcttt agatatatct acttcttcca ctgtccaaaa tgatgcctct 30720 gcctttttat acatgttcca gatgtcataa tattggattg ggaaaataac aaatctattt 30780 ggatttggtg caaggatggg ttccataact aaattaacaa tatcaataaa ttttttttca 30840 gttatctata tgcctgtact tggatttttt gtacatcgat atcgccgcaa tcactacaat 30900 attacaagt attattgata gcattgttat tagtactatc ataattaaat tatcgacatt 30960 catgggtgct gaataatcgt tattatcatc attatcattt tgtaattgtg acatcatact 31020 aaataaatcg tttgcgagat tgttgtggga agcgggcatg gaggatgcat tatcattatt 31080 atttaacgcc ttccatttgg attcacaaat gttacgcaca ttcaacattt tatggaaact 31140 ataatttgtgt gaaaacagat aacaagaaaa ctcgttatcg ttcaaattttt taacgatagt 31200 aaaccgatta aacgtcgagc taatttctaa cgctagcgac tctgttggat atgggtttcc 31260 agatatatat cttttcagtt cccctacgta tctataatca tctgtaggaa atggaagata 31320 tttccattta tctactgttc ctaatatcat atgtggtggt gtagtagaac cattaagcgc 31380 gaaagatgtt atttcgcatc gtattttaac ttcgcaataa tttctggtta gataacgcac 31440 tctaccagtc aagtcaatga tattagcctt tacagatata ttcatagtag tcgtaacgat 31500 gactccatct tttagatgcg atactccttt gtatgtacca gaatcttcgt acctcaaact 31560 cgatatattt aaacaagtta atgagatatt aacgcgtttt atgaatgatg atatataacc 31620 agaagtttta tcctcggtgg ctagcgctat aaccttatca ttataatacc aactagtgtg 31680 attaatatgt gacacgttag tgtgggtaca aatatgtaca ttatcgtcta cgtcgtattc 31740 gatacatccg catacagcca acaaatataa aatgacaaat actctaacgc cgttcgtacc 31800 catcttgatg cggtttaata aatgttttga tttcaattta ttgtaaaaaa agattcggtt 31860 ttatactgtt cgatattctc attgcttata ttttcatcta tcatctccac acagtcaaat 31920 ccgtggttag catgcacctc atcaaccggt aaaagactat cggactcttc tatcattata 31980 actctagaat atttaatttg gtcattatta atcaagtcaa ttatcttatt tttaacaaac 32040 gtgagtattt tactcatttt ttataaaaac ttttagaaatattackagactc tatcgtgtgt 32100 ctatatcttc tttttatatc caatgtattt atgtctgatt tttcttcatt tatcatatat 32160 aatggtccaa attctacacg tgcttcggat tcatccagat cattaaggtt cttataattg 32220 taacatcctt ctcttccctc ttctacatct tccttcttat tcttattctt agcgtcacag 32280 aatctaccac agcaggatcc catgacgagc gtcatatta actattcat ttcaattat 32340 atatactgg taatgaccat taaaaaaa atattctca taaccggtaa gaagtgaa 32400 agttcacatt gaaactatgt cagtagtata catcatgaaa tgagatgaa tgatgatata 32460 tatactctat ttggtggag gattatatga tataattcgt ggataatcat ttttagaca 32520 catttcttta ttcgtaaatc tttcacgtt aatgagtgt ccatattttg caatttcttc 32580 atatgatggc ggtgtacgtg gacgaggctg ctcctgttct tgttgtagtc gccgactgtc 32640 gtgtttgcgt ttagatccct ccattatcgc gattgcgtag atggagtact attatatacc 32700 ttgtaattaa atttttttat taattaacg tataaaaacg ttccgtatct gtatttaaga 32760 gccagatttc gtctaataga aaatagct acagtaaaa taactagaat aattgctaca 32820 cccactagaa accacggatc gtaatacggc aatcggtttt cgataatagg tggaacgtat 32880 attttattta aggacttaac aattgtctgt aaaccacaat ttgctccgc ggatcctgta 32940 ttaactatct gtaaaagcat atgttgaccg ggcggagccg aacattctcc gatatctaat 33000 ttctgtatat ctataatatt attaacctcc gcatacgcat tacagttctt ttctagcttg 33060 gataccgcac taggtacatc gtctagatct attcctattt cttcagcgat agctcttcta 33120 tccttttccg gaagcaatga aatcacttca ataaatgatt caaccatgag tgtgaaacta 33180 agtcgagaat tactcatgca tttgttagtt attcggagcg cgcaattttt aaactgtcct 33240 ataacctctc ctatatgaat agcacaagtg acattagtag ggatagaatg ttgagctaat 33300 ttttgtaaat aactatctat aaaaagatta tacaaagttt taaactcttt agtttccgcc 33360 atttatccag tctgagaaaa tgtctctcat aataaatttt tccaagaaac taattgggtg 33420 aagaatggaa acctttaatc tatatttatc acagtctgtc ttggtacaca tgatgaattc 33480 ttctaatgct gtactaaatt cgatatcttt ttcgatttct ggatatgttt ttaataaagt 33540 atgaacaaag aaatggaaat cgtaatacca gttatgttta actttgaaat tgtttttat 33600 tttcttgtta atgattccag ccacttggga aaagtcaaag tcgtttaatg ccgatttaat 33660 acgttcatta aaaacaaact tttatcctt tagatgaatt attattggtt cattggaatc 33720 aaaaagtaag atattatcgg gtttaagatc tgcgtgtaaa aagttgtcgc agcatggtag 33780 ttcgtaaatt ttaatgtata acagagccat ctgtaaaaag ataaacttta tgtattgtac 33840 caaagattta aatcctaatt tgatagctaa ctcggtatct actttatctg cagaatacag 33900 tgctagggga aaaattaataa tatttcctct ttcgtattcg tagttagttc tcttttcatg 33960 ttcgaaaag tgaaacatgc ggttaaaata gtttataaca ttaatattac tgttaataac 34020 tgccgggtaa aagtgggata gtaatttcac gaatttgata ctgtcctttc tctcgttaaa 34080 cgcctttaaa aaaactttag aagaatatct caatgagagt tcctgaccat ccatagtttg 34140 tatcaataat agcaacatat gaagaacccg tttatacaga gtatgtaaaa atgttaattt 34200 atagtttaat cccatggccc acgcacacac gattaatttt ttttcatctc cctttagatt 34260 gttgtataga aatttgggta ctgtgaactc cgccgtagtt tccatgggac tatataattt 34320 tgtggcctcg atacaaatt ttactacata gttatctatc ttagacta taccatatcc 34380 tcctgtagat atgtgataaaatcgtcgtt tataggataa atcgtttat ccttttgttg 34440 gaaaaaggat gatttaatgt atcattctc ttctatcttt agtagtgttt ccctattaaa 34500 attcttaaaa taatttaaca atctactga cggagcccaa ttttgtgta atctaattg 34560 ggacattata ttgttaaaat acaacagtc tcctaatata acagtatctg ataatctatg 34620 gggagacatc cattgatatt cagggatga atcattggca acaccattt attgtacaaa 34680 aagccccaat ttacaaacga aagtccaggt ttgatagaga caactatta actattttgt 34740 ctctgttttt aatttcttta gtaatgaat tattcacaat atcagtatct tctttatcta 34800 ccagagattt tactacttg ataccttgg ctgtctcatt caataggta gtaatatttg 34860 tatgtgtgat ttgatatct tttgaattg tttcttg aagtgattct ttgatggtgc 34920 cagcatacga attacataa tgcagaaact cggttaacat gcaggaatta tagtaagcca 34980 attccaattg ttgcctgtat tgtattagag tattaatatg cgcaatggtg tccttgcgtt 35040 tctctgatag aatgcgagca gcgattttgg cgttatcatt tgacgatatt tctggaatga 35100 cgaatcctgt ttctactaac tttttggtag gacaaagtga aacaatcaag aagatagctt 35160 ctcctcctat ttgtggaaga aattgaactc ctctagatga tctactgacg atagtatctc 35220 cttgacagat attggaccga attacagaag tacctggaat gtaaagccct gaaaccccct 35280 cattttttaa gcagattgtt gccgtaaatc ctgcactgtg accaagatag agagctcctt 35340 tggtgaatcc atctctatgt ttcagtttaa ccaagaaaca gtcagctggt ctaaaatttc 35400 catctctatc taatacagca tctaacttga tgtcaggaac tatgaccggt ttaatgttat 35460 atgtaacatt gagtaaatcc ttaagttcat aatcatcact gtcatcagtt atgtacgatc 35520 caaacaatgt ttctaccggc atagtggata cgaagatgct atccatcaga atgtttccct 35580 gattagtatt ttctatatag ctattcttct ttaaacgatt ttccaaatca gtaactatgt 35640 tcattttttt aggagtagga cgcctagcca gtatggaaga ggattttcta gatcctctct 35700 tcacatctt tgatctcaat ggaatgcaaa acccatagt gaacaacca acgataaaaa 35760 taatattgtt ttcacttt tataatttta catctgact catggattca taataatctt 35820 tataagagct actaacgtat aattctttat aactgaactg agatatatac accggatcta 35880 tggtttccat attgagtaa atgaatgctc ggcaataact aatggcaat gtatagaaca 35940 acgaaattat actagagttg ttaaagttaa tattttctat gagctgttcc aaaattat 36000 ttgttgtgac tgcgttcaag tcataaatca tcttgatact atccagtaaa cagtctttaa 36060 gttctggaat attatcatcc cattgtaag cccctattc gactatcgaa tatcctgctc 36120 tgagcagt ttcaatcg acggacgtca atactgtaat aaagtgta gtattgtcat 36180 catcgtgata aactactgga atatggtcgt tagtaggtac ggtaacttta cacaacgcga 36240 tatataactt tccttttgta ccatttta cgtagttggg acgtcctgca gggtattgtt 36300 ttgaagaat gatatcgaga acgatttga tacgatattt gttggattcc tgatttatta 36360 ctataatata atctagacag atagatgatt cgataaatag aaaaggtata tcgttggtag 36420 gataatacat ccccattcca gtattctcgg atactctatt aatgacacta gttaagaaca 36480 tgtcttctat tctagaaaac gaaaacatcc tacatggact cattaaaact tctaacgctc 36540 ctgattgtgt ctcgaatgcc tcgtacaagg atttcaagga tgccatagat tctttgacca 36600 acgatttaga attgcgttta gcatctgatt ttttattaa atcgaatggt cggctctctg 36660 gtttgctacc ccaatgataa caatagtctt gtaaagataa accgcaagaa aatttatacg 36720 catccatcca aataacccta gcaccatcgg atgatattaa tgtattatta tagattttcc 36780 atccacagtt attgggccag tatactgtta gcaacggtat atcgaataga ttactcatgt 36840 aacctactag aatgatagtt cgtgtactag tcataatatc tttaatccaa tctaagaaat 36900 ataaattag atcttttaca ctgttaaagt taacaaaggt attacccgga tacgtggata 36960 tcatatatgg cattggtcca ttatcagtaa tagctccata aactgatacg gcgatggttt 37020 ttatatgtgt ttgatctaac gaggaagaaa ttcgcgccca caattcatct ctagatatgt 37080 atttaatc aaacggtac acatcaattt cgggacgcgt attgtttct aaatttttaa 37200. 37200. 37200. 37200. 37200. 37200. 37200. 37200. 37200 agaacttacg atacatctgt ttcctgtaat cgttaaattt tacaaatcta taacatgcta aaccttttga cgacaaccat tcattaatt ctgatatgga atctgtattc tcgataccgt attgttctaa agccagtgct atatctccct gttcgtggga acgctttcgt father tcaacggata atctgaagtt tttggagaat aatatgactc atgatctatt tcgtccataa acaatctaga cataggaatt ggaggcgatg atcttaattg tgtgcaatga gtcgtcaatc ctataacttc taatcttgta atattcatca tcgacataat actatctatg ttatcatcgt attachment accatgacct tcttcatttc gtgccaaaat gatatacagt cttaaatagt tacgcaatat ctcaatagtt tcataattgt tagctgtttt catcaagatt tgtaccctgt ttacatgat ggcgttctat acgtttctat tttctatttt ttaaattttt aacgatttac tgtggctaga tacccaatct ctctcaaata tttttagc ctcgcttaca agctgtttat 37800 ctatactatt aaaactgacg aatccgtgat tttgtaatg ggttccgtcg aaatttgccg 37860 aagtgatatg aacatattcg tcgtcgacta tcaacaattt tgtattattc tgaatagtga 37920 aaaccttcac agatagatca tttgacac acacgcgtc tagactctg gcggttgcca 37980 tagaatac gtcgttctta tcccattac caactagag tctgatctta actccctctat 38040 taatggctgc ttctataatg gagttgtaaa tgtcgggcca atagtagcta ttaccgtcga 38100 cacgtgtagt gggaactatg gccaaatgtt caattactat actagtctta gctgacctga 38160 gtttatcaat actacatcg gtatctagat cttagaata tcccaatagg tgttccggag 38220 aatcagtaaa gaacactcca cctataggat tcttatatg atacgcagtg ctaactggca 38280 gracaacaagc cgcagagcat aaattcacc atgaatttt tgcgctatta aaggctttaa 38340 aagtatcaa tctctacga agatctgtgg ccagcggggg ataatcaga atacaccta 38400 acgttttaat cgtatgtata gatcctccag taaatgacgc gtttcctaca taacatctt 38460 catcatctga cacccaaaaa caccgagta gtagtcccac attatttttt ttatctatat 38580. tccggttat aaaattata tccggggcagt gactttgtag ctctcccaga tttctttccga ctcgttcatc tagcaaaact attattttaa tccctttttc agatgcctct tttagttttat 38700. cgctccccta gtcgtactca gaggattaca acaaaagat gctatgtata tatattctt agctagagtg ataatttcgt taaaacattc aaatgttgtt aaatgatcgg atctaaaatc catattttct ggtagtgttt ctaccagcct acattttgct cccgcaggta 38820. ccgatgcaaa tggccacatt tagttacat aaaaacttat acatcctgtt ctatcaacga ttctagaata tcatcggcta tatcgctaa attttcatca aagtcgacat cacaacctaa ctcagtcaat attack gttccatgat gtcatcttcg tttatttcta tatccgtatc cattgtag tgttgaccga ttatcgagtt taaatcatta ctaatactca atccttcaga atacaatctg tgtttcattg taaattata ggcggtgtat ttagttggt agattttcaa ttatgtatca atatagcaac agtagttctt gctcctcctt gattctagca tcctcttcat 39180 tattttcttc tacgtacata aacatgtcca atacgttaga caacacaccg acgatggcgg 39240 ccgccacaga cacgaatatg actaaaccga tgaccattta aaaacccctc tctagctttc 39300 acttaaactg tatcgattat tcttttagaa catgtataat ataaaaacat tattctattt 39360 cgaatttagg cttccaaaaa tttttcatcc gtaaaccgat aataatatat atagacttgt 39420 taatagtcgg aataaataga ttaatgctta aactatcatc atctccacga ttagagatac 39480 aatatttaca ttctttttgc tgtttcgaaa ctttatcaat acacgttaat acaaacccag 39540 gaaggagata ttgaaactga ggctgttgaa aatgaaacgg tgaatacaat aattcagata 39600 atgtaaaatc atgattccgt attctgatga tattagaact gctaatggat gtcgatggta 39660 tgtatctagg agtatctatt ttaacaaagc atcgatttgc taatatacaa ttatcctttt 39720 gattaattgt tattttattc atattcttaa aaggtttcat atttatcaat tcttctacat 39780 taaaaatttc catttttaat ttatgtagcc ccgcaatact cctcattacg tttcattttt 39840 tgtctataat atccattttg ttcatctcgg tacatagatt atccaattga gaagcgcatt 39900 tagtagtttt gtacatttta agtttattga caatcgtcg aaactagtt atagttaca 39960 ttttattatt tgataccctg atattac ccctgccgtt acttattatt atactgatg 40020 taatccacgt aacattagaa ttaattatcg atagtaatgc atcgacgctt ccaaaattgt 40080 ctattataaa ctcaccgata atttttt tgcatgtttt catattcatt aggattca 40140 aatctttaat cttattacga ttgtagcgt tgatattgca agacgtcatt ctaaaagacg 40200 gaggatctcc atcaatgcc aaacaatcac gtacaaagta catggaata ggttttgttc 40260 tattgcgcat catagattta tatagacac ccgtagaaat actaatttgt tttactctat 40320 aaatactaa tgcatctatt tcatcgtttt gtataacgtc ttccaagtg tcaattcca 40380 aattttttc attgagta ccaaattctt ctatctcttt aactacttgc atagataggt 40440 aattacagtg atgcctacat gccgtttttt gaaactgaat agatgcgtct agaagcgatg 40500 ctacgctagt cacaatcacc actttcatat ttagaata tgtagtaaa atatagtag 40560 aatttcattt tgttttttc tatgctataa atgaattctc attttgcatc tgctcatact 40620 ccgttttata tcaataccaa agaaggaga tattttggttc taaaagccgt taaagtagc 40680 gatgttagaa ctgtagaatg tgaggagt aaagcttcct gcgtactcaa agtagataa 40740 ccctcatcac ccgcgtgtga gagaagacct tcgtcccctt ccagatgcga gagaatgaat 40800 aacccaggaa aacaagttcc gtttatgagg acggacatgc tacaaatat gttcgcggct 40860 aatcgcgata atgtagcttc tagactttg tcctaaaata ctattatatc cttttcgata 40920 ttaataaatc cgtgtcgtcc aggtttta tctctttcag tatgtgaata gatagtatt 40980 ttatctctat tcatcatcga atttagaga tccgataac attgttgta ttctccagat 41040 gtcagcatct gatacaa tatatgtgca cataaacctc tggcacttat ttcatgtacc 41100 ttccccttat cactaggag atagtattt gagaaatatg tatacatgat attatcatga 41160 attagatata cagaatttgt aacactctcg aaatcacacg atgtgtcggc gttaagatct 41220 aatatatcac tcgataacac attttcatct agatacacta gacatttttt aaagctaaaa 41280 tagtctttag tagtgacagt aactatgcga ttattttcat cgatgataca tttcatcggc 41340 atattattac gcttaccatc aaagactata ccatgtgtat atctaacgta ttctagcatg 41400 gttgccatac gcgcattaaa cttttcagga tctttggata gatcttccaa tctatctatt 41460 tgagaaaaca tttttatcat gttcaatagt tgaaacgtcg gatccactat atagatatta 41520 tctataaaga ttttaggaac tacgttcatg gtatcctggc gaatattaaa actatcaatg 41580 atatgattat cgttttcatc tttatcacc atatagtttc taagatatgg gattttactt 41640 aatataatat tatttcccgt gataaatttt attagaagg ccaaatctat aagaaaagtc 41700 ctagaattag tctgaagaat atctatatcg ccgtatagta tatttggatt aattagatat 41760 agagaatatg atccgtaaca tatacaactt ttattatggc gtctaagata ttcttccatc 41820 aacttattaa catttttgac tagggaagat acattatgac gtcccattac ttttgccttg 41880 tctattactg cgacgttcat agaatttagc atatctcttg ccaattctc cattgatgtt 41940 acattataag aattttaga tgaattaca tttggagctt tatagtaag aactcctaat 42000 atgtccgtgt atgtggtcac taatacagat tgtagttcta taatcgtaaa taatttacct 42060 atattatatg tttgagtctg tttagaaag tagctagta tacgatcttt tattctct 42120 gcagatgtat taacatcgga aaaaaatctt ttttactct ttttacta agatacaaat 42180 atgtctttgt taaaaacagt tattttttga atatttctag cttgtaattt taacatatga 42240 tattcgttca cactaggtac tctgcctaaa taggtttcta taatctttaa tgtaatatta 42300 ggaaaagtat tctgatcagg attcctattc attttgagga tttaaactc tgattattgt 42360 ctaatatggt cttacgcaa actttcac agagcgag agttttgat aactcgtttt 42420 tcttaagaaa tataaaacta ctgtctccag agctcgctct atctttatt ttatctatt 42480 cgatacaaac tcctgatact gttcagaaa gtattcatt aattttcagt cctttataga 42540 agatatttaa tatagatat acaaatctt cagtttttga tatcgatctg attgatccta 42600 gaactagata tattatac gtgctcatta ggcagtttat ggcagcttga tattagata 42660 tagtatattc cagttcatat ttattagata ccgcattgcc cagatttga tattctatga 42720 attcctctga aataaatcc aaataacta gatatctat tttgtgga ttagtgtact 42780 ctcttccctc tatcatgttc actactggtg tccacgatga taaatatcta gaggaatat 42840 atatagtcc ataggatgcc aatctagcaa tgtcgaataa ctgtaatttt attcttcgct 42900 cttcattatg attgattct tgaggtataa acctacaca aattatatta ttagactttt 42960 cgtatgtaat gtctttcatg ttataagtttt ttaatcctgg atagaatct attttaatga 43020 ggcttttaaa cgcagagttc tccacgagt caaagcataa tactctgttg ttttcttat 43080 attackgtt acgattttct tctttgaatg gataggtttt tgattagt attack 43140 aacataatag attaggagt gtgcaatag tacgcggaaaaacatata gctcccctgt 43200 ttcatccat ggttttaagt aaatgatcac tggctcttt agtcaatgga tattcgaaca 43260 ttaccgttt catcatcatt ggacagaatc catattttt atgtaaga gtgatcaaat 43320 cattgtgttt attgtaccat cttgttgtaa atgtgtattc ggttatcgga tctgctcctt 43380 tttctattaa agtatcgatg tcgatctcgt ctaagaattc aactatatcg acatattca 43440 tttgtataca cataaccatt actaacgtag atgtatagg aagagatgta acgggaacag 43500 ggtttgttga ttcgcaact attctaatac atattctc tgttaatacg tcttgcacgt 43560 aatctattat agatgccaag attackctatat attackttg taagagatg ttaactatgt 43620 gatctatata agtagtgtaa taattcatgt attttgatat atgttccaac tctgtctttg 43680 tgatgtctag tttcgtaata tctatagcat cctcaaaaa tatattcgca tatattccca 43740 agtcttcagt tctatcttct aaaaaatctt caacgtatgg atatataa tctattttac 43800 ctcttctgat atcattaatg atagtttt tgacactatc ttctgtcaat tgattcttat 43860 tcactatatc taagaaacgg atagcgtccc taggacgac tactgccatt aatctcta 43920 ttatagcttc tggacataat tcatctatta taccagaatt atgggaact attccgtatc 43980 tatctaacat agttttaaga aagtcagaat ctaagacttg atgttcatat attggttcat 44040 acatgaaatg atctctattg atgatagtga ctatttcatt ctctgaaaat tggtaactca 44100 ttctatatat gctttccttg ttgatgaagg atagaatata ctcaatagaa tttgtaccaa 44160 caaactgttc tcttatgaat cgtatatcat catctgaaat aatcatgtaa ggcatacatt 44220 taacaattag agacttgtct cctgttatca atatactatt cttgtgataa tttatgtgtg 44280 aggcaaattt gtccacgttc tttaattttg ttatagtaga tatcaaatcc aatggagcta 44340 cagttcttgg cttaaacaga tatagttttt ctggaacgaa ttctacaaca tttataaa 44400 ggactttggg tagataagtg ggatgaaatc ctattttaat taatgcgata gccttgtcct 44460 cgtgcagata tccaaacgct tttgtgatag tatggcattc attgtctaga aacgctctac 44520 gaatatctgt gacagatatc atctttagag atatactag tcgcgttaat agtactacaa 44580 tttgtatttt ttaatctatc tcaataaaaa aattaatatg tatgattcaa tgtataacta 44640 aactactaac tgttattgat aactagaatc agaatctaat gatgacgtaa ccaagaagtt 44700 tatctactgc caatttagct gcattatttt tagcatctcg tttagatttt ccatctgcct 44760 tatcgaatac tcttccgtcg atatctacac aggcataaaa tgtaggagag ttactaggcc 44820 ccactgattc aatacgaaaa gaccaatctc tcttagttat ttggcagtac tcattaataa 44880 tggtgacagg gttagcatct ttccaatcaa taattttttt agccggaata acatcatcaa 44940 aagacttatg atcctctctc attgattttt cgcgggatac atcatctatt atggcgtcag 45000 ccataacatc agcatccggc ttatccgcct ccgttgtcat aaaccaacga ggaggaatat 45060 cgtcggagct gtacaccata gcactacgtt gaagatcgta cagagcttta ttaacttctc 45120 gcttctccat attaagttgt ctagttagtt gtgcagcagt agctccttcg attccaatgt 45180 ttttaatagc cgcacacaca atctctgcgt cagaacgctc gtcaatatag atcttagaca 45240 tttttagaga gaactaacac aaccagcaat aaaactaatt tattttatca tttttttatt 45300 catcatcctc tggtggttcg tcgtttctat cgaatgtgga tctgattaac ccgtcatcta 45360 taggtgatgc tggttctgga gattctggag gagatggatt attatctgga agaatctctg 45420 ttattcctt gttttcatgt atcgattgcg ttgtaacatt aagattgcga aatgctctaa 45480 atttgggagg cttaaagtgt tgtttgcaat ctctacacgc atgtctaact agtggaggtt 45540 cgtcagcggc tctagtttga atcatcatcg gcgtagtatt cctactttta cagttaggac 45600 acggtgtatt gtatttctcg tcgagaacgt taaaataatc gttgtaactc acatccttta 45660 ttttatctat attgtattct actcctttct taatgcattt tataccgaat aagagatagc 45720 gaaggaattc ttttcggtg ccgctagtac ccttaatcat atcacatagt gttttatatt 45780 ccaaatttgt ggcaatagac ggtttatttc tatacgatag tttgtttctg gaatcctttg 45840 agtattctat accaatatta ttctttgatt cgaatttagt ttcttcgata ttagattttg 45900 tattacctat attcttgatg tagtactttg atgatttttc catggcccat tctattaagt 45960 cttccaagtt ggcatcatcc acatattgtg atagtaattc tcggatatca gtagcggcta 46020 ccgccattga tgtttgttca tggatgagt aactactaat gtatacattt tccatttata 46080 acacttatgt attackttg ttcatttata ttttcatt attatgttga tattaacaa 46140 agtgaatata tatatatgtt aaattgta ttgtggttat acggctacaa ttttataatg 46200 agtgaaagtc agtgtccgat gatcaatgac gatagcttta ctctgaaag aaagtatca 46260 atcgatagtg cggagtcaac aaaaaatg gatagaga ggataagtt tcagaataga 46320 gccaaaatgg tAAaagaat aaatcagaca atagagcag cacaactca ttacgagaca 46380 ttgaaactag gatacataaa atttagaga atgattagga ctactactct agagatata 46440 gcaccatcta ttccaataa tcagaaaact tataaactat tctcggacat ttcagccatc 46500 ggcaaagcat cacagaatcc gagtaagatg gtatatgctc tgctgcttta catgtttccc 46560 aatttgtttg gagatgatca tagattcatt cgttatagaa tgcatccaat gagtaaaatc 46620 aaacacaaga tctctctcc ttcaactt aatcttatta gatatagt ggaagaaga 46680 ttctataata atgaatgcag atctataa tggaaaataa ttggaacaca agttgataaa 46740 atgttgatag ctgaatctga taaataca atagatgcaa ggtataacct aaaacccatg 46800 tagaatca agggaatc tgaggagat acccttta tcaacagat ggtagacaa 46860 tgtgtgacat cccaggaatt ggtggaaaaa gtgttgaaga tacttttag agatttgttc 46920 aagagtggag atacaagc gtacagatac gatgatg tegaatgg atttattg 46980 ttggatacac taaaattaaa cattgttcat gatatagttg aaccatgtat gcctgttcgt 47040 aggccagtgg ctaagatact gtgtaagaa atggtaaata atactttga gatccgcta 47100 catattattg gtaaaaatct tcagagtgc attgactttg ttagtgaata ggcatttcat 47160 ctttctccaa tactattca aattgttaaa ttaataatgg atagtataaa tagttattag 47220 tgaaaaata gtaaaaata ttattagaat aagagtgtag tatcatagat aactctcttc 47280 tataaaaatg gatttattc gtagaaagta tcttatatac acagtagaaa atatataga 47340 ttttttaaag gatgatacat taagtaagt aaacaattt accctcaatc atgtactagc 47400 tctcaagtat ctagttagca atttcctca acacgttatt actaggatg tattagctaa 47460 taccaattttt ttgttttca tacatatggt acgatgttgt aaagtgtacg aagcggtttt 47520 acgacacgca ttgatgcac ccacgttgta cgttaaagca ttgactaaga attatttac 47580 gtttagtaac gcaatacaat cgtacaagga aaccgtgcat aaactacac aagatgaaaa 47640 atttttagag gttgccgaat acatggacga attaggagaa cttataggcg taaatttaga 47700 cttagttctt aatccattat ttcacggagg ggaacccatc aagatatgg aaatcatttt 47760 tttaaaactg tttaagaaaa cagactcaa agttgttaaa aaattaagtg ttataagatt 47820 acttattgg gcatacctaa gcaagaaga tacaggcata gagtttgcgg atatgatag 47880 axagatata tatactctat ttcacaac tggtagaatc gtccatagca atctaacaga 47940 aacgtttaga gattatatct ttcccggaga tagactagc tattggttgt ggttaaacga 48000 aagtatagct aatgatgcgg atatcgttct taatagacac gccattacca tgtatgataa 48060 aattcttagt tatatatact ctgagataaa acagggacgc gttataaaa acatgcttaa 48120 gttagtttat atctttgagc ctgaaaaaga tatcagagaa cttctgctag aaatcatata tgatattcct ggagatatcc tatctattat tgatgcaaaa aacgacgatt ggaaaaaata ttttattagt ttttataag ctaattttat taacggtaat acatttatta gtgatagaac gtttaacgag gacttattca gagttgttgt tcaatagat cccgaatatt tcgataatga acgaattatg tctttattct ctacgagtgc tgcggacatt aaacgatttg atgagttaga father father father father ttatgaggtg aacgatatca cattagatac aatggatgat atgaagaagt gtcaaatctt taacgaggat acgtcgtatt atgttaagga atacaataca tacctgtttt tgcacgagtc ggatcccatg gtcatagaga acggaatact 48600 48660. aaagaaactg tcatctaa aatccaagag tagacggctg aacttgttta gcaaaaacat tttaaaatat tatttagacg gacaattggc tcgtctaggt cttgtgttag atgattata aggagacttg ttagttaaaa tgataaacca tcttaagtct gtggaggatg tatccgcatt cgttcgattt tctacagata aaaaccctag tattctcca tcgctaatca aaactatttt 48840 agctagttat atattcca tcatcgtctt atttcaagg ttttaagag ataatctata 48900 tcatgtagaa gattcttgg aaaagcat ccatctaacc aagacggata agaaatatat 48960 acttcaattg atagacacg gtagatcata gaacagacca atattatta taataatttg 49020 tatatacata gatatta tcacatatta aaaattcaca cattttgat aaatgggaac 49080 tgctgcaaca attcagactc ccaccaatt aatgaataaa gaaaatgcag aaatgatttt 49140 ggaaaaaatt gttgatcata tagttatgta tattagtgac gatcaagtg attcagaaaa 49200 taatcctgaa tatattgat ttcgtaacag atacgagac tatagatctc tcattataa 49260 aagtgatcac gagtttgtaa agctatgtaa aaatcatgca gagaaagtt ctccagaaac 49320 gcacaaatg attcaaac acaatacga acaatactt attccagtat ctgaagtact 49380 attaaaacct ataatgtcca tgggtgacat aattacatat aacggatgta aagacaatga 49440 atggatgcta gaacaactct ctaccctaa ctttacacaat ctccgcacat ggaactcatg 49500 tagcataggc aatgtaacgc gtctgtttta tacatttttt agttatctga tgaaagataa 49560 actaaatata taagtataat cccattctaa tactttaacc tgatgtatta gcatcttatt 49620 agaatattaa cctaactaaa agacataaca taaaaactca ttacatagtt gataaaaagc 49680 ggtaggatat aaatattatg gctgccaccg ttccgcgttt tgacgacgtg tacaaaaatg 49740 cacaaagaag aattctagat caagaaacat tttttagtag aggtctaagt agaccgttaa 49800 tgaaaaacac atatctattt gataattacg cgtatggatg gataccagaa actgcaattt 49860 ggagtagtag atacgcaaac ttagatgcaa gtgactatta tcccatttcg ttgggattac 49920 ttaaaaagtt cgagtttctc atgtctctat ataaaggtcc tattccagta tacgaagaaa 49980 aagtaaatac tgaattcatt gctaatggat cgttctctgg tagacgta tcatatcttc 50040 gaaagttttc tgctcttcca acaaacgagt ttattagttt tttgttactg acttccattc 50100 caatctataa tatcttgttc tggtttaaaa atactcagtt tgatattact aaacacacat 50160 tattcagata cgtctataca gataatgcca aacacctggc gttggctagg tatatgcatc 50220 aaacaggaga ctataagcct ttgtttagtc gtctcaaaga gatttatata tttaccggtc 50280 ccgttccaat aggtatcaa gatataaatc accctaatct tagtagagca agaagtccat 50340 ccgatttaga gatatagct atattagta ctatattgta ctttaccaag tatgatccgg 50400 tattaatgtt tttattgtt tacgtacctg ggtattcaat tactacaaaa attackccag 50460 ccgtagaata tctaatggat aactgaatc taacaagag cgacgtacaa ctgttgtaaa 50520 ttctttatg cttcgtaaaa tgtaggtttt gaaccaaca ttctttcaa gatgagatg 50580 cataaaactt tattatcha tagattgact atttcggacg tcaatcgtttt aaagtaact 50640 tcgtaaaata ttctttgatc actgccgagt ttaaaacttc tatcgataat tgttcatat 50700 gttttaatat ttacaagtttt ttggtccat ggtacattag ccggacaaat attgcaaaa 50760 taatatcgtt ctccaagttc tatagttctt ggattatttt tattatattc agtaaccaaa 50820 tacatattag ggttatctgc ggatttataa tttgagtgat gcattcgact siacataaat 50880 aattctagag gagacgatct actatcaaat tcggatcgta aatctgtttc taaagaacgg agaatatcta tacatacctg attachment atccgtcctt cagacaacat ctcagacagt ctggtcttgt atgtcttaat catattctta tgaaacttgg aaacatctct tctagtttca ctagtacctt tattaattct ctcaggtaca gattttgaat tcgacgatgc cgagtatttc atcgttgtat atttcttctt cgattgcata atcagattct fatherccgc ctcaaactct attttaaaat tattaaacaa tactctatta ttaatcagtc gttctaactc ctttgctatt tctatggact tatctacatc ttgactgtct atctctgtaa acacggagtc ggtatctcca 51360. 51360. 51360. 51360. 51360. 51360. 51360. 51360 atatctctat cgtccatata aaatggatta cttaatggat tggcaaaccg taacataccg ttgataact ctgctccatt tctgataca agatcattct acgtcctatg gatgtgcaac tcttagccga agcgtatgag father tatttctaaa tcccatcaga ccatatactg agttggctac tatcttgtac gtatattgca tggaatcata gatggccttt 51600 tcagttgaac tggtagcctg ttttaacatc ttttatatc tggctctctc tgccaaaaat 51660 gttcttaata gtctaggaat ggttccttct atcgatctat cgaaaattgc tatttcagag 51720 atgaggttcg gtagtctagg ttcacaatga accgtaatat atctaggagg tggatatttc 51780 tgaagcaaga gctgattatt tatttcttct tccaatctat tggtactaac aacgacaccg 51840 actaatgttt ccggagatag atttccaaag atacacacat taggatacag actgttataa 51900 tcaaagatta atacattatt actaaacatt ttttgttttg gagcaaatac cttaccgcct 51960 tcataaggaa acttttgttt tgtttctgat ctaactaaga tagttttagt ttccaacaat 52020 agctttaaca gtggaccctt gatgactgta ctcgctctat attcgaatac catggattga 52080 ggaagcacat atgttgacgc acccgcgtct gttttttgttt ctactccata atactcccac 52140 aaatactgac acaaacaagc atcatgaata cagtatctag ccatatctaa agctatgttt 52200 agattaat ccttatacat ctgagctaaa tcaacgtcat cctttccgaa agataattta 52260 tatgtatcat taggtaaagt aggacataat agtacgactt taaatccatt ttcccaaata 52320 tctttacgaa ttactttaca tataatatcc tcatcaacag tcacataatt acctgtggtt 52380 aaaacctttg caaatgcagc ggctttgcct ttcgcgtccg tagtatcgtc accgatgaac 52440 gtcatttctc taactcctct atttaatact ttacccatgc aactgaacgc gttcttggat 52500 atagaatcca atttgtacga atccaatttt tcagattttt gaatgaatga atatagatcg 52560 aaaaatatag ttccattatt gttattaacg tgaaacgtag tattggccat gccgcctact 52620 cccttatgac tagactgatt tctctcataa atacagagat gtacagcttc ctttttgtcc 52680 ggagatctaa agataatctt ctctcctgtt aataactcta gacgattagt aatatatctc 52740 agatcaaagt tatgtccgtt aaaggtaacg acatagtcga acgttagttc caacaattgt 52800 ttagctattc gtaacaaaac tatttcagaa cataaaacta gttctcgttc gtaatccatt 52860 tccattagtg actgtatcct caaacatcct ctatcgacgg cttcttgtat ttcctgttcc 52920 gttaacatct cttcattaat gagcgtaac ataatcgtt taccactta atcgatataa 52980 cagtaacttg tatgcgagat tgggttaata atacagaag gaacttctt atcgaagtga 53040 cactctatat ctagaaataa gtacgatctt gggatatcga atctaggtat tttttagcg 53100 aaacagttac gtggatcgtc acaatgataa catccattgt taatctttgt caatattgc 53160 tcgtccaacg agtaacatcc gtctggagat atcccgttag aaatataaaa ccactaata 53220 ttgagaaatt catccatggt ggcattttgt atgctgcgtt tctttggctc ttctatcaac 53280 cacatatctg cgacggagca tttctatct ttaatatcta gattataact tattgtctcg 53340 tcaatgtcta tagttctcat ctttcccac ggcctcgcat taatggagg aggagacaat 53400 gactgatata ttcgtccgt caccgtaa taaaagtaat gaggaatcg tataaatacg 53460 gtctcaccat ttcgacatct ggatttcaga tataaaaatc tgttcacc gtgactttca 53520 aaccaattta tgcaccgaac atccatttat agaatttaga atatatttt catttaaatg 53580 aatccaaac attggggaag agccgtatgg accattattt tttagtact ttcgcaagcg 53640 ggtttagacg gcaacataga agcgtgtaaa cgaaaactat atactatagt tagcactctt 53700 ccatgtcctg catgtagacg gcacgcgact atcgctatag aggacaataa tgtcatgtct 53760 agcgatgatc tgaattatat ttattatttt ttcatcagat tatttaacaa tttggcatct 53820 gatcccaaat acgcgatcga tgtgacaaag gttaaccctt tataaactta acccattata 53880 aaacttatga ttagtcacga ctgaaataac cgcgtgatta tttttggta taattctaca 53940 cggcatggtt tctgtgacta tgaattcaac ccccgttaca ttagtgaaat ctttaacaaa 54000 cagcaagggt tcgtcaaaga cataaaactc attgtttaca atcgaaatag accccctatc 54060 acacttaaaa taaaaaatat ccttatcctt taccaccaaa taaaattctg attggtcaat 54120 gtgaatgtat tcacttaaca gttccacaaa tttatttat aactccgagg cacatacatc 54180 gtcggtattt tttatggcaa actttactct tccagcatcc gtttctaaaa aaatattaac 54240 gagttccatt tatatcatcc aatattatg aaatgacgtt gatggacaaa tgatacaaat 54300 aagaaggtac ggtacctttg tccaccatct cctccaattc atgctctatt ttgtcattaa 54360 ctttaatgta tgaaaacagt acgccacatg cttccatgac agtgtgtaac actttggata 54420 caaaatgttt gacattagta taattgttca agactgtcaa tctataatag atagtagcta 54480 tatatattc tatgatggta ttgaagaaga tgacaacctt ggcatattga tcatttaaca 54540 cagacatggt atcaacagat agcttgaatg aaagagaatc agtaattgga ataagcgtct 54600 tctcgatgga gtgtccgtat accaacatgt ctgatatttt gatgtattcc attaaattat 54660 ttagtttttt ctttttattc tcgttaaaca gcatttctgt caacggaccc caacatcgtt 54720 gaccgattaa gttttgattg atttttccgt gtaaggcgta tctagtcaga tcgtatagcc 54780 tatccaataa tccatcgtct gtgcgtagat cacatcgtac actttttaat tctctataga 54840 agagcgacag acatctggag caattacaga cagcaatttc tttattctct acagatgtaa 54900 gatacttgaa gacattccta tgatgatgca gaattttgga taacacggta ttgatggtat 54960 ctgttaccat aattccttg atggctgata gtgtcagagc acaagatttc caatctttga 55020 caatttttag caccattatc tttgttttga tatctatatc agacagcatg gtgcgtctga 55080 caacacaagg attaagacgg aaagatgaaa tgattctctc aacatcttca atggatacct 55140 tgctattttt tctggcatta tctatatgtg cgagaatatc ctctagagaa tcagtatcct 55200 ttttgatgat agtggatctc aatgacatgg gacgtctaaa ccttcttatt ctatcaccag 55260 attgcatggt gatttgtctt ctttctttta tcataatgta atctctaaat tcatcggcaa 55320 attgtctata tctaaaatca tatatgaga tgtttacctc tacaaatatc tgttcgtcca 55380 atgttagagt attacatca gttttgtatt ccaaattaaa catggcaacg gatttaattt 55440 tatattcctc tattaagtcc tcgtcgataa taacagaatg tagataatca tttaatccat 55500 cgtacatggt tggaagatgc tcgttgacaa aatctttaat tgtcttgatg aaggtgggac 55560 tatatctaac atcttgatta ataaaattta taacattgtc cataggatac tttgtaacta 55620 gtttataca catctcttca tcggtaagtt tagacagaat atcgtgaaca ggtggtatat 55680 tatattcatc agatatacga agaacaatgt ccaaatctat attgtttaat atattatata 55740 gatgtagtgt agctcctaca ggaatatctt taactaagtc aatgatttca tcaaccgtta 55800 gatctatttt aaagttaatc atataggcat tgatttttaa aaggtatgta gccttgacta 55860 cattctcatt aattaaccat tccaagtcac tgtgtgtaag aagattatat tctatcataa 55920 gcttgactac atttggtcc gataccatta aagaattctt atgatataag gaaacagatt 55980 ttaggtactc atctactcta caagaatttt ggagagcctt aacgatatca gtgacgttta 56040 ttatttcagg aggaaaaaac ctaacattga gaatatcgga attaatagct tccagataca 56100 gtgatttg caatagtccg tgtaatccat aatccagtaa cacgagctgg tgcttgctag 56160 acaccttttc aatgtttaat ttttttgaaa tagactttga taaagccttc ctcgcaaatt 56220 ccggatacat gaacatgtcg gcgacatgat taagtattgt ttttcatta tttttatatt 56280 ttctcaacaa gttctcaata ccccaataga tgatagaata tcacccaatg cgtccatgtt 56340 gtctatttcc aacaggtcgc tatatccacc atagaagtt ttcccaaaaa agattctagg 56400 aacagttcta ccaccagtaa tttgttcaaa atagtcacgc aattcatttt cgggtttaaa 56460 ttctttaata tcgacaattt catacgctcc tcttttgaaa ctaaacttat ttagaatatc 56520 cagtgcattt ctacaaaaag gacatgtata cttgacaaaa attgtcactt tgttattggc 56580 caacctttgt tgtacaaatt cctcggccat tttatatattt aagtgatata aaactatctc 56640 gacttattta actctttagt cgagatatat ggacgcagat agctatatga tagccaacta 56700 cagaaggcaa acgctataaa aaacataatt acgacgagca tatttataaa tatttttatt 56760 cagcattact tgatatagta atattaggca cagtcaaaca ttcaaccact ctcgatacat 56820 taactctctc atttcttta acaaattctg caatatcttc gtaaaaagat tcttgaaact 56880 ttttagaata tctatcgact ctagatgaaa tagcgttcgt caacatacta tgttttgtat 56940 acataaaggc gcccatttta acagtttcta gtgacaaaat gctagcgatc ctaggatcct 57000 ttagaatcac atagattgac gattcgtctc tcttagtaac tctagtaaaa taatcataca 57060 atctagtacg cgaaataata ttatccttga cttgaggaga tctaaacaat ctagttttga 57120 gaacatcgat aagttcatcg ggaatgacat acatactatc tttaatagaa ctcttttcat 57180 ccagttgaat ggattcgtcc ttaaccaact gattaatgag atcttctatt ttcatcattt 57240 ccagatgata tgtatgtcca ttaaagttaa attgtgtagc gcttctttt agtctagcag 57300 ccaatacttt aacatcacta atatcgatat acaaaggaga tgatttatct atggtattaa 57360 gaattcgttt ttcgacatct gtcaaaacca attccttttt gcctgtatca tccagttttc 57420 catccttgtgt aaagaaatta ttttctacta gactattaat aagactgata aggattcctc 57480 cataattgca caatccaaac ttttcacaa aactagactt tacaagatct acaggaatgc 57540 gtacttcagg tttcttagct tgtgattttt tctttgtgg acattttctt gtgaccaact 57600 catctaccat ttcattgatt ttagcagtga aataagcttt caatgcacgg gcactgatac 57660 tattgaaaac gagttgatct tcaaattccg ccatttaagt tcaccaaaca acttttaaat 57720 acaaatatat caatagtagt agaataagaa ctataaaaaa aataataatt aaccaatacc 57780 aaccccaaca accggtatta ttagttgatg tgactgtttt ctcatcactt agaacagatt 57840 taacaatttc tataaagtct gtcaaatcat cttccggaga ccccataaat acaccaaata 57900 tagcggcgta caacttatcc atttatacat tgaatattgg cttttcttta tcgctatctt 57960 catcatattc atcatcaata tcaacaagtc ccagattacg agccagatct tcttctacat 58020 tttcagtcat tgatacacgt tcactatctc cagagagtcc gataacgtta gccaccactt 58080 ctctatcaat gattagtttc ttgagtgcga atgtaatttt tgtttccgtt ccggatctat 58140 agaaaactac aggtgtgata attgccttgg ccaattgtct ttctctttta ctgagtgatt 58200 ctagttcacc ttctatagatat ctgagaatgg atgattctcc agtcgaaaca tattctacca 58260 tggctccgtt taatttgttg atgaagatgg attcatcctt aaatgttttc tctgtaatag 58320 tttccaccga aagactatgc aaagaatttg gaatgcgttc cttgtgctta atgtttccat 58380 agacggcttc tagaagttga tacaacatag gactagccgc ggtaactttt attttagaa 58440 agtatccatc gcttctatct tgtttagatt tatttttata aagtttagtc tctccttcca 58500 acataataaa agtggaagtc atttgactag ataaactatc agtaagtttt atagagatag 58560 acgaacaatt agcgtattga gaagcattta gtgtaacgta ttcgatacat tttgcattag 58620 atttactaat cgattttgca tactctataa cacccgcaca agtctgtaga gaatcgctag 58680 atgcagtagg tcttggtgaa gtttcaactc tcttcttgat taccttactc atgattaaac 58740 ctaaatatt gtactttgta atataatgat atatattttc actttatctc atttgagaat 58800 aaaaatgttt ttgtttaacc actgcatgat gtacagattt cggaatcaca aaccaccggt 58860 ggttttatt tatccttgtc caatgtgaat tgaatgggag cggatgcggg tttcgtacgt 58920 agatagtaca ttcccgtttt tagaccgaga ctccatccgt aaaaatgcat actcgttagt 58980 ttggaataac tcggatctgc tatatggata ttcatagatt gactttgatc gatgaaggct 59040 cccctgtctg cagccatttt tatgatcgtc ttttgtggaa tttcccaaat agttttataa 59100 actcgcttaa tatcttctgg aaggtttgta ttctgaatgg atccaccatc tgccataatc 59160 ctattcttga tctcatcatt cataatttt ctctcggtta aaactctaag gagatgcgga 59220 ttaactactt gaaattctc agacaatact ctccgagtgt aaatattact ggtatacggt 59280 tccaccgact cattatttcc caaaatttga gcagttgatg cagtcggcat aggtgccacc 59340 aataaactat ttctaagacc gtatgttctg attttatctt ttagaggttc ccaattccaa 59400 agatccgacg gtacaacatt ccaaagatca tattgtagaa taccgttact ggcgtacgat 59460 cctacatatg tatcgtatgg tccttccttc tcagctagtt cacaactcgc ctctaatgca 59520 ccgtaataaa tggttcgaa gatcttctta ttagatctt gtgcttccag gctatcaaat 59580 ggataattta agagaataaa cgcgtccgct aatccttgaa caccaatacc gataggcta 59640 tgtctcttat tagagatttc agcttctgga ataggataat attaataatc tataatttta 59700 ttgagatttc tgacaattac ttgaccaca tccttcagtt tgagaaaatc aaatcgccca 59760 tctattacaa acatgttcaa ggcaacagat gccagattac aaacggctac ctcattagca 59820 tccgcatatt gtattatctc agtgcaaaga ttactacact tgatagttcc taattttgt tgattactct ttttgttaca cgcatcctta taagaatga atggagtacc agtttcaatc tgagattcta taatcgcttt ccagacgact cgagcctttta ttatagtt gtatctcctt tctctttcgt atagtgtata caatcgttcg aactcgtctc cccaaacatt gtccaatcca ggacattcat ccggacacat caacgaccac tctccgtcat ccttcactcg tttcataaag agatcagga tccaaagagc father tctctggttc tatgttcctc gtttcctgta ttctttttaa gatcgagga cgccataata tcagaatgcc acggttccaa gtatatggcc ataactccag gccgtttgtt tcctccctga tctatgtatc tagcggtgtt attataact ctcaacattg gaatatacc gtttgatata ccattggtac cggagatata gcttccactg gcacgaat tactaattga tagacctatt ccccctgcca ttttagat taatgcgcat cgttttaacg tgtcatag accctctatg ctatcatcga tcatgttaag tagaaaacag ctagacattt ggtgacgact agttcccgca ttaataagg taggagaagc gtgcgtaaac catttttcag aaagtagatt gtacgtctca atagctgagt ctatatccca ttgatgaatt 60600 cctactgcga cacgcattaa catgtgctga ggtctttcaa cgatcttgtt gtttattttc 60660 aacaagtagg atttttccaa agttttaaaa ccaaaatagt tgtatgaaaa gtctcgttcg 60720 taaataataa ccgagttgag tttatcctta tatttgttaa ctatatccat ggtgatactt 60780 gaaataatcg gagaatgttt cccattttta ggattaacat agttgaataa atcctccatc 60840 acttcactaa atagtttttt tgtttccttg tgtagatttg atacggctat tctggcggct 60900 agaatggcat aatccggatg ttgtgtagta caagtggctg ctatttcggc tgccagagtg 60960 tccaattcta ccgttgttac tccattatat attccttgaa taaccttcat agctatttta 61020 ataggatcta tatgatccgt gtttaagcca taacataatt ttctaatacg agacgtgatt 61080 ttatcaaaca tgacattttc cttgtatcca tttcgtttaa tgacaaacat ttttgttggt 61140 gtaataaaaa aattatttaa cttttcatta atagggattt gacgtacgta gcgtacaaaa 61200 tgattgttcc tggtatatag ataaagagtc ctatatattt gaaaatcgtt acggctcgat 61260 taaactttaa tgattgcata gtgaatatat cattaggatt taactccttg actatcaggg 61320 cggcaccaga aattaccatc aaaagcatta atacagttat gcctatcgca gttagaacgg 61380 ttatagcatc caccatttat atctaaaaat tagatcaaag aatatgtgac aaagtcctag 61440 ttgtatattg agaattgaca aaacaatgtt tcttacatat ttttttttta ttagtaaccg 61500 acttaatagt aggaactgga aaactagact tgattattct ataagtatag atacccttcc 61560 aaataatatt ctctttgata aaagttccag aaaatgtaga attttttaaa aagttatctt 61620 ttgctattac caagattgtg tttagacgct tattattaat atgagtgatg aaatccacac 61680 cgcctctaga tatcgccttt atttccacat tagatggtaa atccaatagt gaaactatct 61740 ttttaggaat gtatggactc gcgtttagag gagtgaacgt cttgggcgtc ggaaaggatg 61800 attcgtcaaa cgaataaaca atttcacaaa tggatgttaa tgtattagta ggaaattttt 61860 tgacgctagt ggaattgaag attctaatgg atgatgttct acctatttca tccgataaca 61920 tgttaatttc cgacaccaac ggttttaata tttcgatgat atacggtagt ctctctttcg 61980 gacttatata gcttattcca caatacgagt cattatatac tccaaaaaac aaaataacta 62040 gtataaaatc tgtatcgaat gggaaaaacg aaattcga cataggtata gaatccggaa 62100 cattgaacgt attaatactt aattcttttt ctgtggtaag taccgatagg ttattgacat 62160 tgtatggttt taaatattct ataacttgag acttgataga tattagtgat gaattgaaaa 62220 ttatttttat caccacgtgt gtttcaggat catcgtcgac gcccgtcaac caaccgaatg 62280 gagtaaaata aatatcatta atatatgctc taaatattag tatttttatt aatcctttga 62340 ttcatctt ctcgtacgcg aatgattcca tgatcaagag tgatttgaga acatcctccg 62400 gagtattaat gggcttagta aacagtacat cgttgcaata ataaaagtta tccaagttaa 62460 aggatattat gcattcgttt aaagatatca cctcatctga cggagacaat ttttggtag 62520 gttttagaga ctttgaagct acttgtttaa caaagttatt catcgtcgtt tactattcta 62580 tttaattttg tagttaattt atcacatatc acattaattg actttttggt ccacttttcc 62640 atacgtttat attcttttaa tcctgcgtta tccgtttccg ttatatccag tgatagatcg 62700 tgcaggttaa atagaatgct cttaaataat gtcattttct tatccgctaa aaatttaaag 62760 aatgtataaa cctttttcag agatttgaaa ctcttaggtg gtgtcctagt acacaatatc 62820 ataaacaaac taataaacat tccacattca gattccaaca gctgattaac ttctacatta 62880 atacagccta ttttcgctcc aaatgtacat tcgaaaaatc tgaataaaac atcgatgtca 62940 caatttgtat tatccaatac agaatgtctg tgattcgtgt taaaaccatc ggagaaggaa 63000 tagaataaa aattattata gtggtggaat tcagttggaa tattgcctcc ggagtcataa 63060 aaggatacta aacattgttt tttatcataa attacacatt tccaatgaga caaataacaa 63120 aatccaaaca ttacaaatct agaggtagaa cttttaattt tgtctttaag tatatacgat 63180 aagatatgtt tattcataaa cgcgtcaaat ttttcatgaa tcgctaagga gtttaagaat 63240 ctcatgtcaa attgtcctat ataatccact tcggatccat aagcaaactg agagactaag 63300 ttcttaatac ttcgattgct catccaggct cctctctcag gctctatttt catcttgacg 63360 acctttggat tttcaccagt atgtattcct ttacgtgata aatcatcgat tttcaaatcc 63420 atttgtgaga agtctatcgc cttagatact ttttcccgta gtcgaggttt aaagaaatac 63480 gctaacggta tactagtagg taactcaaag acatcatata tagaatggta acgcgtcttt 63540 aactcgtcgg ttaactcttt cttttgatcg agttcgtcgc tactattggg tctgctcagg 63600 tgccccaact ctactagttc caacatcata ccgataggaa tacaagacac tttgccagcg 63660 gttgtagatt tatcatattt ctccactaca tatccgttac aatttgttaa aaatttagat 63720 acatctaat tgctacataa tccagctagt gaatatat gcatataata attggtaaat 63780 cctagttctg gtattttact aattactaaaa tctgtatatc tttccattta tcatggaaaa 63840 gaatttacca gatatcttct tttttccaaa ctgcgttaat gtattctctt acaaatattc 63900 acaagatgaa ttcagtaata tgagtaaaac ggaacgtgat agtttctcat tggccgtgtt 63960 tccagttata aaacatagat ggcataacgc acacgttgta aaacataaag gaatatacaa 64020 agttagtaca gaagcacgtg gaaaaaaagt atctcctcca tcactaggaa aacccgcaca 64080 cataaaccta accgcgaagc aatatatata cagtgaacac acaataagct ttgaatgtta 64140 tagtttcta aaatgtataa caaatacaga aatcaattcg ttcgatgagt atatattaag 64200 aggactatta gaagctggta atagtttaca gatattttcc aattccgtag gtaaacgaac 64260 agatactata ggtgtactag ggaataagta tccatttagc aaaattccat tggcctcatt 64320 aactcctaaa gcacaacgag agatattttc agcgtggatt tctcatagac ctgtagtttt 64380 aactggagga actggagtgg gtaagacgtc acaggtaccc aagttattgc tttggtttaa 64440 ttattattt ggtggattct ctactctaga taaaatcact aactttcacg aaagaccagt 64500 cattctatct cttcctagga tagctttagt tagattgcat agcaatacca ttttaaaatc 64560 attgggattt aaggtactag atggatctcc tatttcttta cggtacggat ctataccgga 64620 agaattaata aacaaacaac caaaaaaaata tggaattgta ttttctaccc ataagttatc 64680 tctaacaaaa ctatttagtt atggcactct tattatagac gaagttcatg agcatgatca 64740 ataggagat attattag cagtagcgag aaagcatcat acgaaatag attctatgtt 64800 tttaatgact gccacgttag aggatgaccg agaacggcta aaagtatttt tacctaatcc 64860 cgcattatta catattcctg gagatacact gtttaaaatt agcgaggtat ttattcataa 64920 windows ccatctcca gatggcata catagagaa gaaagagaa atttagttac 64980 tgctatacag atgtatactc ctcctgatgg atcatccggt atagtttg tggcatccgt 65040 tgcacagtgt cacgaatata aatcatattt agaaaaaga ttaccgtag atatgtatat 65100 tattcatggt aaggtcttag atatagacga atattagaa aaagtgtatt catcacctaa 65160 tgtatcgata attatttcta ctccttattt ggaatccagc gttactatac gcaatgttac 65220 acacatttat gatatgggta aagttttgt ccccgctcct tttggaggat cgcaagaatt 65280 tatttctaaa tctatgagag atcaacgaaa aggaagta ggaagagtta atcctggtac 65340 atacgtctat ttctatgatc tgtcttatat gaagtctata cagcgaatag attcagaatt 65400 tctacataat tatatattgt acgctaataa gtttaatcta acacccccg aagatttgtt 65460 tataatccct acaaatttgg atattctatg gcgtacaaag gatatatatag actcgttcga 65520 tattagtaca gaaacatgga aaattatt atccaatt tattagaga tgatagagta 65580 tgctaaactt tatgtactaa gtcctattct cgctgaggag ttggatact ttgaggac 65640 gggagaatta actagtattg tacgagaagc cattttatct ctaaatttac actagat 65700 tttaaatttt aaactaaag atgatgatac gtatatacac tttgtaaaa tattattcgg 65760 tgtctataac ggaacaacg ctactatata ttatcataga cctctaacgg gatatgaa 65820 tatgatttca gatactatat ttgttcctgt agataataac taaaaatca actctaatga 65880 ccacatcttt ttttagagat gaaaaatttt ccacatctcc tttgtagac acgactaaac 65940 attttgcaga aaaagttta ttagtgttta gatacgta tacttcatca gtgtagatag 66000 taaatgtgaa cagataaag gtattcttgc tcaatagatt ggtaaattcc atagaata 66060 ttaatccttt cttcttgaga tcccacatca tttcaaccag agacgtttta tccaatgatt 66120 tacctcgtac tataccacat acaaaactag attttgcagt gacgtcgtac ctggtattcc 66180 taccaaacaa aattttactt ttagttcttt tagaaaattc taaggtagaa tctctatttg 66240 ccaatatgtc atctatggaa ttaccactag caaaaaatga tagaaatata tattgataca 66300 tcgcagctgg ttttgatcta ctatacttta aaaacgaatc agattccata attgcctgta 66360 tatcatcagc tgaaaaacta tgttttacac gtattccttc ggcatttctt tttaatgata 66420 tatcttgttt agacaatgat aaagttatca tgtccatgag agacgcgtct ccgtatcgta 66480 taaatttc attagatgtt agacgcttca ttaggggtat acttctataa ggtttcttaa 66540 ttagtccatc atttgttgcg tcaagaacta ctatcggatg ttgttgggta tctctagtgt 66600 tacacatggc cttactaaag tttgggtaaa taactatgat atctctatta attatagatg 66660 catatattc atttgtcaag gatattagta tcgacttgct atcgtcatta atacgtgtaa 66720 tgtaatcata taaatcatgc gatagccaag gaaattcaa atagatgttc atcatataat 66780 cgtcgctata attcatatta atactttgac attgactaat ttgtaatata gcctcgccac 66840 gaaagct ctcgtattca gtttcatcga taaaggatac cgttaaatat aactggttgc 66900 cgatagtctc atagtctatt aagtggtaag tttcgtacaa atacagaatc cctaaaatat 66960 tatctaatgt tggattaatc tttaccataa ctgtataaaa tggagacgga gtcatacta 67020 ttttaccgtt tgtacttact ggaatagacg aaagaataat ctccggacat gctggtaaag 67080 acccaaatgt ctgtttgaag aaatccaatg ttccaggtcc taatctctta acaaaaatta 67140 cgatattcga tcccgatatc ctttgcattc tatttaccag catatcacga actatattaa 67200 gattatctat catgtctatt ctcccaccgt tatataaatc gcctccgcta agaaacgtta 67260 gtatatccat aaatggaat acttcatttc taaaatga ttcgttttct aattctttaa 67320 tgtgaaatcg tatactagaa agggaaaaat tatctttgag ttttccgtta gaaaagaacc 67380 agaaactaa tgttctgatt gcgtccgatt ccgttgctga attaatggat ttacaccaaa 67440 aactcatata acttctagat gtagaagcat tcgctaaaaa attagtagaa tcaaaggata 67500 tagtagatg ttccaacaag tgagcaattc ccaagatttc atctatatca ttctcgaatc 67560 cgaaattaga aattcccaag tagatatcct ttttcatccg atcgttgatg aaatacgaa 67620 ctttattcgg taagacaatc atttactaag gagtaaaata ggaagtaatg ttcgtatgtc 67680 gttatcatcg tataaattaa aggtgtgttt tttaccatta agtgacatta taattttacc 67740 aatattggaa ttataatata ggtgtatttg cgcactcgcg acggttgatg catcggtaaa 67800 tatagctgta tctaatgttc tagtcggtat ttcatcattt cgctgtctaa tatagcgtt 67860 ttctctatct gtttccatta cagctgcctg aagtttattg gtcggataat atgtaaaata 67920 ataagaaata catacgaata acaaaaataa aataagatat aataaagatg ccatttagag 67980 atctaattt gtttaacttg tccaaattcc tacttacaga agatgaggaa tcgttggaga 68040 tagtgtcttc cttatgtaga ggatttgaaa tatcttatga tgacttgata acttactttc 68100 cagataggaa ataccataaa tatattcta aagtatttga acatgtagat ttatcggagg 68160 aattaagtat ggaattccat gatacactc tgagagattt agtctctt agattgtaca 68220 agtattccaa gtgtatacgg ccgtgttata aattaggaga taatctaaaa ggcatagttg 68280 ttaaagga caggaattt tattagag aagcaatga tgacttgata gatatctcc 68340 tcaggaata cactcctcag atttacat attctaatga gcgcgtcccc atactggtt 68400 caaaattaat tctttgtgga tttctcaag ttcatttat ggcgtataca acgtcgcata 68460 taacaaaaaaaggta gatgttctcg ttccaaaaa atgtatagat gaactagtcg 68520 atccaataa ttcaata cttcaaatt tatttgaata aggagcgga acaataaca 68580 aaatactcag gaagatattt tattcggtaa ccggtggcca aactcataa ttgcttttt 68640 ctatttcgga ttttagaatt tccaaattca ccagcgattt atcggtttg gtgaaatcca 68700 aggatttatt aatgtccaca aatgccattt gttttgtctg tggattgtat ttgaaaatgg 68760 aaacgatgta gttagataga tgcgctgcaa agttttcctat taggttccg cgctttacgt 68820 cacccagcat acttgaatca ccatcctttta aaaaaatga windows acatggagta 68880 tatcatactc ggattttaat tcttctactg catcactgac attttcaca attackacaat 68940 acggtttacc gaaaataatc agtacgttct tcatttatgg gtatcaaaa cttaaaatcg 69000 ttactgctgg aaaataatc actgacgata ttagatgata attataca agtatacaat 69060 ggaatatttg tggatacaat gagtatttat atagccgtcg ccaattgtgt cagaaactta 69120 gagagttaa ctacggtatt cataaaatac gtaaacggat gggtaaaaa gggaggcat 69180 gtaacccttt ttacgatag aggagtata aaaattaac aagacgttag agacaagaga 69240 cgtaaatatt ctaaattac caaggacaga aaatgctag attagaaa gtgtacatcc 69300 gaatacaaa atgttaccgg atttatgaa gagaaata agcagaat gcaattaaaa 69360 atcgataaac tcacatttca atatattta tctgattctg atacataa atatcattg 69420 aatgagatac acacattt acaatt gagaatgtta cattatt tgtgatgaa 69480 cgagacgcag aattcgttat gtgtctcgag gctaaaacac atttctctac cacaggagaa 69540 tggccgttga tataagtac cgatcaggat actatgctat ttgcatctac tgataatcat 69600 cctaagatga taaaaaactt aactcaactg tttaaatttg ttccctcggc agaggataac 69660 tatttagcaa attaacggc gttagtgaat ggatgtgatt tctttcctgg actctatggg 69720 gcatctataa cacccaccaa cttaaacaaa atacaattgt ttagtgattt tacaatcgat 69780 aatatagtca ctagttggc attaaaaat tattatagaa agactaactc taccgtagac 69840 gtgcgtaata ttgttacgtt tataaacgat tacgctaatt tagacgatgt ctactcgtat 69900 gttcctcctt gtcaatgcac tgttcaagaa tttatatttt ccgcattaga tgaaaaatgg 69960 aacaatttta aatcatctta tttagagacc gttccgttac cctgccaatt aatgtatgca 70020 ttagaaccac gcaaggagat tgatgtttca gaagttaaaa ctttatcatc ttatatagat 70080 ttcgaaaata ctaaatcaga tatcgatgtt ataaaatcta tatcttcgat cttcggatat 70140 tctaacgaaa actgtaacac tatagtgttc ggcatctata aggataattt actactgagt 70200 aatatagtt cattttactt taactagt ctgttaataa ccaatacta aagtgataat 70260 ataataata taggttacta gattaaaaat ggtgttccaa ctcgtgtgct ctacatgcgg 70320 chaatatt tctcacgaac gatataattt gattacga aaaaatcat taaaggatgt 70380 actcgtcagt gtaagaacg aatgttgtag gttaaaatta tctacacaaa tagaactca 70440 acgtaactta acagtgcaac ctctattgga tataaactaa tattccg gttaattta 70500 tcaagacata tgcgcctaga ggttctatta ttttattaa ttataccatg tcattaacaa 70560 gtcatttgaa tccatcgata gaaaaacatg tgggtattta ttatggtacg ttattatcgg 70620 aacacttggt agttgaatct acctatagaa aaggattcg atagtccca ttggatagtt 70680 ttttgaagg atatcttagt gcaaagtat acatgttaga gatatttcaa gttatgaaaa 70740 tagcagctga tacgtcatta actttattgg gtattccgta tggattggt catgatagaa 70800 tgtattgttt taaattgta gctgaatgtt aaaaatgc cggtattgat acatcgtcta 70860 aacgaatatt aggtaaagat atttttga gccaaaactt cacagatgat aatagatgga 70920 taaagatata tgattctaat aatttaacat tttggcaaat tgattacctt aaagggtgag 70980 ttaatatgca taactactcc tccgttgttt tttccctcgt tctttttctt aacgttgttt 71040 gccatcactc tcataatgta aagatattct aaaatggtaa acttttgcat atcggacgca 71100 gaaattggta taaatgttgt aattgtatta tttccccgtca atggactagt cacagctcca 71160 tcagttttat atcctttaga gtatttctca ctcgtgcta acattctaga gcattccatg 71220 atctgttat cgttgatatt ggccggaaag atagattttt tattttttat tatattacta 71280 ttggcaattg tagatataac ttctggtaaa tatttttcta ccttttcaat ctcttctatt 71340 ttcaagccgg ctatatattc tgctatattg ttgctagtat caataccttt tctggctaag 71400 aagtcatatg tggtattcac tatatcagtt ttaactggta gttccattag cctttccact 71460 tctgcagaat aatcagaaat tggttcttta ccagaaaatc cagctactat aataggctca 71520 ccgatgatca ttggcaaaat cctatattgt accagattaa tgagagcata tttcatttcc 71580 aaatttctg ctagttcttg agacattgat ttatttgatg aatctagttg gttctctaga 71640 tactctacca tttctgccgc atacaatac ttgttagata aaatcagggt tatcaaagtg 71700 tttagcgtgg ctagaatagt gggcttgcat gtattaaaga atgcggtagt atgagtaaac 71760 cgttttaacg aattatatag tctccagaaa tctgtggcgt tacatacatg agccgaatga 71820 catcgaagat tgtccaatat ttttaagc tgctcttgt ccattattc tatatttgac 71880 tcgcaacaat tgtagatacc attaatcacc gattcctttt tcgatgccgg acatagcac 71940 aattgtttag ctttggactc tatgtattca gatttaatag atatatctct taatacagat 72000 tgcactatac attttgaaac tatgtcaaaa attgtagaac gacgctgttc tgcagccatt 72060 taactttaaa taatttacaa aaatttaaaa tgagcatccg tataaaaatc gataaactgc 72120 gccaaattgt ggcatatttt tcagagttca gtgagaagt atctataaat gtagactcga 72180 cggatgagtt aatgtatatt ttgccgcct tgggcggatc tgtaacatt tgggccatta 72240 tacctctcag tgcatcagtg ttctaccgcg gagccgaaaa cattgtgttt aatcttcctg 72360. ttgtccaaggt aaaatcgtgt ttgtgtagtt ttcacaatga tgccatcata gatatagaac ctgatctgga aaataatcta gtaaaacttt ctagttatca tgtagtaagt gtcgattgta acaaggaact gatgcctatt aggacagata ctactatttg tctaagtata gatcaaaaga aatcttacgt gtttaatttt cacaagtatg aagaaaaatg ttgtggtaga accgtcattc atttagaatg gttgttgggc tttatcaagt gtattagtca gcatcagcat ttggctatta tgtttaaaga tgacaatatt attachment ctcctggtaa tactgatgcg ttttccaggg aatattctat gactgaatgt tctcaagaac tacaaaagtt ttctttcaaa atagctatct cgtctctcaa caactacga ggattcaaaa agagagtcaa tgtttttga actagaatcg 72840. 72840. 72840. 72840. 72840. 72840. 72840. 72840 agatcaacat ctttatgacg tttttagatt aatactttca atgagataaa tatgggtggc ggagtaagtg ttgagctccc taaacgggat ccgcctccgg gagtacccac tgatgagatg ttattaaacg tggataaaat gcatgacgtg atagctcccg ctaagctttt agaatatgtg 73020 catataggac cattagcaa agataagag agataagta agaaagata tccagagtttt 73080 agattagtca acacaggacc cggtggtctt tcggcattgt taagacaatc gtataatgga 73140 accgcaccca attgctgtcg cactttaat cgtactcatt attggaagaa ggatggaaag 73200 attcagata agtatgaaga gggtgcagta ttagaatcgt gttggccaga cgttcacgac 73260 accggaaaat gcgatgttga tttattcgac tggtgtcagg gggatacgtt cgatagaaac 73320 atatgccatc agtggatcgg ttcagcctttt ataggagta atagaactgt agagggtcaa 73380 caatcgttaa aatctgta aatagatg aacatt gtagtaaga tgctagtgta 73440 ccaatatgtg atcatttt gcatcattta cgcgcacaca atacagaga tagcaagag 73500 atgatcgatt atattctaag acacagtct gcggacttta aacagaaata tatgagatgt 73560 agttatccca ctagagataa gttagaagag tcattaaaat atgcggaacc tcgagaatgt 73620 tgggatccag agtgttcgaa tgccaatgtt aatttcttgc taacacgtaa ttataataat 73680 ttaggacttt gcaatattgt acgatgtaat actagcgtga acaacttaca gatggataaa 73740 acttcctcat taagattgtc atgtggatta agcaatagtg atagatttc tactgttccc 73800 gtcaatagag caaaagtagt tcaacataat attaaacact cgttcgacct aaaattgcat 73860 ttgatcagtt tattatctct cttggtaata tggatactaa ttgtagctat ttaaatgggt 73920 gccgcggcaa gcatacagac gacggtgaat acactcagcg aacgtatctc gtctaaatta 73980 gaacaagaag cgaatgctag tgctcaaaca aaatgtgata tagaaatcgg aaattttat 74040 atccgacaaa accatggatg taacctcact gttaaaaata tgtgctctgc ggacgcggat 74100 gctcagttgg atgctgtgtt atcagccgct acagaaacat atagtggatt aaccggaa 74160 caaaaagcat acgtgccagc tatgttact gctgcgttaa acattcagac gagtgtaaac 74220 actgttgtta gagattttga aaattatgtg aaacagactt gtaattctag cgcggtcgtc 74280 gataacaaat taaagataca aaacgtaatc atagatgaat gttacggagc cccaggatct 74340 sparrow tggaattt tatacagga tctagcaag gaattgtgc cattaaggcg 74400 ttgatgcaat tgacgactaa ggccactact caatagcac ctaaacaagt tgctggtaca 74460 ggagttcagt ttatatgat tgttatcggt gttaatatat tggcagcgtt gtttatgtac 74520 tatgccaagc gtatgttgtt cacacacc aatgataaaa tcaacttat tttagccaat 74580 aaggaaaacg tccattggac tacttacatg gandacattct tccattc tccgatggtt 74640 attgctacca cggatatgca aactgaaaa tatattgata atattttaat agattaacat 74700 ggaagttatc actgatcgtc tegacgat agtgaaaaa atatagcgg atgaaaaatt 74760 tgtagatttt gttatacacg gtctagagca tcaatgtcct gctatacttc gaccattaat 74820 taggttgttt attgatatac tattattgt tatattttta cggtacgtct 74880 agtaagtaga atatcaa tgttgttggc gttggtggcg ctagtcatca cattaactat 74940 ttttattac tttatactat atagtacta gactgacttc taacaaacat ctcacctgcc 75000 ataaataaat gcttgatatt aaagtcttct atttctaaca ctattccatc tgtggaaaat 75060 aatactctga cattatcgct aattgacaca tcggtgagtg atatgcctat aaagtaataa 75120 tcttctttgg gcacatatac cagtgtacca ggttctaaca acctatttac tggtgctcct 75180 atagcatact ttttctttac cttgagaata tccatcgttt gcttggtcaa tagcgatatg 75240 tgatttttta tcaaccactc gaaaaagtaa ttggagtgtt catatcctct acgggctatt 75300 gtctcatggc cgtgtatgaa atttaagtaa cacgactgtg gtagatttgt tctatagagc 75360 cggttgccgc aaatagatag aactaccaat atgtctgtac aaatgttaaa cattaattga 75420 ttaacagaaa aaacaatgtt cgttctggga atagaaacca gatcaaaaca aaattcgtta 75480 gaatatatgc cacgtttata cattgaatat aaaataacta cagtttgaaa aataacagta 75540 tcatttaaac atttaacttg cggggttaat ctcacaactt tactgttttt gaactgttca 75600 aaatatagca tagatccgtg agaaatacgt ttagccgcct ttaatagagg aaatcccacc 75660 gcctttctgg atctcaccaa cgacgatagt tctgaccagc aactcatttc ttcatcatcc 75720 acctgtttta acatataata ggcaggagat agatatccgt cattgcaata ttccttctcg 75780 taggcacaca atctaatatt gataaaatct ccattctctt ctctgcattt attatcttgt 75840 ttcggtggct gattaggctg tagtcttggt ttaggcttg gtatatcgtt gttgaatcta 75900 ttttggtcat taaatctttc attctctct ggtatatttt tatcacctg ttggttgga 75960 ttttgtcta tattatcgtt tgtaacatcg gtacgggtat tcatttatca caaaaaaaac 76020 ttctctaaat gagtctactg ctagaaaacc tcatcgaaga agataccata tttttgcag 76080 gaagtatatc tgagtatgat gatttacaa tggttattgc cggcgcaaa tccaaatttc 76140 cagatctat gctttctatt ttatatatag tacctagaac gatgtcaaa tatgagttgg 76200 agttgattca taacgaaat atcacaggag caatgtttac cacaatgtat atatagaa 76260 acatttggg tctaggagat gataaacta ctattgaagc cattgaaac tattctttgg 76320 atcctaacaa tgaagttatg cctcttatta ttatatac ggatatgact gccgtcattc 76380 ctaaaaaag tggtaggaga aagaataaga acatggttat cttccgtcaa ggatcatcac 76440 ctatcttgtg tattttcgaa actcgtaaaa agattaatat ttataaagaa aatatggaat 76500 ccgcgtcgac tgagtataca cctatcggag acaacaaggc tttgatatct aaatatgcgg 76560 gaattaatgt cctgaatgtg tattctcctt ccacatccat gagattgaat gccatttacg 76620 gattcaccaa taaaaataaa ctagagaaac ttagtactaa taaggaacta gaatcgtata 76680 gttctagccc tcttcaagaa cccattaggt taaatgattt tctgggacta ttggaatgtg 76740 ttaaaaagaa tattcctcta acagatattc cgacaaagga ttgatacta taaatggaga 76800 atgttcctaa tgtatacttt aatcctgtgt ttatagagcc cacgtttaaa cattctttat 76860 taagtgttta taaacacaga ttaatagttt tatttgaagt attcgttgta ttcattctaa 76920 tatatgtatt ttttagatct gaattaaata tgttctttat gcctaaacga aaaatacccg 76980 atcctattga tagattacga cgtgctaatc tagcgtgtga agacgataaa ttaatgatct 77040 atggattacc atggatgaca actcaaacat ctgcgttatc aataaatagt aaaccgatag 77100 tgtataaaga ttgtgcaaag cttttgcgat caataaatgg atcacaacca gtatctctta 77160 acgatgttct tcgcagatga tgattcattt tggctagtca agatgatgaa 77220 tcttcattat ctgatatatt gcaaatcact caatctag actttctgtt attattg 77280 atccaatcaa aaaataatt agaagccgtg gtcattgtt atgaatctct ttcagaggaa 77340 spacecraft tgacaaatt spacett spacettt aaaactgtt spaceggtc 77400 cctattgtta cagatggaag ggtcaaactt aaaaggat atttgttcga ctttgtgatt 77460 agtttgatgc gattcaaaa agaatccctct ctagctacca ccgcaataga tcctattaga 77520 tacatagatc ctcgtcgtga tatcgcattt tctaacgtga tggatatatt aaagtcgaat 77580 aaagtgaaca atattaatt ctttattgtc atcatgaacg gcggacatat tcagttgata 77640 atcggcccca tgttttcagg taaagtaca gatttatta gacgagttaa acgttatcaa 77700 atagctcaat ataatgcgt gacttaaaa tattctaacg atatagata cggaacggga 77760 ctatggacgc atgataagaa taatttgaa gcattggaag caactaact atgcgatgtt 77820 ttggaattaa ttacagattt ctccgtgata ggtatcgatg aaggacagtt ctttccagac 77880 attgttgaat tctgtgagcg tatggcaac gaaggaaaaa tagttagt agccgcactc 77940 gatgggacat ttcaacgtaa accgtttaat atattttga atcttattcc attatctgaa 78000 atggtggtaa aactactgc tgtgtgtag aatgcttta aggaggcttc cttttctaaa 78060 cgattgggtg aggaaccga gataaaaata ataggaggta atgatatgta tcaatcggtg 78120 tgtagaaagt gttacatcga ctcatatatat tatattttt atctaaaaa ctaaaaataa 78180 acattgatta aattttaata taatactta aaatggatgt tgtgtcgtta gataaaccgt 78240 ttgtattt tgaggaattt gatatgagt tagattacga accagaagt gcaatgagg 78300 tcgcaaaaa actgccgtat caggacagt taaaactatt actaggagaa ttttttc 78360 ttagtaagtt acagcgacac ggtatag atggtgccac cgtagtgtat ataggatctg 78420 ctcccggtac acatacgt tatttgagag atcatttcta taatttagga gtgatcatca 78480 aatggatgct aattgacggc cgccatcatg atcctatttt aatggattg cgtgatgtga 78540 ctctagtgac tcggttcgtt gatgaggat atctacgatc catcaaaaaa caactgcatc cttctaagat tattttaatt tctgatgtga gatccaaacg aggaggaat gacctagta cggcggattt actaagtaat tacgctctac aaaatgtcat gattaagtatt ttaaaccccg tggcgtctag tcttaaatgg agatgcccgt ttccagatca atggatcaag gacttttata tcccacacgg father ttacaacctt ttgctccttc atattcagct father tattagtat ttataccggt gagaacatga gactgactcg agttaccaaa ttagacgctg 78960. 78960. 78960. 78960. 78960. 78960. 78960. 78960 actttgatta tcctaatcag gaattgact attttcacat gtactttatg ctgaggaccg tgtactgcaa taaacattt cctactacta aagcaaaggt actatttcta caacaatcta tatttcgttt cttaaatatt snow snow snow snow 79140 snow snow snow snow aacgtaaaat atctagcaa aattctatgt ctaaaaacag aaatagcaag agatccgtac 79200 gcggtataata atagaacgt gctactgaga tatactaccg atagagta taatgattta 79260 gttactttaa taaccgttag actaaaattt gattctatga aactgtgtt tcaggtattt 79320 aacgaatcat ccataatta tactccggtt gatgatgatt atggaacc aatcattata 79380 acatcgtatc ttcaaaaagg tcataacaag tttcctgtaa attttctata catagatgtg 79440 gtaatatctg acttattcc tagctttgtt agactagata ctacagaaac taatatagtt 79500 atagtgtac tacaacagg tgatggtaaa aagactctc gtcttcccaa atgttagag 79560 acggaaatag ttgtcagat tcttatcgc cctaatatac cattaaaaat tgttagattt 79620 ttccgcaata acatggtaac tggagtagag atagccgata gatctgttat ttcagtcgct 79680 tgattaatca tgtaga tgagataat attattaat atcattaat attctta 79740 tcttatatct tatatcttat atcttgttta gaaaaatgct atattaaaa tagctaacgc 79800 tagtaatcca atcggaagcc atttgatatc tataataggg tatctaattt cctgatttaa 79860 atagcggaca gctatattct cggtagctac tcgtttggaa tcacaaacat tatttacatc 79920 taatttacta tctgtaatgg aaacgtttcc caatgaaatg gtacaatccg atacattgca 79980 ttttgtata tttttttta aagaggctgg taacaacgca tcgcttcgtt tacatggctc 80040 gtaccaacaa tatagggta atcttgtatc tattcctatc cgtactatgc ttttatcagg 80100 aatacat ttacatcgta tatcgtcttt gttagcatca cagaatgcat aaatttgttc 80160 gtccgtcatg ataaaaattt aaagtgtaaa tataactatt atttttatag ttgtaataaa 80220 aagggaaatt tgattgtata ctttcggttc tttaaaagaa actgacttga taaaaatggc 80280 tgtaatctct aaggttacgt atagtctata tgatcaaaaa gagattaatg ctacagatat 80340 tatcattagt catgttaaaa atgacgacga tatcggtacc gttaaagatg gtagactagg 80400 tgctatggat ggggcattat gtaaaacttg tgggaaaacg gaattggaat gttcggtca 80460 ctggggtaaa gtaagtattt ataaaactca tatagttaag cctgaattta tttcagaaat 80520 tattcgttta ctgaatcata tatgtattca ctgcggatta ttgcgttcac gagaaccgta 80580 ttccgacgat attaacctaa aagagttatc gggacacgct cttaggagat taaaggataa 80640 aattatcc aagaaaaagt catgttggaa cagcgaatgt atgcaaccgt atcaaaaaat 80700 tactttttca aagaaaaagg tttgtttcgt caacaagttg gatgatatta acgttcctaa 80760 ttctctcatc tatcaaaagt taatttctat tcatgaaaag ttttggccat tattagaaat 80820 tcatcaatat ccagctaact tattttatac agactacttt cccatccctc cgctgattat 80880 tagaccggct attagtttt ggatagatag tatacccaaa gaaaccaatg aattaactta 80940 cttattaggt atgatcgtta agaattgtaa cttgaatgct gatgaacagg ttatccagaa 81000 ggcggtaata gaatacgatg atattaaaat tatttctaat aacactacca gtatcaattt 81060 atcatatatc acatccggca aaataatat gattagaagt tatatcgtcg cccggcgaaa 81120 agatcagacc gctagatctg taattggtcc cagtacatct atcaccgtta atgaggtagg 81180 aatgcccgca tatattagaa atacacttac agaaaagata tttgttaatg cctttacagt 81240 ggataagtt aaacaactat tagcgtcaaa ccaagttaa ttttacttta ataaacgatt aaaccaatta acaagac gccaagga gtttatcaaa aataatac atttattgcc tggtgattgg gtagaagtag ctgttcaaga fathercaagt attatttttg fathercagcc gtctctacat agatacaacg tcatcgcttc atctatcaga gctaccgaag gagatactat 81540. cccggaattg ccaactctca aaatgctgat ttcgacgggg atgaggaatg 81600. 81600. ctaaagctgt aattgaacaa agtattctta tgtatccgac gacgttactc aaacacgata ttcatggagc ccccgtttat ggatctattc aagatgaaat cgtagcagcg tattcattgt ttaggataca agatctttgt ttaggag tattgaacat cttggggaa tatggaagag agttcgatcc taaggtaaa tgtaaattca gcggtaaaga tatctatact tacttgatag gtgaaaagat tattatccg ggtctcttaa aggatggtga aattattgca aacgacgtag atagtaattt tgttgtggct atgaggcatc tgtcattggc tggactctta tccgatcata agtcgaacgt ggaaggtatc aactttatta tcaagtcatc 81960 ttatgttttt aagagatatc tatctattta cggttttggg gtgacattca aagatctgag 82020 accaaattcg acgttcacta ataaattgga ggccatcaac gtagaaaaaa tagaacttat 82080 caaagaagca tacgccaaat atctcaacga tgtaagagac gggaaatag ttccattatc 82140 taaagcttta gaggcggact atgtggaatc catgttatcc aacttgacaa atcttaatat 82200 ccgagagata gaagaacata tgagacaaac gctgatagat gatccagata ataacctcct 82260 gaaaatggcc aaagcgggtt ataaagtaaa tcctacagaa ctaatgtata ttctaggtac 82320 gtatggacaa caaaggattg atggtgaacc agcagagact cgagtattgg gtagagtctt 82380 accttactat cttccagact ctaaggatcc agaaggaaga ggttacattc ttaattcttt 82440 aacaaaagga ttaacgggtt ctcaatatta cttttcgatg ctggttgcaa gatctcaatc 82500 tactgatatc gtctgtgaaa catcacgtac cggaacactg gctagaaaaa tcattaaaaa 82560 gatggaggat atggtggtcg acggatacgg acaagtagtt ataggtaata cgctcatcaa 82620 gtacgccgcc aattatacca aaattctagg ctcagtatgt aaacctgtag atcttatcta 82680 82740 gggattcgtt tactctcaga aacagaaact tgcaaagaag acattggcgc cgtttaattt 82800 cctagtattc gtcaaaccca ccactgagga taatgctatt aaggttaagg atctgtacga 82860 tatgattcat aacgtcattg atgatgtgag agagaaatac ttctttacgg tatctaatat 82920 agattttatg gagtatat tcttgacgca tcttaatcct tctagaatta gaattacaaa 82980 agaaacggct atcactatct ttgaaaagtt ctatgaaaaa ctcaattata ctctaggtgg 83040 tggaactcct attggaatta tttctgcaca ggtattgtct gagaagttta caaacaagc 83100 cctgtccagt tttcacacta ctgaaaaaag tggtgccgtc aaacaaaaac ttggtttcaa 83160 cgagtttaat aacttgacta atttgagtaa gaataagacc gaattatca ctctggtatc 83220 cgatgatatc tctaaacttc aatctgttaa gattaatttc gaatttgtat gtttgggaga 83280 attaaatcca gacatcactc ttcgaaaaga aacagatagg tatgtagtag atataatagt 83340 caatagatta tacatcaaga gagcagaaat taccgaatta gtcgtcgaat atatgattga 83400 acgattatc tcctttagcg tcattgtaaa ggaatggggt atggaaacat tcattgagga 83460 tgaggataat attagattta ctgtctacct aaatttcgtt gaaccggaag aattgaatct 83520 tagtaagttt atgatggttc ttccgggtgc cgccaacaag ggcaagatta gtaaattcaa 83580 gattcctatc tctgactata cgggatatga cgacttcaat caaacaaaaa agctcaataa 83640 gatgactgta gaactcatga atctaaaaga attgggttct ttcgatttgg aaaacgtcaa 83700 cgtgtatcct ggagtatgga atacatacga tatcttcggt atcgaggccg ctcgtgaata 83760 cttgtgcgaa gccatgttaa acacctatgg agaagggttc gattatctgt atcagccttg 83820 tgatcttctc gctagtttac tatgtgctag ttacgaacca gaatcagtga ataaattcaa 83880 gttcggcgca gctagtactc ttaagagagc tacgttcgga gacaataaag cattgttaaa 83940 cgcggctctt cataaaaagt cagaacctat taacgataat agtagctgcc acttttttag 84000 caaggtccct aatataggaa ctggatatta caaatacttt atcgacttgg gtcttctcat 84060 gagaatggaa aggaaactat ctgataagat atcttctcaa aagatcaagg aaatggaaga 84120 aacagaagac ttttaattct tatcaataac atattttct atgatctgtc ttttaaacga 84180 tggattttcc acaaatgcgc ctctcaagtc cctcatagaa tgatacacgt ataaaaaata 84240 tagcataggc aatgactcct tatttttaga cattagatat gccaaaatca tagccccgct 84300 tctatttact cccgcagcac aatgaaccaa cacgggctcg ttcgttgat cacatttaga 84360 taaaaaggcg gttacgtcgt caaaatattt actaatatcg gtagttgtat catctaccaa 84420 cggtatatga ataatattaa tattagagtt aggtaatgta tatttatcca tcgtcaaatt 84480 taaaacatat ttgaacttaa cttcagatga tggtgcatcc atagcatttt tataatttcc 84540 caaatacaca ttattggtta cccttgtcat tatagtggga gatttggctc tgtgcatatc 84600 tccagttgaa cgtagtagta agtatttata caaacttttc ttatccattt ataacgtaca 84660 aatggataaa actactttat cggtaaacgc gtgtaattta gaatacgtta gagaaaaggc 84720 tatagtaggc gtacaagcag ccaaaacatc aacacttata ttctttgtta ttatattggc 84780 aattagtgcg ctattactct ggtttcagac gtctgataat ccagtcttta atgaattaac 84840 gagatatatg cgaattaaaa atacggttaa cgattggaaa tcattaacgg atagcaaaac 84900 aaaattagaa agtgatagag gtagacttct agccgctggt aaggatgata tattcgaatt 84960 caaatgtgtg gatttcggcg cctattttat agctatgcga ttggataaga aaacatatct 85020 gccgcaagct attaggcgag gtactggaga cgcgtggatg gttaaaaagg cggcaaaggt 85080 cgatccatct gctcaacaat tttgtcagta tttgataaaa cacaagtcta ataatgttat 85140 tacttgtggt aatgagatgt taaatgaatt aggtatagc ggttatttta tgtcaccgca 85200 ttggtgttcc gattttagta atatggaata gtgttagata aatgcggtaa cgaatgttcc 85260 tgtaaggaac cataacagtt tagatttaac gttaaagatg agcataaaca taataaacaa 85320 aattacaatc aaacctataa cattaatatc aaacaatcca aaaaatgaaa tcagtggagt 85380 agtaaacgcg tacataactc ctggataacg tttagtagct gccgttccta ttctagacca aaaattcggt ttcatgtttt cgaaacggtg ttctgcaaca agtcggggat cgtgttctac atatttggcg gcattatcca gtatctgcct attgatcttc atttcgtttt caattctggc 85560. tatttcaaaa taaatcccg atgatagacc tccagacttt ataatttcat ctacgatgtt cagcgccgta gtaactcta fatherggc tgataagcta acatcatacc ctcctgtata tgtgaattg gcatgatttt tgtccattac aagctcggtt ttaactttat tgcctgtaat aatttctctc atctgtagga tatctatttt tttgtcatgc attgccttca agacgggacg 85800. 85860. aagaaacgta attachment to attachment gttttctaca attachment attctacctt tttattttct aactcggtaa aaaaattaga atcccatagg gctaatgtc tagcgatatt tcttttcgtt tcctctgtac acaaaaccct gaaaagaagt gagtatactt gtcatcattt ctaatgtttc ctccagtcca ctgtataac gcataatcct tgtaatgatc tggatcatcc ttgactacca caacatttct ttttctggc ataacttcgt tgtcctttac 86100 atcatcgaac ttctgatcat tatatgctc atgaacatta ggaaatgttt ctgatggaag 86160 tctatcaata actggcacaa caataacagg agttttcgcc gccgccattt agttattgaa 86220 attaatcata tacaactctt tatacgagt tatattttcg tctatccatt gtttcacatt 86280 tacatatttc gacaaaaaga tataaaatgc gtattccaat gcttctctgt ttaatgaatt 86340 actaaaatat acaaacacgt cactgtctgg caataaatga tatcttagaa tattgtaaca 86400 atttattttg tattgcacat gttcgtgatc tatgagttct tcttcgaatg gcataggatc 86460 tccgaatctg aaaacgtata aataggagtt agaataataa tatttgagag tattggtaat 86520 atataaactc tttagcggta taattagttt ttttctctca atttctattt ttagatgtga 86580 tggaaaaatg actaattttg tagcattagt atcatgaact ctaatcaaaa tcttaatatc 86640 ttcgtcacac gttagctctt tgaagttttt aagagatgca tcagttggtt cgaccgatgg 86700 agtaggtgca acaatttttt gttcgatgta tgtatgtact ggagccattg ttttaactat 86760 aatggtgctt gtatcgaaaa actttaatgc agatagcgga agctcttcgc cgcgactttc 86820 tacatcgtaa ttgggttcta acgccgatct ctgaatggat actagttttc taagttctaa 86880 tgtgattctc tgaaaatgta aatccaattc ctccggcatt atagatgtgt atacatcggt 86940 aaataaaact atagtatcca acgatccctt ctcgcaaatt ctagtcttaa ccaaaaaatc 87000 gtatataacc acggagatgg cgtatttaag agtggattct tctaccgttt tgttcttgga 87060 tgtcatatag gaaactataa agtccgcact actgttaaga atgattacta acgcaactat 87120 atagttcaaa ttaagcattt tggaaacata aaataactct gtagacgata cttgactttc 87180 gaataagttt gcagacaaac gaagaaagaa cagacctctc ttaatttcag aagaaaactt 87240 ttttcgtat tcctgacgtc tagagttat atcaataaga aagttaagaa ttagtcggtt 87300 aatgttgtat ttcattaccc aagtttgaga tttcataata tttcaaaag acatgataat 87360 attaaagata aagcgctgac tatgaacgaa atagctatat ggttcgctca aaatatagt 87420 cttgttaac gtggaaacga taactgtatt tttaatcacg tcagcggcat ctaattaaa 87540. 87540. 87540. 87540. 87540. 87540. 87540 ttcgttagca aaatttattaa ttttagtgaa atagttagcg tcaactttca tagcttcctt caatctaatt tgatgctcac acggtgcgaa ttccactcta acatcccttt tccatgcctc aggttcatcg atctctaa tatctagttt tttgcgtttc acaaacacag gctcgtctct cgcgatgaga tctgtatagt aactatgtaa atgataacta gatagaaaga tgtagctata 87840. 87840. 87840. 87840. 87840. 87840. 87840. 87840. 87840. 87840. 87840 atggtcttcg gaaaaaat ttttataaat ttttccagta ttttccaaat atacgtactt aacatctaa aaatccttaa tgataatagg aatggataat ccgtctattt tataagaaa 88020. 88020. 88020. 88020. 88020. 88020. 88020. 88020. 88020 tgcaaagtct aaatattttt tagagaatct taattggtcc aaattcttt ccaagtacgg father ttcatattga acggtatctt cttaatctct ggttctagtt ccgcattaaa tgatgaaact aagtcactat ttttataact aacgattaca tcacctctaa catcatcatt 88200 taccagaata ctgatcttct tttgtcgtaa atacatgtct aatgtgttaa aaaaaagatc 88260 atacaagtta tacgtcattt catctgtggt attcttgtca ttgaaggata aactcgtact 88320 aatctcttct ttaacagcct gttcaaattt atacctata tacgaaaaaa tagcaaccag 88380 tgtttgatca tccgcgtcaa tattctgttc tatcgtagtg tataacaatc gtatatcttc 88440 ttctgtgata gtcgatacgt tataaaggtt gataacgaaa atatttttat ttcgtgaaat 88500 aaagtcatcg taggattttg gacttatatt cgcgtctagt agatatgctt ttatttttgg 88560 aatgatctca attagaatag tctctttaga gtccatttaa agttacaaac aactaggaaa 88620 ttggtttatg atgtataatt ttttagttt ttatagattc tttattctat acttaaaaaa 88680 tgaaaataaa tacaaaggtt cttgagggtt gtgttaaatt gaaagcgaga aataatcata 88740 aattatttca ttatcgcgat atccgttaag tttgtatcgt aatggcgtgg tcaattacga 88800 aaagcgga tactagtagc ttcacaaaga tggctgaaat cagagctcat ctaaaaaata 88860 gcgctgaaaa tAAgataaa aacgaggata ttttcccgga agatgtata attccatcta 88920 ctaagcccaa aaccaaacga gccactactc ctcgtaaacc agcggctact aaagatcaa 88980 ccaaaaagg gaagtgaa gagaagtag ttatagagga attackcatcaaaactgaa 89040 aaaattctcc atctcctgga gtcagcgaca ttgtagaag cgtggccgct gtagagctcg 89100 atgatagcga cggggatgat gaacctatgg tacaagttga agctggtaaa gtaaatcata 89160 gtgctagaag cgatctttct gacctaagg tggctaccga caatcgtt aagatctta 89220 agaaaattat tactgaatc tctgcagtat cgacggttct agaggatgtt caagcagctg 89280 gtatctctag acaatttact tctatgacta aagctattac aacactatct gatcttagtca 89340 ccgagggaaa atctaaagtt gttcgtaaaa agttaaaac ttgtaagaag taaatgcgtg 89400 cacttttta taagatggt aactcttta ccgataataa ttttttaat cctgtatcag 89460 acgataatcc agcgtatgag gttttgcaac atgttaaaat tcctactcat ttaacagatg 89520 tagtagtata tgacaacg tgggaggagg cgttaactag attaatttt gtgggaagcg 89580 attcaaagg acgtagacaa tactttacg gaaaaatgca tgtacagaat cgcaacgcta 89640 aaagagatcg tattttgtt agagtatatata acgttatgaa acgattaat tgttttataa 89700 aaaaataat aaagaaatcg tccacagatt ccaattatca gttggcggtt tttagttaa 89760 tggaaactat gtttttt agatttggta aatgaata tctttaggag atgaacag 89820 taggttatt aacactaaaaaaacaca tagaaaag tcccgatgaa atagttatca 89880 agtttgtagg aaggacaaa gtttcacatg atttgttgt tcataagtct atagactat 89940 aaaccgct attgaactg acggattt ctagtcccga agaatttctg ttcacaaac 90000 taagtgaacg aaggtatac gatgtatca aacagttttgg tattagatc aaggatctcc 90060 gaacgtatgg agtcattat acgtttttat ataatttg gandaatgta aagtccatat 90120 ctcctcttcc atcaccaaaa aagttaatag cgttaactat siacaact gctgaagtgg 90180 taggtcatac tccatcaatt tcaaaaagag cttacatggc aacgactatt ttagaaatgg 90240 taaaggataa aaattttta gatgtagtat ctaaaactac gttcgatgaa ttcctatcta 90300 tagtcgtaga tcacgttaaa tcatctacgg atggatgata tagatcttta cacaaataat 90360 tacaagaccg ataaatggaa atggataagc gtatgaaatc tctcgcaatg accgctttct 90420 ttggggagct aagcacatta gatattatgg cattgataat gtctatatttt aaacgccatc 90480 caaacaatac cattttttca gtggataagg atggtcagtt tatgattgat ttcgaatacg 90540 ataattataa ggcttctcaa tatttggatc tgaccctcac tccgatattt ggagatgaat 90600 gcaagactca cgcatcgagt atagccgaac aattggcgtg tgcggatatt attaaagagg 90660 atattagcga atacatcaaa actactcccc gtcttaaacg atttataaaa aaataccgca 90720 atagatcaga tactcgcatc agtcgagata cagaaaagct taaatagct ctagctaaag 90780 gcatagatta cgaatatata aaagacgctt gttaataagt aaatgaaaaa aaactagtcg 90840 tttataataa aacacaatat ggatgccaac atagtatcat cttctactat tgcaacgtat 90900 atagacgctt tagcgaagaa tgcttcagaa ttagaacaga ggtctaccgc atacgaaata 90960 aataatgaat tggaactagt atttattaag ccgccattaa ttactttgac aaatgtagtg 91020 aatatctcta cgattcagga atcgtttatt cgatttaccg ttactaataa ggaaggtgtt 91080 aaaattagaa ctaagattcc attatctaag gtacatggtc tagatgtaaa aaatgtacag 91140 ttagtagatg ctatagataa catagtttgg gaaaagaaat cattagtgac ggaaaatcgt 91200 cttcacaaag aatgcttgtt gagactatcg acagaggaac gtcatatatt tttggattac 91260 aagaaatatg gatcctctat ccgactagaa ttagtcaatc ttattcaagc aaaaacaaaa 91320 aactttacga tagactttaa gctaaaatat tttctaggat ccggtgccca atctaaaagt 91380 tctttgttgc acgctattaa tcatccaaag tcaaggccta atacatctct ggaaatagaa 91440 ttcacaccta gagacaatga aaaagttcca tatgatgaac tataaagga attgacgact 91500 ctatcacgtc atatatttat ggcttctcca gagaatgtaa ttctttctcc gcctattaac 91560 gcacctataa agactttt gttgcctaaa caatatag taggtctgga tctggaaat 91620 ctatatgccg taactaagac tgacggcatt ctataacta tcagagttac atcaacggg 91680 ttgtattgtt attacaca tcttggttat attattagat atcctgttaa gagaataata 91740 gattccgaag tagtagtctt tggtgaggca gttaaggata agaactggac cgtatatctc 91800 attaagctaa tagctgt gatgcaatc atgatagac tagagaag tagtgtt 91860 gatctaaac tagtggatat ttgtgatcgg atagtattca agtcaaagaa attgaaggt 91920 ccgtttacta caacagtga agtcgtcgat atgttatcta catattacc aaagcaacca 91980 gaaggtgtta ttctgttcta ttcaaggga cctaaatcta acatgattt taaaatttaa 92040 aaggaaaata ctatagacca aactgcaaat gtagtattta ggtacatgtc cagtgaacca 92100 attatctttg gagaatcgtc tatctttgta gagtataaga atttagcaa cgataaggc 92160 tttcctaaag atatggttc tggtaagatt gtgttatata acggcgttaa ttatctaaat 92220 atatctatt gtttggaata tattaca cataatgaag tgggtattaa gtccgtggtt 92280 gtacctatta agtttatagc agaattctta gttaatggag aaatactta acctagaatt 92340 gataaaacca tgaaatatat taactcagaa gattattag gatatcaca windowcata 92400 gttgaacatt windowgatca aagcatcaa atggata tctttaacga ggataaacta 92460 tcggatgtgg gatacaata cgccaataat gataattta gattaaatcc agaagttagt 92520 tattttacga attaacgaac taggaccg ttgggaattt tattcaacta cgtcagact 92580 cttcttattt ctatgtattg ttccaaaca ttttagacg attccaaca acgaaaggta 92640 ttggcgattg attttggaa cggtgctgac ctggaaaaat acttttgg agagattgcg 92700 ttattggtag cgacggatcc ggatgctgat gctatagcta gaggaatga aagatacaac 92760 aaattaact ctggaattta aaccaagtac tacaatttg actacattca ggaaactatt 92820 cgatccgata catttgtctc tagtgtcaga gaagtattct attttggaaa gtttaatatc 92880 atcgactggc agtttgctat ccattattct ttcatccga gatatgc taccgtcatg 92940 ataacttat ccgaactaac tgcttctga ggcaggtat taatcactac catggacgga 93000 gaaattatta aaattaac agataaaag acttttatta ttcattagaa tttacctagt 93060 agcgaaaact atatgtctgt agaaaaaata gctgatgata gatagtggt atataatcca 93120 tcaacaatgt ctactccaat gactgaatac atttacaaa agaacgatat agtcagagtg 93180 tttaacgaat acggattgt tcttgtagat aacgttgatt tcgctacaat tatagaacga 93240 agtaaaaagt ttattaatgg cgcatctaca atggagata gaccgtctac aaaaaacttt 93300 ttcgaactaa atagaggagc cattaaatgt gaagttttag atgtcgaaga cttacttagt 93360 tactatgttg tttagtctt ttctaagcgg taaataataa tatggtatgg gttctgatat 93420 ccccgttcta atgcattaa atatcca taggaccttc ttgttccta taggaccttc 93480 caactgtgga tactctgtat tgttaataga tatatta ctttgtcgg gtaacagagg 93540 ttctacgtct tctaaaaata aaagttgat aacatctggc ctgttcataa aaaaactt 93600 ggcgattcta tatatactct tattatcaa tctagccatt gtcttataga tgtgagctac 93660 tgtaggtgta ccatttgatt ttctttctaa tactatatat ttctcgaa gaagttcttg 93720 cacatcatct gggaataaaa tactactgtt gagtaaatca gttatttt ttatatcgat 93780 attgatggac atttttag taggata tagtatccc aaagtagata acgacgataa 93840 cgagtattt atactttg gaatcaca tgactttatc agatcaaat taacaaatt 93900 aaaggagcat gtattttt ctgaatatat tgtgactcca gataaatatg gatctttatg 93960 cgtcgaatta aatgggtcta gttttcagca cggcggtaga tatatagagg tggaggaatt 94020 tatagatgct ggaagacaag ttagatggtg ttctacatcc atcatatat ctgaagatat 94080 acccgaagat atacacactg ataaatttgt catttatgat atacactt ttgacgcttt 94140 caagataaa cgattggtat tcgtacaggt acctccgtcg ttaggagatg atagctattt 94200 gactaatccg ttattgtctc cgtattatcg taattcagta gccagacaa tggtcaatga 94260 tatgattttt atcagatt cattttaaa atattatta gaacatctga ttagaagcca 94320 ctatagagtt tctaaacata taacaatagt tagatacaag gataccgaag aattaaatct 94380 aacgagaata tgttataata gagataagtt taaggcgttt gtattcgctt ggtttaacgg 94440 cgtttcggaa aatgaaaagg tactagatac gtataaaaag gtatctaatt tgatataatg 94500 aattcagtga ctgtatcaca cgcgccatat actattactt atcacgatga ttgggaacca 94560 gtaatgagtc aattggtaga gttttataac gaagtagcca gttggctgct acgagacgag 94620 acgtcgccta ttcctgataa gttctttata cagttgaaac aaccgcttag aaataaacga 94680 gtatgtgtgt gcggtataga tccgtatccg aaagatggaa ctggtgtacc gttcgaatca 94740 ccaaatttta caaaaaaatc aattaaggag atagcttcat ctatatctag attaaccgga 94800 gtaattgatt ataaaggtta taaccttaat ataatagacg gggttatacc ctggaattat 94860 tacttaagtt gtaaattagg agaaacaaaa agtcacgcga tctactggga taagatttcc 94920 aagttactgc tgcagcatat aactaaacac gttagtgttc tttattgttt gggtaaaaca 94980 gatttctcga atatacgggc caagttagaa tccccggtaa ctaccatagt cggatatcat 95040 ccagcggcta gagaccgcca attcgagaaa gatagatcat ttgaaattat caacgtttta 95100 ctggaattag acaacaaggc acctataaat tgggctcaag ggtttattta ttaatgcttt 95160 agtgaaattt taacttgtgt tctaaatgga tgcggctatt agaggtaatg atgttatctt 95220 tgttcttaag actataggtg tcccgtcagc gtgcagacaa aatgaagatc caagatttgt 95280 agaagcattt aaatgcgacg agttagaaag atatattgag aataatccag aatgtacact 95340 attcgaaagt cttagggatg aggaagcata ctctatagtc agaattttca tggatgtaga 95400 tttagacgcg tgtctagacg aaatagatta tttaacggct attcaagatt ttattatcga 95460 ggtgtcaaac tgtgtagcta gattcgcgtt tacagaatgc ggcgccattc atgaaaatgt 95520 aataaaatcc atgagatcta atttttcatt gactaagtct acaaatagag ataaaacaag 95580 ttttcatatt atctttttag acacgtatac cactatggat acattgatag ctatgaaacg 95640 aacactatta gaattaagta gatcatctga aaatccacta acaagatcga tagacactgc 95700 cgtatatagg agaaaaacaa ctcttcgggt tgtaggtact aggaaaaatc caaattgcga 95760 cactattcat gtaatgcaac caccgcatga taatatagaa gattacctat tcacttacgt 95820 ggatatgaac aacaatagtt attacttttc tctacaacaa cgattggagg atttagttcc 95880 tgataagtta tgggaaccag ggtttatttc attcgaagac gctataaaaa gagtttcaaa 95940 aatattcatt aattctataa taaactttaa tgatctcgat gaaataatt ttacaacggt 96000 accactggtc atagattacg taacaccttg tgcattatgt aaaaaacgat cgcataaaca 96060 tccgcatcaa ctatcgttgg aaaatggtgc tattagaatt tacaaaactg gtaatccaca 96120 tagttgtaaa gttaaaattg ttccgttaga tggtaataaa ctgtttaata ttgcacaaag 96180 aattttagac actaactctg ttttattaac cgaacgagga gaccatatatag tttggattaa 96240 taattcatgg aaatttaaca gcgaagaacc cttgataaca aaactaattt tgtcaataag 96300 acatcaacta cctaaggaat attcaagcga attactctgt ccaagaaaac gaaagactgt 96360 agaagctaac atacgagaca tgttagtaga ttcagtagag accgatacct atccggataa 96420 acttccgttt aaaaatggtg tattggacct ggtagacgga atgttttact ctggagatga 96480 tgctaaaaaa tatacgtgta ctgtatcaac cggatttaaa tttgacgata caaagttcgt 96540 cgaagacagt ccagaaatgg aagagttaat gaatatcatt aacgatatcc aaccattaac 96600 ggatgaaaat aagaaaaata gagagctata tgaaaaaaca ttatctagtt gtttatgtgg 96660 tgctaccaaa ggatgtttaa cattcttttt tggagaaact gcaactggaa agtcgacaac 96720 caaacgtttg ttaaagtctg ctatcggtga cctgtttgtt gagacgggtc aaacaatttt 96780 aacagatgta ttggataaag gacctaatcc atttatcgct aacatgcatt tgaaaagatc 96840 tgtattctgt agcgaactac ctgattttgc ctgtagtgga tcaaagaaaa ttagatctga 96900 aatattaaa aagttgacag aaccttgtgt cattggaaga ccgtgtttct ccaataaaat 96960 97020 gatagataac gcattaatga gaagaattgc cgtcgtgcga ttcagaacac acttttctca 97080 accttctggt agagaggctg ctgaaaata tgacgcgtac gataagtca aactattaga 97140 cgaggggtta gatggtaaaa tacaaataga ttcgcatttc tatacttgtt 97200 ggtgaaatgg tacagaaat atcatgttcc tattatgaa ctatatccta caccggaaga 97260 gattccggac tttgcattct atctcaaat aggtactctg ttagtatcta gctctgtaaa 97320 gcatattcca ttaatgacgg acctctccaa aaagggatat atattgtacg ataatgtggt 97380 cactcttccg ttgactactt tccacagaa atatccaag tattttat ctagactatt 97440 tggacacgat atagagagct tcatcatag acatagaaa ttgccaatg tagtgatga 97500 atatctgcaa tatatattca tagaggatat ttcatctccg taaatatatg ctcatatatt 97560 tatagaat atcacatatc taatgaata ccggaatcat agatttatt gatacatg 97620 ttgatagtat accaactata ttacctcatc agttagctac tctagattat ctagttagaa 97680 ctatcataga tgagaacaga agcgtgttat tgttccatat tatgggatca ggtaaaacaa 97740 taatcgcttt gttgttcgcc ttggtagctt ccagatttaa aaagtttac attctagtgc 97800 ctaatatcaa cattttgaaa atttttaatt atatatggg tgtagctatg aacttgttta 97860 atgacgaatt catagctgag atatcttta ttcattccac aacaagtttt tattctctta 97920 attataacga taacgtcatt aattataacg gattatctcg ctacaataac tctattttta 97980 tcgttgatga ggcacataat atctttggga atatactgg agaacttatg accgtgataa 98040 aaaaaaa aaaaaaaa tgtctctt tgtctgatc tcccattact aacacaccta 98100 atactctggg tcatattata gatttaatgt ccgaagagac gatagatttt ggtgagatta 98160 ttagtcgtgg tagaagta attcagacac ttcttaacga acggcggtgtg atgtactta 98220 aggatttgct taaggaga atatcatatt acgaatgcc tgataagat ctaccaacga 98280 taagatatca cggacgtaag tttctagata ctagagtagt atattgtcac atgtctaaac 98340 ttcaagagag agattatatg attactagaczgagctatg attacatgaa atgtttgata 98400 aaatatgta taacgtgtca atggcagtat tgggacaact taatctgatg ataatttag 98460 atactttatt tcaggacag gataggaat tgtaccaaa tctgaaaata ataatggcg 98520 tgttatacgg agaagaattg gtaacgttaa acattagttc caatttaaa tactttatta 98580 atcggataca icactcaac ggaaaacatt ttatatactt ttctattct acataggtg 98640 gattggtaat taaatatatc atgctcagta atggatattc tgaatataat ggttctcagg 98700 gaactaatcc acatagata aacggcaaac caaaaacatt tgctatcgtt actagtaaaa 98760 tgaaatcgtc tttagaggat ctattagatg tgtataatttc tcctgaaaac gatgatggca 98820 gtcaatgat gttttgttt tcatcaaca ttatgtccga atcctatact ctaaaagagg 98880 taaggcatat ttggtttg actatcccag atactttc tcaatacaac caattcttg 98940 gacgatctat tagaaaatttc tcttacccg atatttctga accagttaat gtatatcttt 99000 tagccgccgt atttccgat ttcaatgacg aagtaacgtc attaaacgat tacacacagg 99060 atgaattgat taatgtttta ccatttgaca tcaaaagct gttgtatcta aaatttaaga 99120 cgaaagaaac gatagaata tactctattc ttcaagagat gtctgaaacg tattctctc 99180 caccacatcc atcaatgta aaagttttat tgggagaatt ggtcagacaa ttttttata 99240 atattctcg tattagtat aacgactcca agttacttta aatggttaca tcagttataa 99300 aaaaayaga agacgctagg attackacatag atgatattgt aaacggtcac ttctttgtat 99360 cgaataagt atttgataaa tctcttttat acaatacga aaacgatatt attackacagtac 99420 cgtttagact ttcctacgaa ccattgtttt ggggagttaa ctttcgtaaa gatataacg 99480 tggtatcttc tccataaaac tgatgaaata tataaagaaa taatgtcga gctttgttac 99540 caatggatac cttccagtta cattggaacc acacgagctg acgttagaca taaaaactaa 99600 tattaggaat gccgtatatata agacgtatct ccatagagaa attagtgta aaatggccaa 99660 gaaatagaa attcgtgaag acgtggaatt acctctcggc gaaatagtta atattctgt 99720 agttataac gttccgtgtg taataacta cgcgtattat cacgttgggg atatagtcag 99780 aggaacatta aacatcgaag atgaatcaa tgtaactatt caatgtggag atttaatctg 99840 taaactaagt agagattcgg gtactgtatc atttagcgat tcaaagtact gcttttttcg 99900 aaatggtaat gcgtatgaca atggcagcga agtcactgcc gttctaatgg aggctcaaca 99960 aggtatcgaa tctagttttg ttttctcgc gaatatcgtc gactcataaa aaagagaata 100020 gcggtaagta taaacacgaa tactatggca ataattgcga atgttttatt ctcttcgata 100080 tatttttgat aatatgaaaa acatgtctct ctcaaatcgg acaaccatct cataaatag 100140 ttctcgcgcg ctggagaggt agttgctgct cgtataatct ccccagaata atatacttgc 100200 gtgtcgtcgt tcaatttata cggatttcta tagttctctg ttatataatg cggttttcca 100260 tcatgattag acgacgacaa tagtgttctg aatttagata gttgatcaga atgaatgttt 100320 attggcgttg gaaaaattat catacagcg tctgcagagt ggttgatagt tgttcctaga 100380 tatgtaaaat aatccaactt actaggcagc aaattgcta gataaaatac tgaatcaaac 100440 ggtgcagacg tattggcgga tctaatggaa tccaattgat taactatctt ttgaaaatat 100500 acatttttat gatccaatac ttgtaagaat atagaata tgataagtcc atcatcgtgt 100560 ttttttgcct cttcataaga actatatttt ttttattcc aatgaacaag attaatctct 100620 ccagagtatt tgtacacatc tatcaagtga ttggatccat aatcgtctc ctttccccaa 100680 tatatatgta gtgatgataa cacatattca ttggggagaa accctccact tatatatcct 100740 cctttaaaat taatccttac tagttttcca gtgttctgga tagtggttgg tttcgactca 100800 ttataatgta tgtctaacgg cttcaatcgc gcgttagaaa ttgcttttt agtttctata 100860 ttaataggag atagttgttg cggcatagta aaaatgaat gataactgtt taaaaatagc 100920 tcttagtag ggaattacaa tggatgagga agtgatattt gaactccta gagattaat 100980 atctattaaa cgaataaaag atattccaag atcaaagac acgcatgtgt tgctgcgtg 101040 tataacaagt gacggatatc cgttaatagg agctagaga acttcattcg cgttccaggc 101100 tatattatct spaaatt spagatttat ctttagagta tccattaac tattacggtt 101160 tatgtactac atgaacta gagaaatcttt tagacggttg agaaaggtt ctatchacaa 101220 tatcgatcct cactttgaag agttaatatt attgggtggt aaactagata aaaggaatc 101280 tattaagat tgttaagaa gagaatttaa agaggaaagt gatgaacgta taacagtaaa 101340 agaatttgga atgtattc taaaacttac aacacgggat aaatttatta aaagtata 101400 tataagttat tgcatggcgt gttttatta tcaatcgttg gaggattt cgcatactag 101460 tattacaat gtagaatta gaagattaa atcattaat gattgtatta acgacgaata 101520 atacgaatat ctgtcttata tttatat gctagttaat agtaaatgaa cttttacaga 101580 tctagtataa ttagtcagat tattagtat atagacgac tagctaagtc tattattgc 101640 gaggatgact ctcaattat tacactcacg gcattcgtta accaatgcct atggtgtcat 101700 aaacgagtat ccgtgtccgc tatttta actactgata aaaatatt agtagtaac 101760 agacgagata gttttctcta ttctgaata atttagaacta gaaacatgtc tagaagaaa 101820 cgattatttc tgaattattc caattattg tccaaacagg aaagaagtat actatcgtca tttttttctc tagtccagc tactactgat aatgatagaa taggctat ttatccgggt ggcataccca aaaggggtga gaatgttcca gagtgtttt ccaggaat taagaaga gttaatatag acaattcttt tgtattcata gacactcggt tttttattca tggcatcata gaagatacca ttattaata attttttgag gtaatcttct ttgtcggaag aatatcttta acgagtgatc aaatcattga tacatttaaa agtaatcatg aaatcaagga tctatattt ttagatccga attcaggtaa tggactccaa tacgaaattg caaaattgc tctagatact gcaaaactca aatgttatgg ccatagagga tgttattacg aatcattaaa aaaattaact 102360. 102360. 102360. 102360. 102360. 102360. 102360 gtccggcata tcatgtagt agttaccgtc tacatcgtat actcgaccat ctacgccttt aaatcctcta tttattgaca ttaatctatt agaattgga taccaatat tagtaccctc aattagttta ttggtatatat tttttaga cgatagatcg atggctcttg aaaccaaggt 102540 tttccaaccg gactcattgt cgatcggtga gaagtcttt tcattagcat gatccattc 102600 taatgatgta tgtttaaca ctctaaacaa ttggacaaat tctttgatt tgctttgaat 102660 gatttcaat aggtcttcgt ctacagtagg cataccatta gatacttag ccattataa 102720 gtgcacgttt acatactac gttctggagg agtagaacg tgactattga gacgaatggc 102780 tcttcctact atctgacgaa gagacgccctc gttccatgtc atatctaaaa tgaagatatc 102840 atttattgag aaaaaactaa taccctcgcc tccactagaa gagaatacgc atgttttaat 102900 gcattctccg ttagtgtttg attctttgtt aaactcagcc accgccttga ttctagtatc 102960 ttttgttcta gatgagaact ctatattaga gataccaag actttgaat atagtataataa 103020 gatttctatt cctgactgat taacaatgg ttcaagact agacatttac catgggatgc 103080 taatattccc aacatacat ctataaattt gacgctttc tctttaattt cagtaatag 103140 agagatatca gccgcactag catccccttt caatagttct ccctttttaa aggtatctaa 103200 tgcggattta gaaaactctc tatcttta tgaattttta aaatcattat atagtgttgc 103260 tatctcttgc gcgtattcgc ccggatcacg attttgtctt tcaggaagc tatcgaacgt 103320 aaacgtagta gccatacgtc tcagaattct aaatgatgat atacctgttt ttatttcagc 103380 gagtttagcc ttttgataaa tttctcttg cttttcgac atattaacgt atcgcattaa 103440 tactgttttc ttagcgaatg atgcagaccc ttctacgtca tcaaaatag aaaactcgtt 103500 attackatg tacgaacata ggcctcctag tttggact aattctttct catcaactag 103560 acgtttattc tcaaatagcg attggtgttg taaggatcct ggtcgtagta agttaaccaa 103620 catggtgaat tcttgcacac tattaacgat aggtgtagcc gataaacaa tcatcttatg 103680 gttttttaat gcgatggtct tagataaaa attatatact gaacgagtag gacggatctt 103740 accatcttct tgattaatg attagaat gaagttatga cattcatca taatgacgca 103800 tattctactc ttggaattta tagttttgat attagtaaaaatttattc taaaatttg 103860 atcatcgtaa ttaataaaaa tacaatcctt cgttatctct ggagcgtatc tgagtatagt 103920 gttcatccaa ggatcttcta tcaagcctt ttcaccaat aagataag cccaattcgt 103980 aaataatcc ttaagatgtt tgagaata tacagtagtc attgttttac cgacacccgt 104040 ttcatggaac aaaaagag atgcatact gtctaatcct aagaaactc ttgctacaaa 104100 atgttgataa tccttgaggc gtactacgtc cgacccatc atttcaacgg gcatattagt 104160 agttctgcgc aatgcataat cgatataggc cgcgtgtgat ttactcattt atgagtgata 104220 agtaataact atgttttaa atcacagca gtagtttaac tagtctctc tgatgtttgt 104280 tttcgatact tttgaatca gaagtcatac tagaataag caacgagtga acgtaataga 104340 gagcttcgta tactctattc gaaaactcta agaacttatt aatgaattcc gtatccactg 104400 gattgtttaa atactaaat tgacactgt tcacatcctt ccagagaa gacttagtga 104460 cggacttaac atgagacata aaaatcca aatttttt acaacatca ctagccacca 104520 taatggcgct atctttcaac cagctatcgc ttacgcattt tagcagtcta acatttttaa 104580 agagactaca atattattctc atagtatcga ttacacctct accgataaa gttggaagtt 104640 taatataca atattttcg tttacaaat caataatgg tcgaacacg tcgaaggtta 104700 acatcttata atcgctaatg tatagattgt ttcagtgag atgattatta gatttatag 104760 catctcgttc acgtttgaac agtttattgc gtgcgctgag gtcggcaact acggcgtccg 104820 ctttagtact cctcccataa tactttacgc tattaatctt taaaatttca tagactttat 104880 ctagatcgct ttctggtaac atgatatcat gtgtaaaag ttttaacatg tcggtcggca 104940 ttctatttag atcattaacct ctagaaatct gagaaagta attagctccg tattccagac 105000 taggtaatgg gctttacct agagacagat taagttctgg caatgtttca taaaatggaa 105060 gaaggacatg cgttccctcc cggatatttt ttacaatttc atccatttac aactctatag 105120 tttgttttca ttattattag ttattatctc ccataatctt ggtaatactt accccttgat 105180 cgtaagatac cttatacagg tcattacata caactaccaa ttgtttttgt acataataga 105240 ttggatggtt gacatccatg gtggaataaa ctactcgaac agatagtta tctttccccc 105300 tagatacatt agccgtaata gttgtcggcc taaagaatat cttttggtgta aagttaaaag 105360 ttgggttct tgttccatta ttgctttttg tcagtagttc attataaatt ctcgagatgg 105420 gtccgttctc tgaatataga acatcatttc caaatctaac ttctagtcta gaaataatat 105480 cggtcttatt cttaaaatct attcccttga tgaagggatc gttaatgaac aaatccttgg 105540 cctttgattc ggctgatcta ttatctccgt tatagacgtt acgttgacta gtccaaagac 105600 ttacaggaat agatgtatcg atgatgttga tactatgtga tatgtgagca aagattgttc 105660 tcttagtggc atcactatat gttccagtaa tggcggaaaa cttttagaa atgttatata 105720 taaaagaatt ttttcgtgtt ccaaacatta gcagattagt atgaagataa acactcatat 105780 tatcaggaac attatcaatt tttacataca catcagcatc ttgaatagaa acgataccat 105840 cttctggaac ctcaacaatc tcggcagact ccggataacc agtcggtggg ccatcactaa 105900 caataactag atcatccaac aatctactca catatgcatc tatataatct ttttcatctt 105960 gtgagtaccc tggatacgaa ataaattat tatccgtatt tccataataa ggtttagtat 106020 aaacagagag cgatgttgcc gcatgaactt cagttacagt cgccgttggt tggtttattt 106080 gacctattac tctcctaggt ttctctataa acgatggttt aatttgtaca ttcttaacca 106140 tatatccaat aaagctcaat tcaggaacat aaacaaattc tttgttgaac gtttcaaagt 106200 cgaacgaaga gtcacgaata acgatatcgg atactggatt gaaggttacc gttacggtaa 106260 tttttgaatc ggatagttta agactgctga atgtatcttc cacatcaaac ggagttttaa 106320 tataaacgta tactgtagat ggttctttaa tagtgtcatt aggagttagg ccaatagaaa 106380 tatcattaag ttcactagaa tatccagagt gtttcaaagc aattgtatta ttgatacaat 106440 tattatataa ttcttcgccc tcaatttccc aaataacacc gttacacgaa gagatagata 106500 cgtgattaat acatttatat ccaacatatg gtacgtaacc gaatcttccc atacctttaa 106560 cttctggaag ttccaaactc agaaccaaat gattaagcgc agtaatatac tgatccctaa 106620 ttcgaagct agcgatagcc tgattgtctg gaccatcgtt tgtcataact ccggatagag 106680 aaatatattg cggcatatat aaagttggaa tttgactatc gactgcgaag acattagacc 106740 gtttaataga gtcatcccca ccgatcaaag aattaatgat agtattattc atttcttatt 106800 taaaatggaa aaagcttaca ataaactccg tagagaaata tctataattt gtgagttttc 106860 cttaaagtaa cagcttccgt aaacgccgtc tttatctctt agtaagttta ttgtatttat 106920 aaccttttcc ttatcttcat agaatactaa aggcaacaaa gaaatttttg gttcttctct 106980 aagagctacg tgagacttaa ccatagacgc caacgaatcc ctacatattt tagaacagaa 107040 atacccaact tcaccaccct tgaatgtctc atactaata ggtttaaaaa ccaaatcttg 107100 attack cacacact cattacact atttgtctta atagacacat ctgccataga 107160 tttataac tttggtagta tacaagcgag tgcttcttct tagcgggct taaagactgc 107220 tttaggtgct gaaatacca catctggaag gcttactcgc ttagccattt aattacggaa 107280 ctattttttt atacttctaa tgagcaagta gaaaacctct catctacaa aacatactcg 107340 tgtccataat cctctaccat agttacacgt ttttagatc tcatatgtgc taaaaagttt 107400 tcccatacta attggttact attattttc gtataatttt taacagtttg aggttttaga 107460 tttttagtta cagaagtgat atcgaatatt tttccaaa agaatgaata atttattgtc 107520 ttagaaggag tgttttcttg gcaaagaat accaagtgct taaatattc tactacttca 107580 ttaatctttt ctgtactcag attcagttc tcatcttta ctgattgat tattcaag 107640 actaacttat aatccttttt atttattctc tcgttagcct tagaaact agatacaaaa 107700 ttgcatcta catcatccgt ggatatttga ttttttcca tgatatccaa gagttccgag 107760 aatttctc cagaacattg atgagacaat aatctccgca aatcatttct caatgaata agtttattag acacatggaa gtttgacttt ttttgtacct ttgtacattt ttgaaatacc 107940. 107940. 107940. 107940. 107940. 107940. 107940. 107940 ccgctacata atcgtagatt catgttaaca ctctacgtat ctcgtcgtcc aatattttat ataaaaacat tttatttcta gacgttgcca gaaaatcctg fathertttt agttttttgg gctgtgaata aagtatcgcc ctaatattgt taccgtcttc cgccaatata gtagttaaat tatccgcaca tgcaaaaga caccgcttag gcggattcag tacaatgtta tatttttcgt accaactcat ttaaatatca ttaaataaa tagttctgta atatgtctag cgctaatata ttgatcataa tcctgtgcat fathers fathers ctcgaatca tcgacatggc ttcttccata gttagaagat cgtcgtcaaa gttagcaacg tgattcatca acatttgctg ttttgaggca gcaaatactg aaccgtcgcc attcaaccat tcataaaaac catcgtctga atccattgat aatttcttgt actggttttt gagagctcgc atcaatctag catttctagc 108480 tcccggattg aaaacagaaa gaggatcgta catccagggt ccattttctg taaatagaat 108540 cgtataatgt cccttcaaga agatatcaga cgatccacaa tcaaagaatt ggtctccgag 108600 tttgtaacaa actgcggact ttaacctata catgataccg tttagcatga tttctggtga 108660 tacgtcaatc ggagtatcat ctattagaga tctaaagccg gtgtaacatt ctccaccaaa 108720 catattctta ttctgacgtc gttctacata aaacatcatt gctccattaa cgataacagg 108780 ggaatgaaca gcactaccca tcacattagt tcccaatgga tcaatgtgtg taactccaga 108840 acatcttcca tatcctatgt taggaggagc gaacaccact cttccactat tgccatcgaa 108900 tgccatagaa taaatatcct tggaattgat agaaatcgga ctgtcggatg ttgtgatcat 108960 cttcatagga ttaacaacta tgtatggtgc cgcctgaagt ttcatatcgt aactgatgcc 109020 gtttataggt ctagccacag aaaccaacgt aggtctaaat ccaactatag acaaaataga 109080 agccaatatc tgttcctcat ctgtcataac ttgagagcat ccagtatgaa taatcttcat 109140 tagatgggga tctaccgcat catcatcgtt acataaaaa attcccattc taatgttcat 109200 aattgctttt ctaatcatgg tatgcatgtt tgctctctga atctctgtgg aattagatc 109260 tgatacacct gtaatcacta tcggattatc ctccgtaaga cgatttacca acaacatata 109320 attataagac tttactttc taaattcata aagttgctgg attaggctat aggtgtctcc 109380 atgtacatac gcgttctcga gcgcaggaag tttaataccg atagtgcca tcagaatagg 109440 atgaatatag taattagttt ctggttttct aataataaa gataaatctt gtgaactaga 109500 catatcggta aaatgcatgg attggaatcg tgtagtcgac agagaata gatgattaga 109560 tggagagtat attttatcta actctttgag ttggtcaccg attctaggac tagctcgaga 109620 atgaatagt actaaaggat gagtacattt cacagaaca ctagcattgt tcaatgtgct 109680 ctttacatgg gtaggagtt gaaatagctc gtttctattt gttctgacaa tattagttt 109740 attcataatg ttaagcatat cctgaatagt aaagttagat gtgtcatact tgttagtagt 109800 tagatattta gcaattgcat tcccatcatt tctcaatctc gtactccaat catgtgtaga 109860 tgctacttcg tcgatggaaa catacaatc ctttttgata ggctgttgag attgattatt 109920 tcctgcacgt ttaggtttgg tacgttgatt tctagcccct gcagatataa agtcatcgtc 109980 tacaatttg gataatgaat tgcatacact acaagacaaa gatttatcag aagtgtgaat 110040 atgatcttca tctaccaaag aaagagtttg attagtataa ctagatttta gtcctgcgtt 110100 agatgttaaa aaaacatcgc tattgaccac ggcttccatt attatattc gtagttttta 110160 ctcgaaagcg tgattttaat atccaatctt attacttttg gaatcgttca aaacctttga 110220 ctagttgtag aatttgatct attgccctac gcgtatactc ccttgcatca tatacgttcg 110280 tcaccagatc gtttgttcg gcctgaagtt ggtgcatatc tttttcaaca ctcgacatga 110340 gatccttaag ggccatatcg tctagatttt gttgagatgc tgctcctgga tttggatttt 110400 gttgtgctgt tgtacatact gtaccaccag taggtgtagg agtacataca gtggccacaa 110460 taggaggttg aggaggtgta accgttggag tagtacaaga atacttcca tccgattgtt 110520 gtgtacatgt agttgttggt aacgtctgag aaggttgggt agatggcggt gtcgtcgtct 110580 tttgatcttt attaattta gagatatat cctgaacagc attgctcggc gtcaacgctg 110640 gaaggagtga actcgccggc gcatcagtat ctgcagacag ccaatcaaa agattagaca 110700 tatcagatga tgtattagtt tgttgtcgtg gttttggtgt aggagcagta ctactaggta 110760 gagaatagg agccgatgta gtgtcggaa ccggaaccgg ctgtggagtt atatgaatag 110820 ttggttgtag cggttggata ggctgtctgc tggcggccat catattatct ctagctagtt 110880 gttctcgcaa ctgtctttga taatacgact cttgagactt tagtcctatt tcaatcgctt 110940 catccttttt cgtatccgga tcctttttt cagaataata gattgacgac tttggtgtag 111000 aggattctgc cagcccctgt gagaacttgt taagaagtc cattttaggc ttaaattg 111060 aattgcgatt atagattaa atggcagaca cagacgatat tatcgactat gatccgatg 111120 atctcactga atcgaggat gatgagaag aggagaag tggagtca ctagaaacta 111180 gtgatataga tcccaatct tcttataaga tgtagaatc agcatccact catatagaag 111240 atgcgcattc caatcttaa catatagg atcatatatc tgcttaa cgacgctata 111300 ctagacgtat aagtctattt gaatagcgg gtataatagc agaagctat aacttgcttc 111360 aacgaggaag attackcta gttcagaat ttctgacga acgatgaag caaatatgc 111420 tacatgtaat atacagag atagaggagg gttcttgtcc tatagtcatc gaaagaacg 111480 gagaattgtt gtcggtaaac gattttgaca aagatggtct aaattccat ctagactata 111540 tttcaaat ttggaactt caaaacgat attagaattt atacgaatat cgttctctaa 111600 atgtcacaat caagtctcgc atgttcagca atttattgtc gtactttata tcgtgttcat 111660 taacgatatc ttgcaaata gtaatgattc tatctctcctt cgatagatat tcttcagaga 111720 ttattgtctt atattctttc ttgttatccg atatgaattt gataagactt tgaacattat 111780 tatacccgt ctgtttaatt ttttctacag atattttagt tttggcagat tctatcgtat 111840 ctgtcaatag acatccaaca tcgacattcg acgtcaattg tctataaatc aacgtataaa 111900 ttttagaaat aacattagcg aattgttgtg cattgatgtc gttattctga aacagtatga 111960 ttttaggtag cattttctta acaaagagaa cgtatttatt gttactcagt tgaacagatg 112020 atatatccag attactaacg catctgattc cgtataccaa actttcagaa gaaatggtgt 112080 acaattgttt gtattcattc aatgtctcct tttcagaaat tagtttagag tcgaatactg 112140 caataatttt caagagatag ttttcatcag ataagatttt atttagtgta gatatgataa 112200 aactattgtt ttgttggaga acttgatacg ccgcgttctc tgtagtcgac gctctcaaat 112260 gggaaacgat ctccattatt ttttggaat cggatactat atcttcggta tcttgacgca 112320 gtctagtata catagagtta agagagatta gagtttgtac attaagcaac atgtctctaa 112380 atgtggctac aaacttttcc tttttcacat catctagttt attatatacc gatttcacaa cggcaccaga tttaaggaac cagaatgaaa aactctgata actacaatat ttcatcatag ttacgatttt atcatcttct atagttggtg fathercgca tacctttttc tccaagactg 112620. 112620. 112620. 112620. 112620. 112620. 112620. 112620 cagtctcgcg ttcaagatta tctttactaa tggtgacgaa ctcatcgtat agaactctaa gtttgtccat tatttattta cagatttagt tgtttaattt atttgtgctc ttccagagtt gggatagtat ttttctaacg tcggtattat attack tctacgttca tatgtatcat aatattaatc atccacgttt tgataaatct atctttagct tctgaaata cgtatttaaa 112920. 112920. 112920. 112920. 112920. 112920. 112920. 112920. 112920. 112920 gtatttagac gacagatctt cgttaaaaag ttttccatct atgtagac catcggttgt taacaccatt cccgcgtcag attgaatagg agtttgaata gtttgttttg gaatagatc cttcaataac ttatagttgg gtgggaaaaa atcgatttta tcactagact cttcttttt 113100 tactatcatt acctcatgaa ctatttcttg aatgagtata tgtattttct ttcctatatc 113160 ggacgcgtc attggaaaat ataccatgtc gttaactata agaatatttt tatcctcgtt 113220 tacaaactga ataatatcag atgtagttcg taaacgaact atatcatcac cagcacaaca 113280 tctaactata tgatatccac tagtttcctt tagccgttta ttatcttgtt ccatattagc 113340 agtcattcca tcatttaaga aggcgtcaaa aataataggg agaaatgaca ttttggattc 113400 tgttacgact ttaccaaaat taaggatata cggacttact atctttttct caacgtcaat 113460 ttgatgaaca cacgatgaaa atgtgcttct atgagattga tcatgtagaa aacaacaagg 113520 gatacaatat ttccgcatat catgaaatat attaagaaat cccaccttat tatatttccc 113580 caaaggatcc atgcacgtaa acattatgcc gttatcatta ataaagactt ctttctcatc 113640 ggatctgtaa aagttgttac tgattttttt cattccagga tctagataat tataatgat 113700 gggttttcta ttcttattct ttgtattttg gcatatccta gaccagtaaa cagtttccac 113760 tttggtaaaa tcagcagact tttgaacgct attaaacatg gcattaatgg caataactaa 113820 aaatgtaaaa tatttttcta tgttaggaat atggtttttc actttaatag atatatggtt 113880 tttggccaaa atgatagata tttttttatc cgaggatagt aaaatattat tagtcgccgt 113940 ctctataaaa atgaagctag tctcgatatc caattttatt ctagaattga taggagtcgc 114000 caaatgtacc ttatacgtta tatctccctt gatgcgttcc atttgtgtat ctatatcgga 114060 cacaagatct gtaaatagtt ttacgttatt aatcatcacg gtatcgccgt cgctagataa 114120 cgctaatgta ccatccaagt cccaaatgga gagatttaac tgttcatcgt ttagaataaa 114180 atgattaccg gtcatattaa taaagtgttc atcgtatcta gataacaacg acttataatt 114240 aatgtccaag tcttgaactc gctgaatgat cttttttaac ccagttagtt ttagattggt 114300 acgaaatata ttgttaaact ttgattctat agtaatgtcc aaatctagtt gtggaaatac 114360 ttccatcaac attgtttcaa acttgataat attattatct acatcttcgt acgatccaaa ttccggata gatgtatcgc acgctctggc cacccagata accaaaaagt cacacgctcc aggatataca ttgtataaaa agctatcgtt ttttagtag gtttttttct gcgtgtatac average aaatagtat tatcaacgta actatattcc aaatattct tatgagaata throw tcgtcctta tatcta atttcctaa tatcccttta attgagtcat tcgaagcgtc fathers gtctcttaac tatttccggc tgttgtatas fathers tcgtaaaaaa father gcgacttctc atctatgtaa tcatatggag tgagatatag ggctcgttct acctcctgcc ccttacccac ctgtaatacc aattgcggac ttactatata tcgcatattt atatcgtggg gtaaagtgaa aatctactac cgatgatgta agtcttacaa tgttcgaacc agtaccagat cttaatttgg aggcctccgt agaactaggg gaggtaaata father aacacctatg father fathercccgc fathercggtc tattcgccca tagatctaag gatgatgaga gaaaactagc actacgattc tttttacaa 115080 gactttattt tttagatcat agagagattc attatttgtt cagatgcgtt gacgctgtaa 115140 aagacgtcac tattaccaa aaaaataca ttacgtggc gccttatata gcactttaa 115200 ctatcgcatc aaaggatgc aaacttacag aaacaatgat tgaagcattc tttccagaac 115260 tatataatga acatagtaag aaatttaaat tcaactctca agtatccatc atccaagaaa 115320 aactcggata ccagtttgga aactacacg tttatgatt tgaaccgtat tactctacag 115380 tagctctggc tattcgagat gaacattcat ctggcatttt taatatccgt cagagagtt 115440 atctggtaag ttcattatct gaaatacat atagatttta tctattaat ctaaaatctg 115500 atcttgttca atggagtgct agtacggggcg ctgtataa tcaatggta atactgtat 115560 tgattacagt gtatgaaag ttacactgg tcatagaaaa tgatcacaa tttacatgtt 115620 cattggctgt ggaatcaaa cttccaataa attacktta agatagaat gatttatta 115680 haaaattcat taacgagtta aaaagacca gttcattca gataagcaa cgcgatagg 115740 atacgctact aaaatatttt acttaggact ggagttagaa ttatagacg actcatttcg 115800 tttatcatta ttactaccat cattattagt attctcttg ttatcttgtt cagaaatata 115860 cagcaatgct atgcctaata ctaaatacat tatcatgctt gcaatggctc taacaacgac 115920 gaaccaaaat gatttggtc gtagctttg ttcacaaaa tacataaaga atgtctaca 115980 taaatctatg gcgccattgg ctacttgaa tagcgccagt cctcctacag attttatat 116040 agctgtataa catgacatttt attcatcatc aaagagaca gagtcaccat ctgtcatatt 116100 tagatttt ttcatgtgtt caaagtatcc tctactcatt tcattataat agtttatcat 116160 acttagaatt taggacgga tcaatgagta agacttgact agatcgtcag tagtaatttg 116220 tgcatcgtct attctgcatc cgcttcgtcg ataatgtat agcatcgctt tgagattctc 116280 catagctatc aagtctttat acatgacat ggaaatatct gtgaatactt tatactctc 116340 caacatcgat gccttaacat catcgcctac tttagcattg aaaatacgtt ctattgtgta 116400 gatggatgta acaagatttt taaacaacaa tgccatctta cacgatgatt gcctcaagtc 116460 tccaatcgtt tgtttagaac gattagctac agagtccaat gcttggctga ctagcatatt 116520 attatcttta gaaattgtat tcttcaatga ggcgtttatc atatctgtga tttcgttagt 116580 catattacag tctgactggg ttgtaatgtt atccaacata tcacctatgg atacggtaca 116640 cgtaccagca tttgtaataa tcctatctaa gatgttgtat ggcattgcgc agaaaatatc 116700 ttctcctgta atatctccac tctcgataaa tctactcaga ttatctttaa atgccttatt 116760 ctctggagaa aagatatcag tgtccatcat ttcattaata gtatacgcag aaaagatacc 116820 acgagtatca attctatcca agatacttat cggttccgag tcacagataa tggtttcctc 116880 tccttcggga gatcctgcat agaaatatct aggacaatag tttctatact gtctgtaact 116940 ctgataatct ctaaagtcac taactgatac catgaaattg agaagatcaa acgctgaagt 117000 aattaattt tctgcctcgt tttactaca actagttttc atcaatgtag tgacgatgta 117060 ttgtttagtt acttttggtc taatactgat gatagagata ttattgctc ccataatgga 117120 tcttctagta gtcaccttaa agcccattga tgcgaatagc agatagataa agtcttggta 117180 tgactccttt ctaatatagt acggactacc ttgtcaccc aactttatac ccacataagc 117240 cataacaacc tctttaatag cgtttcatg aggttca gccatgagcc tgagtagttg 117300 gaagaatctc atgaatcccg tctcagaaag tcctatatgc atgatagatt tatctttcct 117360 gggaaactct cgtatagtca tagataa actctcaa gtttctgaaa tagattagt 117420 aacagtctta cctccgacta ctctgggtaa caacaact ctaataggtg ttttctctgc 117480 ggagataata tcagaagga tagagcaata agtagtatta tgtgatt aagaccgaa 117540 tacatacag gtagaattta taaaccat gtcctgaagg ttttagact tgtattccctc 117600 gtaatccata ccgtcccaaa acatggattt ggtaactttg atagccgtag atctttgttc 117660 cttcgccaac aggttaaaga aattaataa gatttgttg tttcttta tgtccacaaa 117720 ttgcacgttt ggaagcgcca cggttacatt cactgcagca tttgaggat cgcgagtatg 117780 aagtacgatg ttattgttta ctggtatatc tggaaagaa tctaccagtc taggaatag 117840 agattgatat cgcatagaaa tagtaagtt tataatctca tcatcgaaga gcattttgtt 117900 accattgtaa taaatatcca ctctgtcata tgtataaatg aagtactgtt caacatgat 117960 gagatgttta tatgttggca tagtagtgag atcgacgtttt ggtaatggca atgtattaag 118020 attackactcca taatgtctag cagcatctgc gatgttataa gcgtcgtcaa agcggggtcg 118080 atcttgtatt gttatatat gtctaacacc tataagatta tcaaatctt gtctgcttaa 118140 tacaccgtta acaattttg ccttgaatttc ttttattgt gcattaataa catccttata 118200 gaggatgtta aaaataag tgttatcaa gttaagatct ggatatttct tttctgctag 118260 aacatccatt gagtcggagc catctggtttt atattacca ccgataaatc tagctctgta 118320 ttctgtatcc gtcaatctaa tattagag gtgttgagtg aaggtggaa gatcgtaaaa 118380 gctgtgagta ttaatgag gattagtttc cgaactaatg ttaattgggg tattataat 118440 atctatattt ccagcgttaa gtgtaacatt aacagtttt attcacgtg aagtagtatc 118500 aattaaataa ttaatgccca atttggatat agcagcctga agctcatctt gtttagttac 118560 ggatcctaat gagttattaa gcaatatatc gaacggatga acgaaggttg tttgagtttt 118620 gtcgcatact ttgtaatcta gatatagatg cggaagaacg gtagaacta tacgaata 118680 atattcagag tcctctatt gatcagagt aactattgac ttataggca tcatttattt 118740 agtattaat gacgaccgta ccagtgacgg atacaaaa cgatttaatt acagagtttt 118800 cagaagataa ttatccattct aacaaaaatt atgaataac tcttcgtcaa atgtctattc 118860 taactcacgt taacaacgtg gtagatagag aacataatgc cgccgtagtg tcatctccag 118920 aggaaatatc ctcacaactt aatgaatc tatttccaga tgatgattca ccggccacta 118980 ttatcgaacg agtacaacct catactacta ttattgacga tactccacct cctacgtttc 119040 gtagagagtt attaatatcg gaacaacgtc aacaacgaga aaaaagattt aatattacag 119100 tatcgaaaaa tgctgaagca ataatggaat ctagatctat gataacttct atgccaacac 119160 aaacaccatc cttgggagta gtttatgata aagataaaaag aattcagatg ttagaggatg 119220 aagtggttaa tcttagaaat caacgatcta atacaaaatc atctgataat ttagataatt 119280 ttaccaaaat actatttggt aagactccgt ataaatcaac agaagttaat aagcgtatag 119340 ccatcgttaa ttatgcaaat ttgaacgggt ctcccttatc agtcgaggac ttggatgttt 119400 gttcagagga tgaaatagat agaatctata aaacgattaa acaatatcac gaaagtagaa 119460 aacgaaaaat tatcgtcact aacgtgatta ttatgtcat aaatattatc gagcaagcat 119520 tgctaaaact cggatttgaa gaaatcaaag gactgagtac cgatatcact tcagaaatta 119580 tcgatgtgga gatcggagat gactgcgatg ctgtagcatc aaaactagga atcggtaaca 119640 gtccggttct tatattgta ttgtttatac tcaagatatt cgttaaacga attaaaatta 119700 tttaatttaa tacattccca tatccagaca acaatcgtct ggattaatct gttcctgtcg 119760 tctcataccg gacgacatat taatcttttt attagtgggc atctttttag atggttctt 119820 tttcccagca ttaactgagt cgatacctag aagatcgtga ttgatctctc cgaccattcc 119880 acgaacttct aattggccgt ctctgacggt accataaact atttaccag cattagtaac 119940 agcttggaca atctgaccat ccatcgcatt gtacgatgta gtagtaactg ttgttctacg 120000 tttaggagca ccagaagtat ttttggagcc cttggaggct gatgtagaag aagacgagga 120060 ttttgattt ggtttacatg tatacattt tgaactcttt gattttgtat cacatgcgcc 120120 ggcagtcaca tctgtttgag aattaagatt attgttgcct cctttgacgg ctgcatctcc 120180 accgatttgc gctagtagat ttttaagctg tggtgtaatc ttattaactg ttcgatata 120240 atcatcgtaa ctgcttctaa cggctaaatt ttttttatcc gccatttaga agctaaaaat 120300 attttttt atgcagaaga tttaactaga ttatacaatg actatatg atccttttcc 120360 agatttatta siaacttggt atttttttgt tctggaggag gcgaatttaa attcggactt 120420 ggattcagat ttgtaagtt cttgatctta ttatacatcg agtataggat ggcgacagta 120480 actgctacac aaataccgat caaagaga ataccaatca tttattgaca atacttcac 120540 tattgatcaa gtatgcaata tattcatcttt tcactaata agtagtaata atgattcaac 120600 aatgtcgaga tatatggacg ataataattt agttcatgga aatcgcta tgattggtgt 120660 gatgactcc gctactctg tggggtgcgc agtgctttcc ccacatagaa taaattagca 120720 ttccgactgt gataata ccaagtataa acgccataat actcaatact ttccatgtac 120780 gagtgggact ggtagactta ctaaagtcaa taaggcgaa gatacacgaa agaatcaaa 120840 gatgattcc agcgattagc acggccggaa aaatttcc aatcataagc atcatgtcca 120900 tttaactaat aaaattttta aatcgccgaa tgaacaagt ggaataataa ccatataaaa 120960 acaatagttt gtactgcaaa aataatatct atttttgttt tcgaagatat ggtaaaatta 121020 atatagtagta cacagcatgt tataactaac agcagcaacg gctcgtaatt acttatcatt 121080 tactagacga aaaggtggtg ggatattttc ttgctcaaat atacgaata tatcacccat 121140 ccattttatg cgatgttat atactctaat cttaataga tctatagacg acgggtttac 121200 caacaatata gatttatcg attcatctaa tttaaaccct tccttaaacg tgaatgatct 121260 attatctggc ataacgatga ctctacctga tgaatcggac aatgtactgg gccatgtaga 121320 ataaattatc aacgaattat cgtctacgaa catttatatc atttgtttta attttaggac 121380 gcgaataaat ggatataaaa tagaaaataa cagatattac aaccagtgtt atggccgcgc 121440 ccaaccaggt aggcagtttt attttatctt ttactacagg ttctcctgga tgtacgtcac 121500 caacggcgga cgtagttcta gtacaattag acgtaagttc cgcttgggaa ttttttaacg 121560 ctaaagagtt aacgttaatc gtgcacccaa cgtatttaca tctagttctt tgaacatctt 121620 gattataata taaccatttt ctatctctag attcgtcggt gcactcatgt aaccaacata 121680 ccctaggtcc taatatta tctccggaat tagattttgg aatattcgcg caccaacaat 121740 ttctatttcc tttatgatcg ttacaaaga cgtataatgc cgtatcccca aaagtaaat 121800 aatcaggacg ataatttcta aaacatcag aacatatct cgcatccata tgtttggagc 121860 aaatatcgga atagtagac atagccggtt tccgttttgc acgtaaccat tctaaacaat 121920 tggggttcc aggatcgttt ctacaaaatc cagtcatgaa atcgtcacaa tgttctgtct 121980 tgtaattatt attaatatt tttggacagt gtttggtatt tgtcttagaa caacatttg 122040 ctacgctatc actacccccc aggataat ccttttat aaatgacat cgttgcccgg 122100 atgctatata atcagtagcg tgttttaaat ccttaatata ttcaggagtt acctcgttct 122160 gataatagat taatgatcca ggacgaatt tgaaagaact acatggttct ccatgaatta 122220 atacatattg tttagcaat tcaggaacta taaactact acatgatct atcgacatac 122280 catctatcaa acaaacttg gttttaattt ctcccggaga tgtttcataa tagtacgtat 122340 aactttcttc tgcaactta acagcttat tatattcagg ataatttaaa cctattcca 122400 tatatttgtc tcgtatatct gctattcctg gtgctatttt gattctatta agagtaacag 122460 ctgccccat tcttaataat cgtcagtatt taaactgtta aatgttgta tatcacatc 122520 taccttatt cccgcagtat aaggttgtt gcaggtatac tgttcaggaa tggttacatt 122580 tatactctt ctatagtcct gtctttcgat gttcatcaca tatgcaaga acagataaa 122640 caaataatg windowata tattaat ctgtgaatttc gtaaatacat tgattgccat 122700 aaattaca gcagctacaa tacacacaat agacattccc acagtgttgc cattacctcc 122760 acgatacatt tgagttacta agcataggt ataactaag ctagtaagg gcaatagaaa 122820 agatgata atatcatca atatagagat tagaggagg ctatatagag ccagacgaa 122880 caaaatcaaa ccgagtaacg ttctaacatc attatttttg aagattcccca aaatcatt 122940 cattcctcca taatcgtttt gcatcatacc tccatcttta ggcataaacg attgctgctg 123000 ttcctctgta aataaatctt tatcaagcac tccagcaccc gcagagaagt cgtcaagcat 123060 attgtaatat cttaaataac tcatttatat attaaaaaat gtcactatta aagatggagt 123120 ataatcttta tgccgaacta aaaaaaatga cttgtggtca acccctaagt cttttaacg 123180 aagacgggga tttcgtagaa gttgaaccgg gatcatcctt taagtttctg atacctaagg 123240 gattttacgc ctctccttcc gtaaagacga gtctagtatt cgagacatta acaacgaccg 123300 ataataaaat cactagtatc aatccaacaa atgcgccaaa gttatatcct cttcaacgca 123360 aagtcgtatc tgaagtagtt tctaatatga ggaaaatgat cgaatcaaaa cgtcctctat 123420 acattactct tcacttggcg tgtggatttg gtaagactat taccacgtgt tatcttatgg 123480 ctacacacgg tagaaaaacc gtcatttgcg tacccaataa aatgttaata catcaatgga 123540 agacacaggt agaggcagtc ggattggaac ataagatatc catagatgga gtaagtagtc 123600 tattaagga actaagact caagtccgg atgtattaat agtagtcagt agacatctga 123660 caaacgatgc cttttgtaaa tatatcaata agcattatga ttgttcatc ttggatgaat 123720 cacatacgta taatctgatg aacaatacag cagttacaag atttttagcg tattatccctc 123780 cgatgatgtg ttatttta actgctacac ctagaccac taacagaatt tattgtaaca 123840 gtattatta tattgccaag tattccgatc taaaaaaaac tatctatgcg gtagatagtt 123900 tttttgagcc atattccaca gatatta gatgattagat aaaacgatta gatggaccat 123960 ctaataata tcatatatat actgagagt tattatctgt agacgagcct agaatcaac 124020 ttattcttga taccctgta gagaatttca agtcaggac tattacgc attgtta 124080 ttactaact acgtgaacat atggtattct tctacaaacg attattagat ttttcggac 124140 cagaggttgt atttagga gacgcccaaa atagacgtac tccagatg gtcaaatcaa 124200 cat aaatagattt atattcgtat ccaccttatt ttattccggt actggtttag 124260 atattcctag ttggattcg ttgttcattt gctcggcagt atcacaat atgcaatag 124320 agcaattact agggaggta tgtcgagaaa cagaactatt agataggacg gtatatgtat 124380 ttcctaacac atccatcaa gaaataagt acatgatagg aaatttcatg caacgaatta 124440 ttagtctgtc tgtagataa ctaggatttta aaaaaaag tttacggaaa catcaagaat 124500 ccgatcccac ttctgtatgt acacatcct ccagagaga acgtgtatta atagaatat 124560 ttaactcgca aaatcgttaa gaagtttaag cgacgatccg catgctgcgc agccagtgt 124620 attaccccctc atagtattaa tataatccaa tgatactttt gtgatgtcgg aaatcttaac 124680 caatttagac tgacaggcag aacacgtcat gcaatcatca tcgtcatcga taactgtagt 124740 cttgggctc ttttgcggc tctcattcc ggaacgcaca tggtgctt ccatttaggt 124800 agtaaaaaat aagtcagaat atgccctata gcacgatcgt gcaaaacctg gtatatcgtc 124860 tctatcttta tcacaata gtgtatcgac atctttatta ttattgacct cgtttatctt 124920 ggaacatgga atgggaacat ttttgttatc aacggccatc tttgccttaa ttccagatgt 124980 tgtaaaatta taactaaaca gtctatcatc gacacaaatg aaattcttgt ttagacgttt 125040 gtagtttacg tatgcggctc gttcgcgtct cattttttca gatattgcag gtactataat 125100 attaaaata agaatgaaat aacataggat taaaaataaa gttatcatga cttctagcgc 125160 tgatttaact aacttaaaag aattacttag tctgtacaaa agtttgagat tttcagattc 125220 tgcggctata gaaaagtata attctttggt agaatgggga acatctactt actggaaaat 125280 aggcgtgcaa aaggtagcta atgtcgagac gtcaatatct gattattatg atgaggtaaa 125340 aaataaaccg tttaatattg atccgggcta ttacattttc ttaccggtat attttgggag 125400 cgtctttatt tattcgaagg gtaaaaatat ggtagaactt ggatctggaa actcttttca 125460 aataccagat gatatgcgaa gtgcgtgtaa caaagtatta gacagcgata acggaataga 125520 ctttctgaga tttgttttgt taaacaatag atggataatg gaagaatgcta tatcaaaata 125580 tcagtctcca gttaatatat ttaaactagc tagtgagtac ggattaaaca tacccaata 125640 tttagaaatt gaatagagg aagacacatt atttgacgac gagttatact cttattaga 125700 acgctctttc gatgataaat ttccaaaat atccatatcg tatattagt tgggaact 125760 taggcggcaa gttgtagact tttcaatt ctcgttcatg tatattgagt ccatcaggt 125820 agatcgtata ggataata ttttattcc tagcgttata aaaaatcag gaaaaaagat 125880 attagtaaa gatgtagacc attackattacg atccaaggtt agagaacata cattgtaaa 125940 agtaaaaag aaaaaacacat tttchattt attackacactat gatgaacg gaacagaac 126000 taggaggaa gtataaaac gattataga cactatagga cgagactatt atgttaacgg 126060 aaagtatttc tctaggttg gtagtgcagg cttaaagcaa ttgactaata attagatat 126120 taatgagtgc gcaactgtcg atgagttagt tgatgagat aaaatccg gaactgtaaa 126180 acgaaaaata aaaaaccaat cagcattga tttagcaga gatgttttgg gatatccaga 126240 agcggatttt ataacgttag ttaataacat gcggttcaaa atagaaaatt gtaaggttgt 126300 aaatttcaat attgaaaata ctaattgttt aaataacccg agtattgaaa ctatatatgg 126360 aaactttaac cagttcgtct caatctttaa tatcgtcacc gatgtcaaaa aaagattatt 126420 cgagtgaaat aatatgcgcc tttgatatag gtgcaaaaaa tcctgccaga actgttttag 126480 aagtcaagga taactccgtt agggtattgg atatatcaaa attagactgg agttctgatt 126540 gggaaaggcg catagctaaa gatttgtcac aatatgaata cactacagtt cttctagaac 126600 gtcagcctag aaggtcgccg tatgttaaat ttatctattt tattaaaggc tttttatatc 126660 atatacatcggc tgccaaagtt atttgcgtct cgcctgtcat gtctggtaat tcatagagag 126720 atcgaaaaaa gagatcggtc gaagcatttc ttgattggat ggacacattc ggattgcgag 126780 actccgttcc ggatagacgc aaattagacg atgtagcgga tagtttcaat ttggctatga 126840 gatacgtatt agataaatgg aatactaatt atacacctta taataggtgt aaatctagaa 126900 attacataaaaaatgtaa taacgttagt aacgccatta tggataatct attaccttt 126960 ctacatgaaa tagatag atagccaga actattttta acttcatct ataagttgc 127020 gatgaaatag gagatatata tggtcttatg aaagaacgca tttcctcaga ggatatgttt 127080 gataatatag tgtataataa agatatacat cctgccatta agaaactagt gtattgcgac 127140 atccaactta ctaaacacat tattaatcag atacgtac cggtattta cgattcttca 127200 caagtgaaat gttgtcatta ttcgacata aactcagata atagcaat tagctctcgt 127260 acagtagaga tatttgagag ggaaaagtca tctcttgtat catatattaa actaccaat 127320 aagagagaa aggtcatta cggcgaata aagaaaactg ttcatggagg cactaatgca 127380 aattactttt ccggtaaaaa gtctgacgag tatctgagta ctacagttag atccacatt 127440 aatcacctt ggatcaaac catctctaag aggatgagag tgatcat taatcactct 127500 atagtaacgc gtggaaaaag ctctatatta caactatag aattatttt tactaataga 127560 acatgtgtga aaatattcaa ggattctact atgcacatta ttctatccaa ggacaaggat 127620 gaaaaggggt gtatacacat gattgacaaa ttattctatg tctattataa tttatttctg 127680 ttgttcgagg atatcatcca aaacgagtac tttaaagaag tagctaatgt tgtaaaccac 127740 gtactcacgg ctacggcatt agatgagaaa ttatcctaa ttaagaaaat ggctgaacac 127800 gatgtttatg gagttagcaa tttcaaaata gggatgttta acctgacatt tattaagtcg 127860 ttggatcata ccgttttcc ctctctgtta gatgaggata gcaaaataaa gttttttaag 127920 gggaaaaagc tcaatattgt agcattacga tctctggagg attgtataaa ttacgtgact 127980 aaatccgaga atatgataga aatgatgaag gaaagatcga ctattttaaa tagcatagat 128040 atagaaacgg aatcggtaga tcgtctaaaa gaattgcttc taaaatgaaa aaaaacactg 128100 attcagaaat ggatcaacga ctcggatata agtttttggt gcctgatcct aaagccggag 128160 ttttttatag accgttacat ttccaatatg tatcgtattc taattttata ttgcatcgat 128220 tgcatgaaat cttgaccgtc aagcggccac tcttatcgtt taagaataat acagaacgaa 128280 128340 gtattaaagg taagagttat gacgcattag ccacgttcac tgtaaatatc tttaaagagg 128400 taatgaccaa agagggtata tccatcacta aaataagtag ttatgaggga aaagattctc 128460 atttgataaa aattccgcta ctaataggat acgggaataa aaatccactt gatacagcca 128520 agtatcttgt tcctaatgtc ataggtggag tctttatcaa taaaatct gtcgaaaaaag 128580 taggaattaa tctagtagaa aagattacaa catggccaaa atttagggtt gttaagccaa 128640 actcattcac tttctcgttt tcctccgtat cccctcctaa tgtattaccg acaagatatc 128700 gccattacaa gatatctctg gatatatcac aattggaagc gttgaatata tcatcgacaa 128760 agacatttat aacggtcaat attgttttgc tgtctcaata tttatctaga gtgagtctag 128820 aattcattag acgtagttta tcatacgata tgcctccaga agttgtctat ctagtaaacg 128880 cgataataga tagtgctaaa cgaattactg aatctattac tgactttaat attgatacat 128940 acattaatga cctggtggaa gctgaacaca ttaaacaaaa atctcagtta acgattaacg 129000 agttcaaata tgaaatgctg cataactttt tacctcatat gaactataca cccgatcaac 129060 taaagggatt ttatatgata tctttactaa gaaagtttct ctactgtatc ttccacactt 129120 ctagatatcc agatagagat tcgatggttt gtcatcgcat cctaacgtac ggcaaatatt 129180 ttgagacgtt ggcacatgat gaattagaga attacatagg caacatccga aacgatatca 129240 tgaacaatca caagaacaga ggcacttacg cggtaaacat tcatgtacta acaactcccg 129300 gacttaatca cgcgttttct agcttattga gtggaaagtt caaaaagtca gacggtagtt 129360 atcgaacaca tcctcactat tcatggatgc agaatatttc tattcctagg agtgttggat 129420 tttatccgga tcaagtaaag atttcaaaga tgttttctgt cagaaaatac catccaagtc 129480 aatatcttta cttttgttca tcagacgttc cggaaagagg tcctcaggta ggtttagtat 129540 ctcaattgtc tgtcttgagt tccattacaa atatactaac gtctgagtat ttggatttgg aaaagaaat ttgtgagtat atcagatcat attack tgatataagt tactttgaaa 129720. 129720. 129720. 129720. 129720. 129720. 129720. 129720. 129720 gtgattttgt aactgacttt agacgtagaa aacggatggg attcttcggt aacttggagg 129780 tagtattac tttagttagg gatcacatga atgaaattcg cattattatt ggagcggga gattagtcag accattcttg gttgtggata acggagagct catgatggat gtgtgtccgg 129900 129960. 129960. 129960. 129960. 129960. 129960. 129960 tcatcgaaat ggtagatata gacaattta cttttagtaa cgtatgtgaa tcggttcaaa aatttagaat gatgtcaaag gatgaaaga agcaatacga tttatgtgac tttcctgccg aatttaga tggatatgtg gcatcttcat tagtgggat caatcacaat tctggaccca gagctattct tggatgtgct caagctaaac aagctatctc ttgtctgagt tcggatatac gaataaat agacaatgga attcatttga tgtatccaga gaggccaatc gtgattagta aggctttaga aacttcaaag attgcggcta attgcttcgg ccaacatgtt actatagcat 130380. 130380. 130380. 130380. 130380. 130380. 130380. 130380. 130380 agagaggcgg tctcgatata gttaccgcaa agaacatca agtagaatt ccattggaa actttaata caaagaaaga gataggtcta acgcctattc aaaatttaga gataggtcta tagttagact gaatgctttc ttggaatccg gagacgctat ggcacgaat atctcatcaa gaactcttga agatgatttt gctagagata atcagattag cttcgatgtt tccgagaaat attack gtacaaatct cgcgttgaac gagtacaagt agaacttact gacaaagtta aggtacgagt attack aaagaaagaa gacccattct aggagacaaa tttaccacta gaacgagtca aaagggaca gtcgcgtatg tcgcggatga aacggaactt ccatacgacg aaaatggtat cacgccagat gtcattatta attctacatc catcttctct agaaaaacta tatctatgtt gatagaagtt atttacag ccgcatattc tgctaagccg tacaacata 130920 agggagaaaa ccgacctgtc tgttttccta gtagtaacga aacatccatc gatacatata 130980 tgcaatcgc taacaatgt tatgagcatt caatccgaa attgtctgat gagaattat 131040 cggataaaat cttttgtgaa aagattctct atgatcctga aacggataag ccttatgcat 131100 ccaaagtatt tttggacca attack tgcgtctgag acatttaact caggacaagg 131160 aaccgttag atgtagaggt aaaaagacga agctcattag acaggcgaat gagggacgaa 131220 aacgtggagg aggtatcaag ttcggagaa tggagaga ctgtttaata gcgcatggcg 131280 cagccaatac tattacagaa gttttgaag attcggaag agatttaca gatgtgtatg 131340 ttgtgaaaa ttgtggagac atagcagcac aaatcaaggg tattataca tgtcttagat 131400 gttcaaact taatctctct cctctcttaa caaaattga taccaccc gtatctaaag 131460 tattcttac tcaatgaac gccagaggcg taaagtca attagatttc gaacgaac 131520 ctccttcgtt ttataaacca ttagataaag ttgatctcaa gccgtctttt ctggtgtaat 131580 attctagttt ggtagtagat acatatcaat atcatcaaat tcgagatccg aattataaaa 131640 tgggcgtgga ttgttaacta tagaatcgga cgtctgatat tcgaaaatct gtggagtttc 131700 aggttttggt ggaggtgtaa ctgctacttg ggatactgaa gtctgatatt cagaaagctg 131760 tggatgttct ggttcggcat ccaccgatgg tgtcacatca ctaatcggtt cggtaacgtc 131820 tgtggatgga ggtgctactt ctacagaacc tgtagcctca gttgtcaacg gagatacatt 131880 tttaatgcga gaaaatgtat aatttggtaa tggtttctca tgtggatctg aagaagaggt 131940 aagatatcta ctagaaagat accgatcacg ttctagttct cttttgtaga acttaacttt 132000 ttctttctcc gcatctagtt gatattccaa cctcttcacg ttactacgtt cagattccaa 132060 ttcacgttcg catgggttac ctccgcagtt tttacgagcg atttcacgtt cagccttcat 132120 gcgtctctcc ctctctctat cgagtttatc agagcagtct ttctgaaggc gatcgaactc 132180 cataaatttc tccaacgctt tgattgtttc catagatttc cgaacttcag cttctaggac 132240 ggcgattctt tttctttcga attcacagct ggatgtacaa ccgtttccat taccgccatc 132300 tctaagtttc ttttctagat cggcaacatt tcatccccat gccttttaca ttcctcgagt 132360 ctactgtcgt cgaaatatcg ttccagctcc ttttcgacat caataacttt agcacgttgt 132420 ctctcaagct ctcttttgta gttatctgat tccctggcac gtttaagatc ttcatgcaat 132480 tgagtcagct cttaacttcc tctcttgctt cttcgtcata gtacgcgcaa tcactgtgag 132540 atccattgtt accacgtcta cactcggcga gctcgcgttt aagagattca atttcccgtt 132600 tgtattggtc catgtttcca ttgctaccac cattagattt acaggctgct agttgtcgtt 132660 cgagatcaga aatacgggtt ttcttggaat tgatttcgtc gatgtacttg gcatcgaaac 132720 acttattaag ttctttttcc aattctacga ttttatttct ttcgcgagtc aattccctcc 132780 tgtagtaact atctgttttg tcagattcac gctctctacg tagactttct tgcaagttac 132840 taatttgttc cctagcacgt ccgagtttag ttttatatgc tgaatagagt tctgattcat 132900 cctttgagca gatctctagc gatcgtttaa gattcctgat tctagtcttt agcctattta 132960 cctcctcaga agatgttccg ttaccgttgc gtttacactc gttaagctgt ctatcaagat 133020 ccatgattct atctctaaga cgttgcatct ctctttccat atcagcattg ctttcattat 133080 tacgtctgca gtcactcaac tgtctttcaa tatctgagat tctatctcta agacgtcgca 133140 tctctctctg tttcagcatt ggtttcatta ttacgtctac agtcgttcaa ctgtctttca 133200 agatctgata ttctagattg gagtctgcta atctctgtag cattttcacg gcattcactc 133260 agttgtcttt caagatctga aattttagat tggagtctgc taatctctgt aagatttcct 133320 cctccgctct cgatgcagtt ggtcaactta ttctctagtt ctctaatacg cgaacgcagt 133380 gcatcaactt cttgcgtgtc ttcctggttg cgtgtacatt catcgagtct agattcgaga 133440 tctctaacgc gtcgtcgttc ttcctcaagt tctctgcgta ctacagaaag cgtgtcccta 133500 tcttgttgat atttagcaat ttctgattct agagtactga ttttgcttac gtagttacta 133560 atagttgtct tggccttatc aagatcctcc ttgtatttgt cgcattcctt gatatcccta 133620 cgaagtctgg acagttccca ttcgacatta cgacgtttat cgatttcagc tcggagatcg 133680 tcatcgcgtt gttttagcca catacgactg agttcaagtt ctcgttgaca agatccatct 133740 acttttccat tcctaatagt atccagttcc ttttctagtt ctgaacgcat ttctcgttcc 133800 ctatcaagcg attctctcaa ttctcggata gtcttcttat caatttctaa taaatctgaa 133860 ccatcatctg tcccattttg aatatccctg tgttctttga tctcttttgt aagtcggtcg 133920 attctttcgg ttttataaac agaatccctt tccaaagtcc taatcttact gagtttatca 133980 ctaagttctg cattcaattc ggtgagtttt ctcttggctt cttccaactc tgttttaaac 134040 tctccactat ttccgcattc ttcctcgcat ttatctaacc attcaattag tttattaata 134100 actagttggt aatcagcgat tcctatagcc gttcttgtaa ttgtgggaac ataattagga 134160 tcttctaatg gattgtatgg cttgatagca tcatctttat cattattagg gggatggaca 134220 accttaattg gttggtcctc atctcctcca gtagcgtgtg gttcttcaat accagtgtta 134280 gtaataggct taggcaaatg cttgtcgtac gcgggcactt cctcatccat caagtatta 134340 taatcgggtt ctacttcaga atattctttt ctaagagacg cgacttcggg agttagtaga 134400 agaactctgt ttctgtatct atcaacgctg gaatcaatac tcaagttaag gatagcgaat 134460 acctcatcgt catcatccgt atcttctgaa acaccatcat atgacatttc atgaagtcta 134520 acgtattgat aaatagaatc agatttagta ttaaacagat ccttaacctt tttagtaaac 134580 gcatatgtat attttagatc tccagatttc samaatgat cacatgcctt aaatgtcagt 134640 gcttccatga tataatctgg aacactaatg ggtgacgaaa aagatacagc accatatgct 134700 acgttgataa ataaatctga accactaagt agataatgat taatgttaag gaaaagaaaa 134760 tattcagtgt ataggtatgt cttggcgtca tatcttgtac taaacacgct aaacagtttg 134820 ttaatgtgat caatttccaa taggattt agagcagcgg gataccaac aacatatta 134880 ccacatccgt atttctatg attcacat atcatgttaa aaatcttaa tagagagcg 134940 atatctcgt ctgacttaat gagacgtagt tcagcagca catagtcat aactgtaaat 135000 agaacatact ttcctgtagt gttgattcta gactccacat siacaccatt attaaaaata 135060 gttttatata catctttaat ctgctctccg ttaatcgtcg aacgttctag tatacggaaa 135120 cacttgatt tcttatctgt agttaatgac tagtgatat cacgaagaat attacgaatt 135180 acattcttg ttttcttga gagacctgat tcagaactca actcatcgtt ccatagtttt 135240 tctacctcag tggcgaatc ttggagtgc tggtacatt ttcatag gttcgtgacc 135300 tccatttatt aaaaaatt tattcaaac ttaactaca tcggtatt ataagatcgt 135360 aaatctccca tgtggcggaa tactaccatc tatcgcatgt ggatggacag taggtaatgg 135420 ccatgggaac agtaatgat gcatatttat ctttcttgct agtattactg catattgtcc 135480 caatgtttcg atgtgatgtt ctaacctatc aactgccgct gtatcacaac aatagtgtcc 135540 gatgaaatta agattatgat ccaatgtgtt tatatatga ttatcaagtc ttatacgatc 135600 cgcgtcttt ttgacaggat caggttcttc tacaggaaga agttcggcc tcttatgata 135660 ttcatgtctg ggaaacggtg gtctagggtg aggctccggt atcggagtgg gttttggatt 135720 ataatcatca tcgtctatga catcatcatc atcttcgact tcgatattta ttttgctatc 135780 ttgatgatgt cctgtatcag ttgcattttc agcactcgac tgaatattag cgcattcatt 135840 gtctattatt accatatttc taaacccaaa atgtatgtgt tgaacatcag tactatcgtt 135900 gatgagtctt atagcatgaa ttcgcttatc gttatcgggt ttatcttctg tcaccttagc 135960 aattcctttt ttattaaact ctacataatc atatccattt ctattgtttg ttctaatata 136020 aacgagtata gcatcattgc taaatttttc atagtatcg aaaacagaat atcctaaacc 136080 atataatata tattcaggga cactcaaact aaatgtccag gattctccta aatacgtaaa 136140 ctttaatagt gcgaaatcat tcaaaatct accacttata gatagatagt actaaatgc 136200 gtatagtagt ctacctatct ctttatg aaaaccggca ttacgatcat atatgtcgtg 136260 atatacctgt gatccgttta cgttaaacca taaatacatg ggtgatccta taaacatgaa 136320 tttatttcta attctcagag ctatagttaa ttgaccgtgt atatttgct tacatgcata 136380 cttgatacgc tcattaataa atttttatc attgctcgtt atctcagaat cgtatatata 136440 aggagtacca tcgtgattct taccagatat tatacaaat actatatata aatatattg 136500 accaacgtta gtaatcatat aaatgtttaa cgttttaaat ttgtattca atgatccatt 136560 atcatacgct agcatggtct tatgatattc attctttaa atatatatt gtgttagcca 136620 ttgcattggg gctcctaatg gagattttt attctcatcc attttaggat aggctttcat 136680 aaagtcccta ataacttcgt gataatgtt tctatgtttt ctactgatgc atgtatttgc 136740 ttcgattttt ttacccatg ttcatctat catagattta aacgcagtaa tgctcgcaac 136800 attaacatct tgaaccgttg gtacaattcc gttccataaa tttataatgt tcgccattta 136860 tataactcat tttttgaata tacttttaat taacaaaaga gttaagttac tcatatgggc 136920 gccgtccagt ctgaacatca atctttttag ccagagatat catagccgct cttagagttt 136980 cagcgtgatt ttccaaccta aatagaactt catcgttgcg tttacaacac ttttctattt 137040 gttcaaactt tgttgttaca ttagtaatct ttttttccaa attagttagc cgttgtttga 137100 gagtttcctc attgtcgtct tcatcggctt taacaattgc ttcgcgttta gcctctggct 137160 ttttagcagc ctttgtagaa aaaaattcag ttgctggaat tgcaagatcg tcatctccgg 137220 ggaaaagagt tccgtccatt taaagtacag attttagaaa ctgacactct gcgttattta 137280 tatttggtac aacacatgga ttataaatat cgatgttaat aacatcagaa aatgtaaagt 137340 ctatacattg ttgcatcgtg ttaaattttc taatggatct agtattattg ggtccaactt 137400 ctgcctgaaa tccaaatatg gaagcggata caaaaccgtt tcctggataa accacacatc 137460 tccactttg ctttacatca gaaattgtgt cgttgacatc ttgaactc ctactaatg 137520 ccggtgttcc acctatagat tttgaatatt cgaatgctgc atgagtagca ttaaattcct 137580 taatattgcc atattttca tatattgagt aaccctggat aaaagtaaa cacaccgcag 137640 ccgtcgctac cacataaaaaaattgata gagagttcat tatataatcta ttagaagctg 137700 aaaaatttt tttacacgca tcagacaatg ctttaataaa tagttcaca tctactttg 137760 tcatatcgaa ccgatggtat gattctaacc tagattaca tccgaaaaag ttgactatgt 137820 tcatagtcat taagtcatta ahaaaca ttccagactc tggattata gacgatactg 137880 tttcgtcaca attacctacc ttaatcatgt gattatgaat attggctatt agagcacctt 137940 ctaagaaatc tataatatct ttgaacacg atttaaaatc aaaccacgaa tatactctta 138000 cgaagaaagt tagtttaccc ataggaaa taactataaa tggagatcta atacaaaat 138060 ccggatctat gatagtttta acattattat attctctatt aaatacctcc acatctaaaa 138120 atgttaattt tgaaactatg tcttcgttta ttaccgtacc tgaactaaac gctataagct 138180 ctattgtttg agaactcttt aaacgatatt cttgaaatac atgtaacaaa gtttccttta 138240 actcggtcgg tttatctacc atagttacag aatttgtatc cttatctata atataataat 138300 caaaatcgta taaagttata taattatcgc gttcagattg ggatcttttc aaatagacta 138360 aaaaccccat ttctctagta agtatcttat gtatatgttt gtaaaatatc ttcatggtgg 138420 gaatatgctc taccgcagtt agccattcct cattgacagc ggtagatgta ttagacaaaa 138480 ctattccaat gtttaacaag ggccatttta cgagattatt aaatccttgt ttgataaatg 138540 tagccaatga gggttcgagt tcaacgacga ttgaattctc ttcccgcgga tgctgcatga 138600 tgaacgacgg gatgttgttc gattgatttg gaattctttt tcgacttttt gtttatatta 138660 aatattttaa aatttatagc ggatagcaat tcatgtacca cggataatgt agacgcgtat 138720 tgcgcatcga tatctttatt attagataaa tttatcaata aatgtgagaa gtttgcctcg 138780 ttaaggtctt ccatttaaat attattaaaa catttgtgtt tgtatcttat tcgtctttta tggaatagtt ttttactagt aaagctgcaa ttacacactt tgtccgtaaa acataaatat 138960. aaacaccagc ttttatcaat cgttccaaaa agtcgacggc ggacattttt aacatggcat ctattttaaa tacacttagg tttttggaa aaacatcatt tttaattgt aacgattcaa 139080. 139080. 139080. 139080. 139080. 139080. 139080. 139080. 139080. 139080 agcattctac cgttgttaaa tacttgtctg gaggaggtat atatcatgat gatttggttg tattgggga ggtaacaatt aatgatctaa agatgatgct attttacatg gatttatcat atcatggagt gacaagtagt ggagcaattt acaaattggg atcgtctatc gatagacttt ctctaatag gactattgtt acaaaagtta father tgatacattt tttgacgacg atgattgatc gctattgcac aattttgttt ttttactttc taatatagcg tttagattct ttttcatgtg cgaatattga tttactaaaa tatcgatgtt taacttttgt tctatgacgt ccttatcagc ggtatcggta catatacgta attcaccttc acaaaatacg gagtcttcga 139500 taataatagc caatcgatta ttggatctag cggtctgtat catattcaac atgtttaata 139560 tatcctttcg tttccccttt acaggcatcg atcgtagcat attttccgcg tctgagatgg 139620 aaatgttaaa actacaaaaa tgcgtaatgt tagcccgtcc taatattggt acgtgtctat 139680 aagtttggca tagtagaata atagacgtgt ttaaatgcct tccaaagttt aagaattcta 139740 ttagagtatt gcattttgat agtttatcgc ctacatcatc aaaaataagt aaaaagtgtg 139800 ctgatttttt atgattttgt gcgacagcaa tacatttttc tatgttactt ttagttcgta 139860 tcagattata ttctagagat tcctgactac taacgaaatt aatatgattt ggccaaatgt 139920 atccatcata atctggatta taaacgggtg taaacaagaa tatatgttta tattttttaa 139980 ctagtgtaga aaacagagat agtaaataga tagtttttcc agatccagat cctcccgtta 140040 aaaccattct aaacggcatt tttaataaat tttctcttga aaattgtttt tcttggaaac 140100 aattcataat tatatttaca gttactaaat taatttgata ataatcaaa atatggaaaa 140160 ctaaggtcgt tagggag gagaacaaag aaggcacatc gtgacataaa taacatttat 140220 tatcatgatg acaccagaaa acgacgaaga gcagacatct gtgttctccg ctactgttta 140280 cagagacaaa attcagggaa agaataaacg caaacgcgtg attggtctat gtattagaat 140340 atctatggtt atttcactac tatctatgat taccatgtcc gcgtttctca tagtgcgcct 140400 aaatcaatgc atgtctgcta acgaggctgc tattactgac gccgctgttg ccgttgctgc 140460 tgcatcatct actcatagaa aggttgcgtc tagcactacg caatatgatc acaaagaaag 140520 ctgtaatggt tatattacc agggttcttg ttatatatta cattcagact accagttatt 140580 ctcggatgct aaagcaaatt gcactgcgga atcatcaaca ctacccaata aatccgatgt 140640 cttgactacc tggctcattg attatgttaa ggatacatgg ggatctgatg gtaatccaat 140700 tacaaaaact acatccgatt atcaagattc tgatgtatca caagaagtta gaaagtattt 140760 ttgtgttaaa acatgaact atatttatt ttgtacatt aaaatgaa atcgcttaat 140820 agacaaactg taagtaggttg tcggtgccgg ccgctataat gatgatactc 140880 tcaccatta ttagtggcat aggaacattt ctgcattaca aagagaact gatgcctagt 140940 gcttgcgcca atggatggat acatacgat aacattgtt atttagatac taacattaaa 141000 atgtctacag ataatgcggt ttatcagtgt cgtaaattac gagccagatt gcctagaccg 141060 gatactagac atctgagagt atttttta agattattg ggtaagttta 141120 aaaagacca atgataatg gttagatatt aataatgata agatataga tattagtaa 141180 ttAACAATTT ttAACAACT aaacagtacg acggatgctg aagcgtgtta tatatacaag 141240 tctggaaaac tggttaaaac agtatgtaaa agtactcaat ctgtactatg tgttaaaaaa 141300 ttctacaagt gawaaaaaa atgaattta taatagtcg ttaacgtacg ccgccatgga 141360 cgccgcgttt gttattactc caatgggtgt gttgactata acagatacat tgtatgatga 141420 tctcgatatc tcaatcatgg actttatagg accatacatt ataggtaca taaaaactgt 141480 ccaaatagat gtacgggata taaaatattc cgacatgcaa aaatgctact ttagctataa 141540 gggtaaaata gttcctcagg attctaatga ttggctga ttcacattt atgcattg 141600 tgccgcatac agatcaaaaa attackcat catagcatgc gactatgata tcatgttaga 141660 tatagagat aaacatcagc cattttatct attcccatct attgatgttt ttaacgctac 141720 aatcatagaa gcgtataacc tgtatacagc tggagatt catctaatca tcaatccttc 141780 agataatctg aaaatgaat tgtcgtta ttctcattc tgcatatcag acggcaatgg 141840 atggatcata attgatggga atgcaatag taattttta tcataaagt tgtaagtaa 141900 ataaaac aaaatatt gaactagtag tacgtatatt gagcaatcag aaatgatgct 141960 ggtacctctt atcacggtga ccgtagttgc gggaacaata ttagtatgtt atatatta 142020 tattgtagg aaaagatac gtactgtcta taatgacaat aaattatca tgacaaatt 142080 aaaaagata aagagttcta attccagcaa atctagtaa tcactgata gcgaatcaga 142140 ctgggaggat cactgtagtg ctatggaca aaacaatgac gtagatata tttctagga 142200 tgagatattg gacgatgata gcttcgctgg tagttaata tggtaacg aatccaatgt 142260 tatggcgcct agcacagaac acatttacga tagtgttgct ggaagcacgc tgctaataaa 142320 taatgatcgt atgacaga ctatttatca gacactaca gtagtactta atgagatac 142380 caacagaat cctaactatt catccaatcc tttcgtaaat tatataaa ccagtatttg 142440 tagcagtca aatccgttca tacagaact air tttagtgaga ataatccgtt 142500 spacecraft catagcgatg attatcttta tagcagaa spacecraft spacecraft 142560 tatagaatca ttggtgtgat tagttcctt tttataaaat tgaagtaata tttagtatta 142620 ttgctgccgt cacgttgtac aaatggagat attccctgta ttcggcattt ctaaaattag 142680 caatttatt gctaataatg actgtagata tatatagat acagacatc aaaaaattt 142740 atctgatgag atcaatagac agatgatga aacggtactt cttaccaca tcttaagcgt 142800 agaagttgta atgacaatg agatgtacca tcttattcct catagattat cgacgattat 142860 actctgtatt agttctgtcg gaggatgtgt tatctctata gatatgacg tcaatggcaa 142920 aaatattcta acctttccca ttgatcatgc tgtaatcata tccccactga gtaaatgtgt 142980 cgtagttagc aagggtccta caccattatt ggttgttaaa gcggatatac ctagcaaacg 143040 attggtaaca tcgtttaca acgacatact gtatgtaac attctatcac tgattatta 143100 tttgccgttg tctgtattca ttattagacg agttaccgac tattggata gacacatatg 143160 cgatcagata tttgcgaata ataagtggta ttccattata accatcgaca ataagcagtt 143220 tcctattcca tcaactgta taggtatgtc ctctgccaag tacataatt ctagcatcga 143280 gcaagatact ttaatacatg tttgtaacct cgagcatcca ttcgacttag tatacaaaaa 143340 aatgcagtcg tacaatctg tacctatcaa ggaacaata ttgtacggta gattgataa 143400 tataaatatg agcattagta tttctgtgga ttaatagatt tctagtatgg ggatcattaa 143460 tcatctctaa tctctaaata cctcataaaa cgaaaaaaaa gctatatca atactgtac 143520 ggaatggatt cattctctc tcttttg aactctgtt gtatatctac tgataaaact 143580 ggaagchaaaa atctgaata aagaataag aagattaca aggatta tAaataca 143640 atagttcctg gttccctctc cacgtctact agctcgtggt attatacaca tgcctagtaa 143700 tagtctctt gcgttgacgg aaagcagact agaaataca ggctaaaatg ttcacacacc 143760 ataatagttc ccaaccaga taacacaga gtaccatca cacattcctt taaactcaat 143820 cccaaaccca aaccgttaa atgtatccg gccaattgat agtagatat gaggtgtaca 143880 gcgcatgata attackacag taaccaaat gaaatactt tagtatta aagaaata 143940 gatggtaacg tcatcatcaa slowly attgccgga gagtaacat tgacggata 144000 aacaaaaatg ctccgcataa ctctatcatg gcaatacac aaccaatac ttgtaagatt 144060 cctaaattag tagaaaatac aacggatatc gatgtataag tgatctcgag aaataataag 144120 aataaagtaa tgcccgtaaa gataaacatc aacattgttt ggtaatcatt aaaccaatta 144180 gtatgaagtt gaactaattt cacagtagat tttattccag tattatcccc gcatgtataa 144240 gtacctggta agatatcttt atattccata atcaatgaga catcactatc tgataacgaa 144300 tgaagtctag cactagtatg ccatttactt aatattgtcg tcttggaagt tttattataa 144360 gttaaaatat catggttatc caatttccat ctaatatact ttgtcggatt atctatagta 144420 cacggaataa tgatggtatc attacatgct gtatactcta tggtctttgt agttgttata 144480 acaaccaacg tatagaggta tatcaacgat attctaactc ttgacatttt ttatttattt 144540 aaaatgatac ctttgttatt tattttattc tattttgcta acggtattga atggcataag 144600 tttgaaacga gtgaagaaat aatttctact tacttattag acgacgtatt atacacgggt 144660 gttaatgggg cggtatacac atttcaaat aataaactaa acaaaactgg tttaactaat 144720 aataattata taacaacatc tataaaagta gaggatgcgg aaccaataac ggaaatccca 144780 aatgttggaa atagacggt tcagacgacc caaaacatag aggtagagga tacgctcctt 144840 atcaaatag caaagtaacg ataatcagtc acaacggatg tgtactatct gacataaaca 144900 tatcaaaaga aggaattaaa cgatggagaa gatttgacgg accatgtggt tatgattat 144960 acacggcgga taacgtaatt ccaaaagatg gtttacgagg agcattcgtc gataaagatg 145020 gtacttatga caaagtttac attctttca ctgatactat cggctcaaag agaattgtca 145080 aaattccgta tatagcacaa atgtgcctaa acgacgaagg tggtccatca tcattgcta 145140 gtcatagatg gtcgacgttt ctcaaagtcg aattagaatg tgatatcgac ggaagaagtt 145200 atagacaaat tattcattct agaactataa aaacagataa tgatacgata ctatatgtat 145260 tcttcgatag tccttattcc aagtccgcat tatgtaccta ttctatgaat accattaaac 145320 aatctttttc tacgtcaaaa ttggaaggat atacaaagca attgccgtct ccagctcctg 145380 gtatatgttt accagctgga aaagttgttc cacataccac gtttgaagtc atagaaaaat 145440 ataatgtact agatgatatt aataagcctt tatctacca acctactctc gaaggaccgt 145500 ctggtgttaa atggttcgat aaggaga aggaaatga acatcggga tatagaatat 145560 acttcataaa agaaaatttct atatattcgt tcgatacaa atctaaacaa actcgtagct 145620 cgcaagtcga tgcgcgacta tttcagtaa tggtacttc gaaaccgtta ttatagcag 145680 atataggt aggagtagga atgccacaaa tgaaaaaaat acttaaaatg taatcttaat 145740 cgagtacacc gcacgacaat gaacaacat agacagatt atgctggtta tgcttgctgc 145800 gtaatatgcg gtctaattgt tggaattatt tttacagcga cactattaaa agttgtagaa 145860 cgtaattag ttcatacacc atcaatagat aaacgataa aagatgcata tattagagaa 145920 gattgtccta ctgactggat aagctataat aaaatgta tccatttac tactgatcga 145980 aaaaacctgg gaggaggac gtaatgcatg caaagctcta atccaatt cggatctaat 146040 taggatagag actccaaacg agttaagttt ttagaagc cttagacgag gctattggggt 146100 aggagaatcc gaatattaa accagacac cccatataat ttatagcta aaaatgccac 146160 gagaatgga actaaaaaac ggaaatatat ttgtagtaca acgaatactc ccaaactgca 146220 ttcgtgttac actatataac aattacacta catttttac atacactac ttcggttaga 146280 tgttttagaa aaaataaat atcgccgtac cgttcttgtt tttataaaa taacaattaa 146340 cattatcaa atttttctt taatatttta cgtggttgac cattcttggt ggtaaaataa 146400 tctcttagtg ttggaatgga atgctgttta atgtttccgc actcatcgta tattttgacg 146460 tatgcagtca catcgtttac gcaatagtca gactgtagtt ctcatgct tcctacatca 146520 gaaggaggaa cagttttaaa gtctcttggt tttaatctt tgccattt ttcatgaaa 146580 tcctttgttt tatccactc acattttaaa taatgtcca ctatacattc ttctgttaat 146640 tttactagat cgtcatggggt catagaattt ataggttccg tagtccatgg atccaaacta 146700 gcaaacttcg cgtatacggt atcgcgatta gtgtatacac caactgtatg aaaattaaga 146760 aaacagttta ataaatcaac agaaatattt aatcctccgt ttgatacaga tgcgccatat 146820 ttatggattt cggattcaca cgttgtttgt ctgaggtgtt cgtctagtgt tgcttctacg 146880 taaacttcga ttcccatata ttctttattg tcagaatcgc ataccgattt atcatcatac 146940 actgtttgaa aactaaatgg tatacacatc aaaataataa samaaacga gtacattctg 147000 caatattgtt atcgtaattg gaaaattagt gttcgagtga gtcggattat gtgagtactg 147060 gattgtatat tttattttat attttgtaat aagaataaaa tgctaatgtc aagtttattc 147120 caatagatgt cttattaaaaa aacatatata ataaataaca atggctgaat ggcataaaaat 147180 tatcgaggat atctcaaaaa samaaagtt cgaggatgcc gccatcgttg attacaagac 147240 tacaaagaat gttctagctg ctattcctaa cagaacattt gccaagatta atccgggtga 147300 aattatcct ctcatcacta atcgtaatat tctaaaacct cttatggtc agaaatattg 147360 tattgtatat actaactctc taatggatga gaacacgtat gctatggagt tgcttactgg 147420 gtacgcccct gtatctccga tcgttatagc gagaactcat accgcactta tattttgat 147480 gggtaagcca acacatcca gacgtgatgt gtatagaacg tgtagagatc acgctacccg 147540 tgtacgcgca actgtaatt aaaaaaaa gtatattca tatgtagtgt caatttaaa 147600 tgatgatgat gaatggata atatccatat tgacgatgtc ataatgccg gtattggcat 147660 acagctcatc gatttttaga ttcattcag aggatgtgga attatgttat gggcattttgt 147720 attttgatag gatctataat gtagtaata taaaata tccgcatatt ccatatagat 147780 ataattttat taatcgcacg ttaccgtag atgaactaga cgataatgtc ttttttacac 147840 atggttattt tttaaaacac aaatatggtt cacttaatcc tagttgatt gtctcattat 147900 caggaaactt aaaataat gatatacaat gctcagtaaa tgtacgtgt ctcattaaaa 147960 atttggcaac gagtacatct actatattaa catctaaca window tctctacatc 148020 ggtccacgtg father attack attack attctatta atggtataaa fatheratg acaagtata tgacatctat gattttactg caatatgtat gctaatagcg tctacattga 148200. 148200. 148200. 148200. 148200. 148200. 148200. 148200 gaaatggata aaatcaaaat tacggttgat tcaaaaattg gtaatgttgt taccatatcg fatheracttgg aaaagataac tattgatgtt acacctaaaa agaaaaaaga aaaggatgta ttattagcgc aatcagttgc tgtcgaagag gcaaaagatg tcaaggtaga agaaaaaaat attachment ttgaagatga cgatgatatg gatgtagaaa gcgcataata cgatctaa aaataagtat father ctttttattt acggtactct tgtagtggtg ataccctact 148500 caattatttt tttaaaaaaa tacttattct gattcttcta gccatttccg tgttcgttcg aatgccacat cgacgttaaa gataggggag tagttgaaat ctagttctgc attgttggta cgcacctcaa atgtagtgtt ggatatcttc aacgtatagt tgttgagtag tgatggtttt 148680 ctaaatagaa ttctcttcat atcattcttg cacgcgtaca tttttagcat ccatcttgga attctagatc cttgttctat tcccaatggt ttcatcaata gaagattaa catatcgtac gacacgatg gagagtaatc gtagcaaaag tagcatttc ctttaatctt agatcccgga tactggatat attttgcagc caacacgtgc atccatgcag catttcctac fatheracccgg ctatgcaccg cgtcatcatc gactgtacga tacataatgt taccgtgttg cttacattgc tcgtaaaga ctttcgtcaa tttgtctcct tctccgtaa ttccagtggg tcttaggcaa caagtataca attttgctcc attcatgatt acggaatt tggctttcat aaccagttgc 149160. tcggccatac gtttactttt tgcgtataca tgtcctggtg atatatcata aagggtatgc tcatggccga tgaatggatc accgtgttta ttgggtccta ttgcttccat gctactagta tagtcaaat acttgattcc tagtccaca caagctgcca atatagtctg tgttccataa tagtttactt tcatgatttc attackcggtg tattttccaa attackcc tagagcagcc gtatgaataa tcagatttac cccatctagc gcttctctca ccttatcaaa gtcgtttata 149400 tcacattgta tatagttat aaccttaact ttcgaggtta ttggttgtgg atcttctaca 149460 atatctatga ctctgatttc ttgaacatca tctgcactaa ttaacagttt tactatatac 149520 ctgcctagaa atccggcacc accagtaacc gcgtacacgg ccattgctgc cactcataat 149580 atcagactac ttattctatt ttactaaata atggctgttt gtataataga ccacgataat 149640 atcagaggag ttatttactt tgaaccagtc catggaaaag ataaagtttt aggatcagtt 149700 attggattaa aatccggaac gtatagtttg ataattcatc gttacggaga tattagtcaa 149760 ggatgtgatt ccataggcag tccagaaata tttatcggta acatctttgt aaacagatat 149820 ggtgtagcat atgtttattt agatacagat gtaaatatat ttacaattat tggaaaggcg 149880 ttatctattt caaaaaatga tcagagatta gcgtgtggag ttattggtat ttcttacata 149940 aatgaaaaga tatacattt tcttacaatt aacgagaatg gcgtttgata tatcagttaa 150000 tgcgtctaaa acaataaatg cattagttta cttttctact cagcaaaata aattagtcat 150060 acgtaatgaa gttaatgata cacactacac tgtcgaattt gatagggaca aagtagttga 150120 cacgtttatt tcatataata gacataatga caccatagag ataagagggg tgcttccaga 150180 ggaaactaat attggttgcg cggttaatac gccggttagt atgacttact tgtataataa 150240 gtatagtttt aaactgattt tagcagaata tataagacac agaaatacta tatccggcaa 150300 tatttattcg gcattgatga cactagatga tttggctatt aaacagtatg gagacattga 150360 tctattattt aatgagaaac ttaaagtaga ctccgattcg ggactatttg actttgtcaa 150420 ctttgtaaag gatatgatat gttgtgattc tagaatagta gtagctctat ctagtctagt 150480 atctaaacat tgggaattga caaataaaaa gtataggtgt atggcattag ccgaacatat 150540 atctgatagt attccaatat ctgagctatc tagactacga tacaatctat gtaagtatct 150600 acgcggacac actgagagca tagaggatga atttgattat tttgaagacg atgattcgtc 150660 tacatgttct gccgtaaccg acagggaaac ggatgtataa tttttttat agcgtgaagg 150720 atatgataaa aatataatt gttgtattta tcccattcca atcaccttat atgattctgt 150780 aaaaaatta tactgtaaca caataaagga gtcttataga tgtatagagg tcagatactg 150840 gtttgataaa ctgtttattc cacataagta tgtttgactt tatggttaga cccgcatact 150900 ttaacaaatc actgaaaatt ggagttaggt attgacctct cagaatcagt tgccgttctg 150960 gaacattaaa tgtatttttt atgatatact ccaacgcatt tatgtgggca tacaacaagt 151020 cattactaat ggagtattcc aagagtttta gttgtctagt attaacaag agaagagatt 151080 tcaacagact gtttatgaac tcgaacgccg cctcattgtc gcttatattg atgatgtcga 151140 attctcccaa tatcatcact gatgagtagc tcatcttgtt atcgggatcc aagttttcta 151200 aagatgtcat taaaccctcg atcatgaatg gatttatcat catcgttttt atgttggaca 151260 tgagcttagt ccgtttgtcc acatctatag acgacgattt ctgaattatt tcatatatcc 151320 ctctctttaa ctccaggaac ttgtcaggat ggtctacttt atatgttct cgtctaagag 151380 atgaaaatct ttggatggtt gcacgcgact ttctttaaa ggatgacgtt gcccagatc 151440 ctctcttaaa tgaatccatc ttatccttg acagatgga cagtcttatt tccttagatg 151500 gtttaatatt ttgttaccc atgatctata aaggtagacc taatcgtc ggatgaccat 151560 atatttattt tcagttttat tatacgcata aattgtaaaa atatgttag gtttacaaaa 151620 atgtctcgtg gggcattaat cgttttgaa ggattggaca aatctggaa aaaaacacaa 151680 tgtatgaaca tcatggaatc tataccggca aacacgataa atatcttaa ctttcctcag 151740 agatccactg tcactggaaa gatgatagat gactatctaa ctcgtaaaa aacctataat 151800 gatcatatag ttaatctatt atttgtgca atagatgggg agtttgcatc ttttatacaa 151860 gaacaactag aacagggaat tactttata gttgatagat acccattttc tggagtagcg 151920 tatgccgccg ctaaaggcgc gtcaatgact ctcagtaaga gttatgaatc tggattgcct 151980 aaacccgact tagttatat cttggaatct ggtagcaaag aattaatag aaacgtcggc 152040 gaggaaattt atgaatgt tacattccaa aaaggtat tacaagata taaaaaaatg 152100 attgagaag gagatattca ttggcaattt atttctctctg attcgagga agatgtaag 152160 aaggagttga ttaagaat agttagag gctatacaca cggttactgg accagtgggg 152220 caactgtgga tgtaatagtg aaattacatt ttttataat agatgttagt acagtgttat 152280 aaatggatga agcatattac tctggcact tggaatcagt actcggatac gtgtccgata 152340 tgcataccga actcgcatca atatctcaat tagttattgc caagatagaa actatagata 152400 atgatatatt aaaaaggac attgtaattt ttcatgtg tagatcaac ttggataatc 152460 catttatctc tttcctagat actgtatata ctattataga tcaagagatc tatcagaccg 152520 aattgatta ttcattagac gatagaa ttatcgattg tatagttaac aagtttatga 152580 gctttataa ggataaccta gaaaatag tagatactta aaatatataa 152640 tgaataatcc agatttaaa actacgtatg ccgaagtact cggttccaga atagccgata 152700 taggattaa acagtgata cgtagaata tactacaatt gtctaatgat atccgcgaac 152760 gatatttgtg aaaatatta aaaaaaata ctttttat taaatgacgt cgcttcgcga 152820 atttagaaaa ttgctgtg atatatca cgcatcagga tataaagaaa atctaaatt 152880 attagagac ttatacag attaggga taaatattg atcattaagc tattgcttcc 152940 cggattagac gatagaattt atacatgaa cgataaaaaat tatatagtat 153000 atattaaa caatctcagg aagatatgct aagattta ggatacggat ataggaga 153060 cactattagg actttctca aagagacac agaatccgt ccacgagata aaagcatttt 153120 aactttagaa gaagtgata gttttttaac tacgttatca tccgtaacta aagaatcgca 153180 tcaataaaa ttattgactg atgtagcatc tgtttgtaca tgtaatgatt taaaatgtgt 153240 agtcatgctt attgataaag atctaaaaat taaagcggc cctcggtacg tacttaacgc 153300 tattagtcct catgcctatg atgtgtttag aaatctaat aacttgaag agataataga 153360 aaatgcatct aaaaaatc tagactat atctatttct gttatgactc cattaatcc 153420 catgttagcg gatcgtgtg attctgtcaa taaggcgttt aaaaatttc catcaggaat 153480 gtttgcggaa gtcaatacg atggtgaaag agtacaagtt cataaaaata ataacgagtt 153540 tgccttcttt agtagaaca tgaaccagt actctcat aaagtggatt atctcaaga 153600 atacataccg aaagcattta aaaaagctac gtctatcgta ttggattctg aaattgttct 153660 tgtagacgaa cataatgtac cgctaccgtt tggagtttta ggaatacaca aaagaaaga 153720 atataaaaac tctaacatgt gttgttcgt gtttgactgt ttgtactttg atggattcga 153780 tatgacggac attccattgt acgaacgaag atctttctc aagatgtta tggttgaat 153840 acccaataga atagtattct cagagttgac gattattagt aacgagtctc agttaactga 153900 cgtattggat gatgcactaa cgagaaaatt agaaggattg gtcttaaag atattaatgg 153960 agtatacgaa ccgggaaga gagatggtt aaaaataag cgagactatt tgaacgagggg 154020 ttccatggca gattctgccg atttagtagt actaggtgcc tactatggta aaggagcaaa 154080 gggtggtatc atggcagtct ttctaatggg ttgttacgac gatgaatccg gtaaatggaa 154140 gacggttacc aagtgttcag vakacgatga taatacgtta agggttgc aagaccaatt 154200 aagatgatt aaatttaca aggatcccaa aaaaattcca gagtggttag tagttataa 154260 aatctatatt cccgattttg tagtagagga tccgaaaca tctcagatat gggaaatttc 154320 aggagcagag tttacatctt ccaagtccca taccgcaat ggaatatcca ttagatttcc 154380 taggattact aggatagag aggataaac gtgaaagaa tctactcatc taacgattt 154440 agtaaacttg actaaatcttt atagttaca tacaactga aattaaat aacaccattt 154500 agttggtggt cgccatggat gtgttattg tatactgtct aaacgcgtta gtaaaacatg 154560 gcgaggaaat aaatcatata aaaaatgatt tcatgatta accatgttgt gaagagtttt 154620 gtgaaaaagt caagaacgtt cacattggcg gacaatctaa aaacaataca gtgattgcag 154680 atttgccata tatggataat gcggtatccg atgtatgcaa ttcactgtat aaaaagaatg 154740 tatcaagaat atccagattt gctaatttga taaagataga tgacgatgac aagactccta 154800 ctggtgtata taattatttt aaacctaaag atgttattcc tgttatcata tctataggaa 154860 aggataaaga tgtctgtgaa ctattaatct catcagacat atcgtgtgca tgcgtggagt 154920 taaattcata tcacgtagcc attcttccca tgaatgtttc cttttttacc aaaggaaatg 154980 cctcgttgat tattctcctg tttgatttct ctatcgatgc agcacctctc ttaagaagtg 155040 taaccgataa taatgttatt atatctagac accagcgtct acatgacgag cttccgagtt 155100 ccaattggtt caagttttac ataagtataa agtccgacta ttgttctata ttatatatgg 155160 ttgttgatgg atctgtgatg catgcgatag ctgataatag aactcacgca attattagca 155220 aaaatatatt agacaatact acaattaacg atgagtgtag atgctgttat tttgaaccac 155280 agattaggat tcttgataga gatgagatgc tcaatggatc atcgtgtgat atgaacagac 155340 attgtattat gatgaattta cctgatgtag gcgaatttgg atctagtatg ttggggaat 155400 atgaacctga catgattaag attgctctt cggtggctgg taatttata agaatcgag 155460 actacattcc cgggagacga ggctatagct actacgttta cggtatagcc tctagatatat 155520 ttttttaagc acgaataa aaacatatt ttaaaccaat ctatttcata ctattttgtg 155580 tgatcaccat ggacataaag atagatatta gtatttctgg tgataaattt acggtgacta 155640 ctaggaggga aaatgagaa agaaaaaaat atctacctct ccaaaaga aaaactactg 155700 atgttatca acctgatt cttgagtacg atgacttgtt agatagagat gagatgttta 155760 ctattctaga ggaatatttt atgtacagag gtctattagg cctcagaata aaatatggac 155820 gactctttaa cgaaattaa aaattcgaca atgatgcgga agacaatc ggtactatag 155880 aagaactcaa gcagaaactt agattaatt ctgaagagggg agcagataac ttatagatt 155940 atataaaggt acaaaaacag gatatcgtca aacttactgt atacgattgc atatctatga 156000 taggattgtg tgcatgcgtg gtagatgttt ggagaaatga gaaactgttt tctagatgga 156060 aatattgttt acgagcgatt aaactgttta ttaatgatca catgcttgat aagataaaat 156120 ctatactgca gaatagacta gtatatgtgg aaatgtcata gaaagttaat gagagcaaaa 156180 atatataagg ttgtattcca tatttgttat tttttctgta atagttaaaa aaatacattc 156240 gatggtctat ctatcagatt attatgtgtt ataaggtact ttttctcata ataaactaga 156300 gtatgagtaa gatagtgttt ttcaaaacat ataaatctaa aattgatgga tgagatatac 156360 agctattaat ttcgaaaata tataaatcta aaattgatgg ataagatata cagctattaa 156420 tttcgaaaat atattttaat ctgataactt taaacatgga tttttgatgg tggtttaacg 156480 ttttaaaaaa agattttgtt attgtagtat atgataatat taaaagatgg atataaagaa 156540 tttgctgact gcatgtac ttttttacat tactacattg gctacggcag atatacctac 156600 tccgccacca acgggtcatg tgacaaggga gaatcttg ataagaggca taatcaatgt tgtaatcggt gtccacctgg agaatttgcc aaggttagat gtaatggtaa cgataacaca aaatgtgaac gctgcccacc tcatacatat accacaatcc ccaattattc taatggatgt catcaatgta gaaaatgccc aaccggatca tttgataagg taaagtgtac cggaacacag aacagtaaat gttcgtgtct tcctggttgg tattgcgcta ctgattcttc acagactgaa gattgttgaa attgtgtacc aaaaaggaga tgtccatgcg gatactttgg tggaatagat snow atcctatttg snow ctacctacgt 157020 snow ctacctacgt aattatagac ttgatccatt ttctccatgc aaactatcta aatgtaatta attatgattt tgatgataat gttaccatac attatcgc tacttggtta gtgtattatt cagtatgaag acctact attachment cttttgacga tcttgttata attachment aaaaacttat ggcatagtaa ctcataattg ctgacgcgat aaattcgtaa taatctgttt tgttcaaatt tttataagga atctacaggc ataaaaataa aaatataatt tataatac tcttacagcg 157320 cgccatcatg aatagcagca gtaaattaat tgctgttatt aatggattta gaaatagtgg 157380 acgattttgt gatattaata tagttattaa tgatgaaagg ataaacgctc acagactcat 157440 cctatctgga gcctccgaat atttttccat tctgttttcc aataatttta tcgattctaa 157500 tgaatacgaa gttaatctaa gtcatttaga tttcaaagt gttaacgatt tgatcgatta 157560 catttatggg atacctttga gcctaactaa cgataacgtg aaatatattc tttcaaccgc 157620 tgattttta caaattggat ctgccattac tgagtgcgaa aaatacatac ttaaaaatct 157680 ttgttctaga aactgtatcg atttctacat atacgctgat aaatataata acaagaaaat 157740 agaatcagcg tcgtttaaca caatattacg aatattttg agactcatca acgatgaaaa 157800 ctttaaatac ttaacagagg aatcaatgat aaaaatttta agcgatgata tgttaaatat 157860 aaaaaatgag gattttgcac cactaattct cattaaatgg ttagagagta ctcaacaatc 157920 atgcaccgtc gagttactta gatgcctcag aatatcattg ctttccccac aagttataaa atcactttat agtcatcac tggttagttc aatctcgaa tgtataacat tcttaaacaa fathercattc ttggatgat catttcctag attackctag atcgagttga tatctatcgg father tcgcatgata agatttccat aaactgctac aatcataaaa aaaatacatg ggaaatgata tcttcacgta gatataggtg tagtttcgca gtggccgtcc tggataatat tatctatatg atgggtggat atgatcagtc cccgtataga agttcaaagg ttatagcgta caatacatgt acaaattctt ggatatatga father ctaaaatatc ctcgttctaa ttgtggggga ctggctgatg acgaatacat ttattgtata ggcggcatac gcgatcagga 158400 ttcatcgttg acatctagta ttgatagtg gaagccatca aaaccatatt ggcagaagta tgctaaaatg cgcgaaccaa aatgtgatat gggggttgcg atgttaaacg gatatata tgtcatgggt ggaatcgtta aaggtgacac gtgtaccgac gcactagaga gtttatcaga agatggatgg atgaagcatc aacgtcttcc aaaaaatg tccaatatgt cgacgattgt 158640 tcatgatggc aagatttata tatctggagg ttacaacaat agtagtgtag ttaatgtaat 158700 atcgaatcta gtccttagct atatccgat atatgatgaa tggaccaat tatcatcatt 158760 aacattcct agaattaatc ccgctctatg gtcagcgcat aaaattat atgtaggagg 158820 aggaatactct gatgatgttc gaacatac atctgaaca tacgataag aaaagattg 158880 ttggacattg gataatggtc acgtgttacc acgcaattat ataatgtata aatgcgaacc 158940 gattaaacat aaatatccat tggaaaaaac acagtacacg atgattttc taagtattt 159000 ggaaagtttt atagtagtt gatagaaaaatacataat ttgtaaaa taaatcactt 159060 tttatactaa tatgacacga ttaccatac tttgttact atatcatta gtatacgcta 159120 caccttttcc tcagacatct aaaaaaatag gtgatgatgc aacttatca tgtaatcgaa 159180 ataatacaaa tgactacgtt gttatgagtg cttggtataa ggagcccaat tccattattc 159240 ttttagctgc taaaagcgac gtcttgtatt ttgataatta taccaaggat aaaatatctt 159300 acgactctcc atacgatgat ctagttacaa ctatcacaat taaatcattg actgctagag 159360 atgccggtac ttatgtatgt gcattcttta tgacatcaac tacaaatgac actgataaag 159420 tagattatga agaatactcc acagagttga ttgtaaatac agatagtgaa tcgactatag 159480 acataatact atctggatct acacattcac cagaaactag ttctgagaaa ccagaggata 159540 tagataattt taattgctcg tcggtattcg aaatcgcgac tccggaacca attactgata 159600 atgtagaga tcatacagac accgtcacat acactagtga tagcattaat acagtaagtg 159660 catcatctgg agaatccaca acagacgaga ctccggaacc aattactgat aaagaagaag 159720 atcatacagt cacagacact gtctcataca ctacagtaag tacatcatct ggaattgtca 159780 ctactaaatc aaccaccgat gatgcggatc tttatgatac gtacaatgat aatgatacag 159840 taccaccaac tactgtaggc ggtagtacaa cctctattag caattataaa accaaggact 159900 ttgtagaaat atttggtatt accgcattaa ttatattgtc ggccgtggca atattctgta 159960 ttacatatta tatatataat aaacgttcac gtaaatacaa aacagagaac aaagtctaga 160020 tttttgactt acataaatgt ctgggatagt aaaatctatc atattgagcg gaccatctgg 160080 ttcaggaaag acagccatag ccaaaagact atgggaatat atttggattt gtggtgtccc 160140 ataccactag atttcctcgt cctatggaac gagaaggtgt cgattaccat tacgttaaca 160200 gagaggccat ctggaaggga atagccgccg gaaactttct agaacatact gagtttttag 160260 gaaatattta cggaacttct aaaactgctg tgaatacagc ggctattaat aatcgtattt 160320 gtgtgatgga tctaaacatc gatggcgtta gaagtcttaa aaatacgtac ctaatgcctt 160380 actcggtgta tataagacct acctctctta aaatggttga gaccaagctt cgttgtagaa 160440 acactgaagc ggatgatgag attcatcgtc gtgtgatgtt ggcaaaaact gacatggatg 160500 aggcaggtga agccggtcta ttcgacacta ttatcattga agatgatgtg aatttagcat 160560 atagtaagtt attcagata ctacaggacc gtattagaat gtattttaac actattaga 160620 gacttaagac ttaaaacttg atattaata atatactcg ttttatatg tggctatttc 160680 aacgtctaat gtattagtta atattaaaa cttaccacgt aaacttaaa atttaaatg 160740 atatttcatt gagataga tcacatta tgaacttca aggacttg ttactgaca 160800 attgcaaaaa tcaatgggtc gttggaccat taataggaaa aggtggattc ggtagtattt 160860 attacka tgacattaat tatgtagtaaaatagagcc caagctaac ggatcattat 160920 ttaccgaaca ggcattttat actagagtac ttaaaccacc cgttatcgaa gatggaaaa 160980 aatctcacaa tataaagcac gtaggtctta tcacgtgcaa ggcattggt ctatacaaat 161040 ccattaatgt ggaatatcga ttctgtaa ttaatagat aggtgcagat ctagatgcgg 161100 tgatcagagc caataat agattacca aaagtcggt gatgttgatc ggaatcgaaa 161160 tcttaatac catacaattt atgcacgagc aaggatattc tcacggagat attaaagcga 161220 gtaatatagt cttggatcaa atagataaga ataaattata tctagtggat tacggattgg 161280 tttctaaatt catgtctaat ggcgaacatg ttccatttat aagaaatcca aataaaatgg 161340 ataacggtac tctagaattt acacctatag attcgcataa aggatacgtt gtatctagac 161400 gtggagatct agaaacactt ggatattgta tgattagatg gttgggaggt atcttgccat 161460 ggactaagat atctgaaaca aagaattgtg cattagtaag tgccacaaaa cagaaatatg 161520 ttaacaatac tgcgactttg ttaatgacca gtttgcaata tgcacctaga gaattgctgc 161580 aatatattac catggtaaac tctttgacat atttgagga acccaattac gacgagtttc 161640 ggcacatatt aatgcagggt gtatattatt aagtgtggtg tttggtcgat gtaaaattttt 161700 tgtcgataaa attaaaaaa taacttaatt tattattgat ctcgtgtgta caaccgaaat 161760 catggcgatg tttacgcac acgctctcgg tgggtacgac gagaatcttc atgccttttc 161820 tggaatatca tcgactgttg ccaatgatgt caggaaatat tctgttgtgt cagtttataa 161880 taacaagtat gacattgtaa aagacaaata tatgtggtgt tacagtcagg tgaacaagag 161940 atatattgga gcactgctgc ctatgtttga gtgcaatgaa tatctacaaa ttggagatcc 162000 gatccatgat caagaaggaa atcaaatctc tatcatcaca tatcgccaca aaaactacta 162060 tgctctaagc ggaatcgggt acgagagtct agacttgtgt ttggaaggag tagggattca 162120 tcatcacgta cttgaaacag gaaacgctgt atatggaaaa gttcaacatg attattctac 162180 tatcaaagag aaggccaaag aaatgaatgc actcagttca ggacctatca tcgattacca 162240 cgtctggata ggagattgta tctgtcaagt tactgctgtg gacgtacatg gaaaggaaat 162300 tatgagaatg agattcaaaa agggtgcggt gctacagatc ccaaatctgg taaaagttaa 162360 acttggggag aatgatacag aaaatctttc ttctactata tcggcggcac catcgaggta 162420 accacctc aagaagaccg cgtgaataat gtactcatga aacgtttgga aactatacgc 162480 catatgtggt ctgttgtata tgatcatttt gatattgtga atggtaaaga atgctgttat 162540 gtgcatacgc attcatctaa tcaaaatcct ataccgagta ctgtaaaaac aaatttgtac atgaagacta tgggatcatg cattcaaatg gattccatgg aagctctaga gtatcttagc gaactgaagg aatcaggtgg atggagtccc agaccagaaa tgcaggaatt tgaatatcca gatggagtgg aagacactga atcaattgag agttggtag aggagttctt caatagatca gaacttcagg ctggtaaatt agtcaaattt ggtaattcta ttaattgtta aacatacatc tgtttcagct aagcaacta gaacacgtat acggcagcag cttcctttta tactctcatc ttttaccaac acaaagggtg cattttgtt cattggagtt catcacaaagt atttggattc acggtgggtt acgactacct cagactgata cagactgata tagaaaagca 163080. 163080. 163080. 163080. 163080. 163080. 163080. 163080 tcgattcatc aaggtatata aacctgggga tgaggctacc tcgacatacg tgtgcgctat caaagtgga agatgctgtt gtgctgtgtt tgcagattgg ccagaatcat ggtatatgga tactaatggt atcaagagt attctccaga tgaatggtg tcacatataa aattttaatt 163260 aatgtaacta tagacaa atataggtt gtaatcat atagacaata actaacaatt 163320 attacktaac tgttatctct tttacta accactac tatatacta ttaatacatc 163380 gtaattatag ttcttacat ctattaatca ttgattcgct tctttaattt tttataaact 163440 aacattgtta attgaaagg gataacatgt tacagaatat aattatata tggattttt 163500 taaaaaggaa atacttgact ggagtgtata tttatctctt cattatatag cacgcgtgtg 163560 ttccaattct tccacatcc atatataca ggattataat ctcgttcgaa catacgagaa 163620 agtggataaa acatagttg attttttc taggttgcca aatttattcc atattttaga 163680 atatggga atatttctac atatttattc tattgat gctaatacga atttataat 163740 ttttttcta gatagagtat taaatatta taagaacggg tcatttatac acatctcag 163800 gttatcatca tccattaata taaaagata tgtatatcaa ttagttaata atgatcatcc 163860 agatatagg atagactaa tgcttgaaaa tggacgtaga acagacatt tttgtccta 163920 tatcagat acagttaata tctatatatg tatttata aatcatggat tttatataga 163980 tgcagaagac agttacggtt gtacattatt acatagatgt atatacact atagaaatc 164040 agaatcagaa tcatacaatg aattatta gatttgtta aataatggat ccgatgtaga 164100 taaaaaagat acgtacggaa acacacctttt tatcctatta tgtaacacg atcacaa 164160 cgtggaattg tttgagatat gtttagagaa tgctaatata gactctgtag actttaatag 164220 atacacct cttcattatg tctcatgtcg taataatat gatttgtaa agttattaat 164280 ttctaaagga gcaatgtta atgcgcgtaa taattcgga actactccat tttattgtgg 164340 aattatacac ggtatctcgc ttaaaact atatttgga tcagacacag agttagaat 164400 agataatgaa catatagttc gtcatttaat aatttttgat gctgttgaat ctttagatta 164460 tctattatcc agaggagtta ttgatattaa ctacgtact atacaacg aaacatctat 164520 ttacgacgct gtcagttata atgcgtataa tacgttggtc tatctatta acagaaatgg 164580 tgattttgag acgattacta ctagtggatg tacatgtatt tcggagcag tcgcaacaa 164640 caaaaata atatggaag tactattgtc taaacgacca tctttgaaaa tatgataca 164700 gtctatgata gcaattacta aaaaaaca acataatgca gatttattga aaatgtgtat 164760 aaaatatact gcgtgtatga ccgattatga tactcttata gatgtacagt cgctacagca 164820 ataataatgg tatatttta aatgtttcga tgaatagat atcatgaga gatgttatat 164880 aaaaaaay actgtattcc aattagtttt ttgtacaa gatattata ctttaatgag 164940 atatggtaaa catccttctt tcgtgaagtg cactagtctc gacgtatacg gaagtcgtgt 165000 acgtaatatc atagcatcta ttagatcg tcagagatta attagtctat tatccaagaa 165060 gctggatgcg ggataaat ggtcgtgttt tcctaacgaa aaaatata aaatattgga 165120 aaactttaac gataacgaac tatccacata tctaaaaatc ttaaacac tattaaata 165180 taaaatctaa gtaggataaa atcacactac atcattgtttt ctttagtg ctcgacagtg 165240 tatactattt ttacactca taataaaaa tgaaaacgat ttccgttgtt acgttgttat 165300 gcgtactacc tgctgttgtt tattcacat gtactgtacc cactgaat aacgctaaat 165360 taacgtctac cgaaacatcg tttaatgata aacagaaagt tacatttaca tgtgatcagg 165420 gatatcattc tttggatcca aatgctgtct gcgaaacaga taatggaaa tacgaaaatc 165480 catgcaagaa atgtgcaca gtttctgatt atgtctctga attatatgat aagccattat 165540 acgaagtgaa ttccaccatg acactaagtt gcaacggcga aaaaaatat ttcgttgcg 165600 aagaaaaaaa tggaaatact tcttggaatg attackgttac gtgtcctaat gcggaatgtc 165660 aaccctctca attagacac ggatcgtgtc aaccagttaa agaaaaatac tcattgggg 165720 atatatgac tatcaactgt gatgttggat atgaggttat tggtgcttcg tacataagtt 165780 gtacagctaa ttcttggaat gttattccat catgtcaaca aaaatgtgat ataccgtctc 165840 tatctaatgg attaatttcc ggatctacat tttctatcgg tggcgttata catcttagtt 165900 gtaaaagtgg ttttatacta acgggatctc catcatccac atgtatcgac ggtaaatgga 165960 atcccatact cccacatgt gtacgatcta acgaaaaatt tgatccagtg gatgatggtc 166020 ccgacgatga gagatttg agcaaactct cgaaagacgt tgtacaat gacagaaa 166080 tagaatcgtt agaagcaact tatcatataa tcatagtggc gttaacaatt atgggcgtca 166140 tattttaat ctccgttata gtattagttt gttcctgtga caaaataat gaccaatata 166200 agttccataa attgctaccg taaatataaa tccgttaaaa taattaataa tttaataca 166260 aacaagtatc aaagattaa agacttatag ctagaatcaa ttgagatgtc ttctcagtg 166320 gatgttgata tctacgatgc cgttagagca ttttactca ggcactatta taacaagaga 166380 tttattgtgt atggagaag taacgccata ttacataata atacaggct atttacaga 166440 tgcgccgtta taccgttcga tgatatagta cgtactatgc caaatgaatc acgtgttaaa 166500 caatgggtga tggatacact taatggtata atgatgaatg aacgcgatgt ttctgtaagc 166560 gttggcaccg gaatactatt catggaaatg ttttcgatt acaataaaaa tagtatcaac 166620 aatcaactaa tgtatgatat aattaatagc gtatctataa ttctagctaa tgagagatat 166680 agaagcgctt ttaacgacga tggtatatac atccgtagaa atatgattaa caagttgtac 166740 ggatacgcat ctctaactac tattggcacg atcgctggag gtgtttgtta ttatctgttg 166800 atgcatctag ttagtttgta taaataatta tttcaatata ctagttaaaa ttttaagatt 166860 ttaaatgtat aaaaaactaa taacgttttt atttgtaata ggtgcattag catcctattc 166920 gaataatgag tacactccgt ttaataaact gagtgtaaaa ctctatatag atggagtaga 166980 tatatagaa aattcatata ctgatgataa taatgaattg gtgttaaatt ttaaagagta 167040 cacaatttct attattacag agtcatgcga cgtcggattt gattccatag atatagatgt 167100 tataaacgac tataaaatta ttgatatgta taccattgac tcgtctacta ttcaacgcag 167160 aggtcacacg tgtagaatat ctaccaaatt atcatgccat tatgataagt acccttatat 167220 tcacaataat gatggtgatg agcaacaata ttctattact gcagagggaa atgctataa 167280 aggataaaa tatgaataa gtatgatcaa cgatgatact ctattgagaa aacatactct 167340 taaaattgga tctacttata tattgatcg tcatggacat agtatacat attattcaa 167400 atatgatttt taaaaattta aaatatta tcactcagt gagtagtc aaatacaaa 167460 cacaccatg agatatatta taattctcgc agttttgttc attatagta tacacgctaa 167520 ataactagt tataagtttg aatccgtcaa ttttgattcc aaaattgaat ggactgggga 167580 tggtctatac atatatccc ttaaaatta tggcatcaag acgtggcaaa caatgtatac 167640 aaatgtacca gaaggaacat acgacatatc cgcattcca aagaatgat tcgtatcttt 167700 ctgggttaaa tttgacaag gcgattataa agtggaagg tattgtacgg gactatgcgt 167760 cgaagtaaaa attggaccac cgactgtaac attgactga tacgacgacc attcaattt 167820 gtacatcgag catccgtatg ctactagagg tagcaaaaag attcctattt acaaacgcgg 167880 tgacatgtgt gatatctact tgttgtatac ggctaacttc acattcggag attctaaaga 167940 accagtacca tatgatatcg atgactacga ttgcacgtct acaggttgca gcatagactt 168000 tgtcacaaca gaaaaagtgt gcgtgacagc acagggagcc acagaagggt ttctcgaaaa 168060 aattactcca tggagttcga aagtatgtct gacacctaaa aagagtgtat atacatgcgc 168120 aattagatcc aaagaagatg ttcccaattt caaggacaaa atggccagag ttatcaagag 168180 aaaatttaat aaacagtctc aatcttattt aactaaattt ctcggtagca catcaaatga 168240 tgttaccact tttcttagca tgcttaactt gactaaatat tcataactaa tttttattaa 168300 tgatacaaaa acgaaataaa actgcatatt atacactggt taacgccctt ataggctcta 168360 accattttca agatgaggtc cctgattata gtccttctgt tcccctctat catctactcc 168420 atgtctatta gacgatgtga gaagactgaa gaggaaacat ggggattgaa aatagggttg 168480 tgtataattg ccaagattt ctatcccgaa agaactgatt gcagtgttca tctcccaact 168540 gcaagtgaag gattgataac tgaggcaat ggattcagg atatacgaa caccgataa 168600 tttaaaaaa agcaatgtgt ccgctgtttc cgttaataat actatttcg taactggcgg 168660 attattcata ataactcta atagcacgat cgtggttaac atatgAa aacttgacat 168720 ttataaagac aaacaatggt cgattataga atgcctatg gctagggtat atcacggcat 168780 cgactcgaca tttggaatgt tatatttgc cggaggtcta tccgttaccg aacaatatgg 168840 taatttagag aaaaacaacg agatactctg tacaatcct agaacgaata agtggttttga 168900 tattcatat actattatta agatatccat atcatcattg tgtaaactaa ataacgtctt 168960 ctatgtattt agtaaggaca ttggatatgt ggaaaagtat gatggtgcat ggaagttagt 169020 acatgatcgt ctccccgcta taaagcatt atcaacttct ccttattgat tgaaaatgaa 169080 atataata gttttgt atagcagtat taccctatag ttttattgct tactaac 169140 multiplier atgttacaaa tgtagagat atcaataatg aaatagaag aggaagaa 169200 gaatactaa aaatgtaga attgaat aaaaaaca tcacaagaa tcatccaagt 169260 ggatatatta gagagcact cgttattaat acagtagta atagtgattc cattgataaa 169320 gaagttatag atgtatcag tcacgatgta ggaatataga tcatactac taatttttat 169380 aatcgataca aaactaaaaaaactcgt tattacatag caggcatgga atccttcaag 169440 tattgttttg ataacgatgg caagaatgg attatcggaa atactttatta ttctggtaat 169500 tcaatactat aaggtcag aaaaaatttc actagttcgt tctacaatta cgtaatgaaa 169560 atagatcaca aatcacaca gccattgttg tctgaaatac gattctatat atctgtattg 169620 gatcctttga ctatcgacaa ctggacacgg gaacgtggta taaagtattt ggctattcca 169680 gatctgtatg gattggaga aaccgatgat tatatgttct tcgttataa gattcggga 169740 agagtattcg cccaagga tactgaatca gtcttcgaag catgcgtcac tatgataac 169800 acgttagagt ttatacactc tcgaggatttt accatggaa aaatagaacc gaggaatata 169860 ctgattagaa ataacgtct ttcactatt gactattcta gactacaa actatacaag 169920 agtggaaact spacatataga spacecatch space gaatgaa cttscaact spacecattat 169980 atgtgtgtag acaatcatct tggagcaa gtttcaaac gaggagattt agaatgttg 170040 ggatattgca tgatagaatg gttcggtggc aaacttccat ggaaaacga aagtagtata 170100 aaaaaaaaaaaaaaaaaattatag ctactttctt tgaggactgt 170160 tttcctgaag gaatgaacc tctggaatta gttagatata tagacgtta 170220 gattattctc aaactcctaa ttatgacaga ctacgtaaac tgtttataca agattgaat 170280 tatattcttt ttttatagag tgtggtagtg ttacggatat ctaatattaa tattagacta 170340 tctctatcgc gctacacgac caatcgat tactatggat atcttcaggg aaatcgcatc 170400 ttctatgaaa ggagagaatg tattcattc tccagcgtca atctcgtcag tattgacaat 170460 actgtattat ggagctaatg gatccactgc tgaacagcta tcaaaatatg tagaaacgga 170520 ggagaacacg gataaggtta gcgctcagaa tatctcattc aaatccatga ataaagtata 170580 tgggcgatat tctgccgtgt ttaaagattc ctttttgaga aaaattggcg ataagtttca 170640 aactgttgac ttcactgatt gtcgcactat agatgcaatc aacaagtgtg tagatatctt 170700 tactgagggg aaaatcaatc cactattgga tgaaccattg tctcctgata cctgtctcct 170760 agcaattagt gccgtatact ttaaagcaaa atggttgatg ccattcgaaa aggaatttac 170820 cagtgattat cccttttacg tatctccgac ggaaatggta gatgtaagta tgatgtctat 170880 gtacggcaag gcatttaatc acgcatctgt aaaggaatca ttcggcaact tttcaatcat 170940 agaactgcca tatgttggag atactagtat gatggtcatt cttccagaca agattgatgg 171000 attagaatcc atagaacaaa atctaacaga tacaaatttt aagaaatggt gtaactctct 171060 ggaagctacg tttatcgatg ttcacattcc caagtttaag gtaacaggtt cgtataatct 171120 tgtggatact ctagtaaagt caggactgac agaggtgttc ggttcaactg gagattatag 171180 caatatgtgt aattcagatg tgagtgtcga cgctatgatt cacaaaacgt atatagatgt 171240 caatgaagag tatacagaag cagctgcagc aacttgtgca ctggtgtcag actgtgcatc 171300 aacaattaca aatgagttct gtgtagatca tccgttcatc tatgtgatta ggcatgttga 171360 tggaaaaatt cttttcgttg gtagatattg ctctccgaca actaattgtt aacccattttt 171420 tttaaaaaaa tagaaaaaac atgtggtatt agtgcaggtc gttgttcttc caattgcaat 171480 tggtaagatg acggccaact ttagtaccca cgtcttttca ccacagcact gtggatgtga 171540 cagactgacc agtattgatg acgtcagaca atgtttgact gaatatattt attggtcgtc 171600 ctatgcatac cgcaacaggc aatgcgctgg acagttgtat tccacactcc tctcttttag 171660 agatgatgcg gaatcagtgt tcatcgacat tcgcgagctg gtaaaaaata tgccgtggga 171720 tgatgtcaaa gattgtacag aaatcatccg ttgttatata ccggatgagc aaaaaaccat 171780 cagagagatt tcggccatca tcggactttg tgcatatgct gctacttact ggggaggtga 171840 agaccatccc actagtaaca gtctgaacgc attgtttgtg atgcttgaga tgctcaatta 171900 cgtggattat aacatcatat tccggcgtat gaattgatga gttgtacatc ttgacatttt 171960 ctttcttctc ttctcccttt cttctcttct cccttcctcc ctcttctccc tttcccagaa 172020 acaaactttt ttacccacta taaaataaaa tgagtatact acctattata tttcttccta 172080 tattttttta ttcttcattc gttcagactt ttaacgcgcc tgaatgtatc gacaaagggc 172140 aatattttgc atcattcatg gagttagaaa acgagccagt aatcttacca tgtcctcaaa 172200 taaatacgct atcatccgga tataatatat tagatatttt atgggaaaaa cgaggagcgg 172260 ataatgatag aattataccg atagataatg gtagcaatat gctaattctg aacccgacac 172320 aatcagactc tggtatttat atatgcatta ccacgaacga aacctactgt gacatgatgt 172380 cgttaaattt gacaatcgtg tctgtctcag aatcaaatat agatcttatc tcgtatccac 172440 aaatagtaaa tgagagatct actggcgaaa tggtagtcc caatattaat gcatttattg 172500 ctagtaacgt aaacgcagat attatatgga gcggacatcg acgccttaga addaagagac 172560 ttaaacaacg gandacctgga attackacca tagagatgt tagaaaaat gatgctggtt 172620 attackacatg tgttttagaa tatatataca gaggtaaac atataacgta accagaattg 172680 taaaattaga ggtacgggat aaaatatac cttctactat gcaattacca gatggcattg 172740 taacttcaat aggtagtaat ttgactattg cgtgtagagt atcgttgaga cctcccacaa 172800 cggatgcaga cgtctttttgg ataagtaatg gtagttatta cgaagagat gatggggacg 172860 gagacggtag ataagtgta gcaataaa tctatatgac cgatagaga cgtgttatta 172920 catcccggtt aacattaat cctgtcagg aagagatgc tacaacgttt acgtgtatgg 172980 cgtttactat tcctagcatc agcaaacag ttactgttag tataacgtga atgtatgttg 173040 ttacattcc atgtcaatg agtttataag aattttatta cattacttc caacaaca 173100 ttgacgaacg tattgctatg attaactccc acgatactat gcatattatt aatcattaac 173160 ttgcagacta tacctagtgc tattttgaca tactcatgtt cttgtgtaat tgcggtatct 173220 atattattaa agtacgtaaa tctagctata gttttattat ttaatttag tsaaatacc 173280 gtctccttat ttttaaaaat tgccacatcc tttattaaat catgaatggg aatttctatg 173340 tcatcgttag tatattgtga acaacaagag cagatatcta taggaaaggg tggaatgcga 173400 tacattgatc tatgtagttt taaaacacac gcgaactttg aagaatttat ataaatcatt 173460 ccatcgatac atccttctat gttgacatgt atatatccag gaattctttt attaatgtca 173520 ggaaatgtat aaactaaaac attgcccgaa agcggtgcct ctatctgcgt tatatccgtt 173580 cttaacttac aaaatgtaac caataccttt gcatgacttg ttttgttcgg caacgttagt 173640 ttaaacttga cgaatggatt aattacaata gcatgatccg cgcatctatt aagttttttt 173700 actttaacgc ccttgtatgt tttacagag actttatcta aatttctagt acttgtatgt 173760 gttataata taacgggata tagactgaa tcacctacct tagataccca attacatttt 173820 atcagatcca gataataac aaattttgtc gccctaacta attctatatt gttatatatt 173880 ttacaattgg ttatgatatc atgtaataac ttggagtcta acgcgcatcg tcgtacgttt 173940 atacaattgt gatttagtgt agtatatcta cacatgtatt ttccgcact atagtattct 174000 ggactagtga taaaactatc gttatatctg tctcaatga actcatcgag atttgctct 174060 ctgtcatatt catacacctg cataaacttt ctagacatct tacaatccgt gttattttag 174120 gatcatattt acatattac gggtatatca aagatgttag attagttaat gggaatcgtc 174180 tataaatg atattaaac attatatga ggactttac cacaagcat cataaaatg 174240 agtcgtcgtc tgatttatgt ttataatc aaccgcaaat caactcataa atacaagag 174300 aatgaaatat atacatattt tagtcattgc atatagacc atactctac agaacttgat 174360 tttgtagtta aaaactatga tctaaacaga cgacaacatg taactgggta tactgcacta 174420 cactgctatt tgtataataa ttactttaca aacgatgtac tgaagatatt atttaatcat 174480 gacgtaaatg taacgatgaa aaccagtagc ggacgtatgc ctgtttatat attgcttact 174540 agatgttgca atattcaca tgatgtagtg agatatga tagacaaga taaaaaccac 174600 ttacata gagactattc caactatta ctagagtata taaaatctcg ttacatgtta 174660 ttaaggag aggatatcga tgagacata gtatccactt tattagata gggaatcgat 174720 cctaacttta aacaagacgg atacagcg ttacattatt attatttgtg tctcgcacac 174780 gtttataaac caggtgagtg tagaaaccg ataacgataa aaaggccaa gcgaattatt 174840 tctttgttta tacacatgg agctaatcta aacgcgttag atattgtgg taatacacca 174900 ttccattgt atcttagtat tgaaatgtgt ataatattc atatgactaa atgctgttg 174960 acttttaatc cgaatttca atatgtaat atcatggat taacgcctat actatgttat 175020 ataacttccg actacataca acacgatatt cttgttatgt taatacatca ctatgaaca 175080 aatgttggag aaatgccgat agatgagcgt cgtatgatcg tattcgagtt tatcaaaaca 175140 tattctacac gtccggcaga ttcgataact tatttgatga ataggtttaa aaatataaat 175200 atttataccc gctatgaagg aaagacatta ttacacgtag catgtgaata taataataca 175260 cacgtaatag attacttat acgtatcaac ggagatataa atgcgttaac cgacaataac 175320 aaacacgcta cacaactcat tatagataac aaagaaaatt ccccgtatac catcgattgt 175380 ttactgtata tacttagata tattgtagat aagaatgtga taagatcgtt ggtggatcaa 175440 cttccatctc tacctatctt cgatataaaa tcatttgaga aattcatatc ctactgtata 175500 cttttagatg acacatttta cgataggcac gttaagaatc gcgattctaa aacgtatcga 175560 tacgcatttt caaaatacat gtcgtttgat aaatacgatg gtataataac taaatgtcac 175620 gacgaaacaa tgttactcaa actgtccact gttctagaca ctacactata tgcagtttta 175680 agatgccata attcgaaaaa gttaagaaga tacctcaacg agttaaaaaa atataataac 175740 gataagtcct ttaaaatata ttctaatatt atgaatgaga gataccttaa tgtatattat 175800 aaagatatgt acgtgtcaaa ggtatatgat aaactatttc ctgttttcac agataaaaat 175860 tgtctactaa cattactacc ttcagaaatt atatacgaaa tattatacat gctgacaatt 175920 aacgatcttt ataatatatc gtatccacct accaaagtat agttgtattt ttctcatgcg 175980 atgtgtgtaa aaaaactgat attatataaa tattttagtg ccgtataata aagatgacga 176040 tgaaaatgat ggtacatata tatttcgtat cattattgtt attgctattc cacagttacg 176100 ccatagacat cgaaaatgaa atcacagaat tcttcaataa aatgagagat actctaccag 176160 ctaaagactc taaatggttg aatccagcat gtatgttcgg aggcacaatg aatgatatag 176220 ccgctctagg agagccattc agcgcaaagt gtcctcctat tgaagacagt cttttatcgc 176280 acagatataa agactatgtg gttaaatggg agaggctaga aaagaataga cggcgacagg 176340 tttctaataa acgtgttaaa catggtgatt tatggatagc caactataca tctaaattca 176400 gtaccgtag gtatttgtgt accgtaacta caagaatgg tgactgtgtt cagggtatag 176460 ttagatctca tattaaaaaa cctccttcat gcattccaa aacatatgaa ctaggtactc 176520 atgataagta tggcatagac ttatactgtg gattcttta cgcaaacat tataata 176580 taacttggta windows aaggaatta atcgacga cattaagtat tcacaacgg 176640 gaaagaatt attackatcat aatccagagt tagatag tggatac aactgttacg 176700 ttcattacga cgacgttaga atcagatg atatcgtagt atcagatgt aaatactta 176760 cggttatacc gtcgcaagac cacaggttta aactaatact agatccaaa atcaacgtaa 176820 cgataggaga acctgccaat atacatgca ctgctgtgtc aacgtcatta ttgattgacg 176880 atgtactgat tgaatgggaa aatccatccg gatggcttat aggattcgat tttgatgtat 176940 actctgtttt aactagtaga ggcggtatta ccgaggcgac cttgtacttt gaaatgtta 177000 ctgaagaata tatagtaat acatataat gtcgtggaca caactattat ttgaaaaaa 177060 cccttacaac tacagtagta ttggagtaa tacacaatgc attttat acattactga 177120 atattatta ttattatta tatcgtattt gtgctataac gcgactatct aggtattgt 177180 atctcactga tagagacat aataatag actctatta acagttgtgt aaatatca 177240 atcctaatag atgtggatgt acggctttac atgagtactt tattaattat agatcagtca 177300 acggaaaata caagtataga tacaacggtt actatcaata ttttactct agcgatttag 177360 aaaattataa tgaatattat tatgatgat atgatagaac tggtagaac agtgagagtg 177420 fathertatc atcaaca gatatgaat tctatgatga aacacagat caagtacac 177480 aactagtagg ttacgacatt aaactcaaaa ccaatgagga tgatttatg gctatgatag 177540 atcagtgggt gtccatgatt atagatga atcattaat aaagtagtat atggagaga 177600 gtctcacgta agatggcgggg atatatggca agaacataat gatggcgtat acagtatagg 177660 aaaggagtgc atagataata tatacgaag caccatacc gtagacgaat tctacagat 177720 agacagcgta tcagatgtag atgacgcgga acacatatct ccgataacta atgatgtatc 177780 tacacaaca tgggaaaga atcagagtt agatagatac atggaatgt atcctcgtca 177840 tagatatagt aagcattctg tctttaaggg atttctctgac aaagttagaa aaatgattt 177900 agacatgaat gtggtaaag aattacttc taacggtgca tctctacaa taggatag 177960 cagtaatag gatcaata ccgtttattt tcgagaacg atatgaatt tagaatgat 178020 tgatattatt aaaaacata caactattga tgaacgaag tatatagtac actcctatct 178080 aaaaaattat aaaaatttcg atttaccatt ttcaggag ttagttttga ctataaaca 178140 ttgtctcaac attattata atataagcga cagcaatat ggacaccgc tacatatatt 178200 ggcgtctaat aaaaaattta taactcctaa ttacatgag ttattagtgt ataacggaaa 178260 tgattaac gcacgaggtg agatacaca aatgcgaact ccattacaca atattgtg 178320 taaatttgta tatcataata ttgaatatgg tatccgatc taatgaaa agattataga 178380 cgcattatta gagttaggag ccgatctaac tattccaat aacgatggaa tgataccagt 178440 agtttactgt atacactca atgcagata tggttatac atattacta acataagat 178500 atacgtaaa ctacttaatc ttagtagacg tgcgtcacat attcttta gagatcgagt 178560 catgcacgat tatatagta atacatatat tgatcttgag tgtttagata ttattagatc 178620 gttggatgga ttcgatatca atggttactt tgaaggacgt acaccacttc attgcgctat 178680 acaacataac ttcactcaga ttgctagta cttattagat cgaggagctg atatagtcgt 178740 acccacaca ttgattatac atcagtacat accataata gcatagatat ggagggat 178800 aaataattt caataagt tataaggtac aacactgtca atatatg gagacatta 178860 cctaacttct ggactggaac tataaatcca ggcgtggtct cgcataaga tgatatatat 178920 gttgtatgcg acatcaaga tgaaaaaaat gttaagactt gtatattag attackacacg 178980 atacgtata acggatggga attggttacg acgacagaaa gcagattatc agctctgcat 179040 actattcttc atgacaatac cataatgatg ttacattgtt atgaatcgta tatgttacaa 179100 gatacattta atgtgtacac tcgcgaatgg aatcatatgt gtcatcaa ttcgaatagt 179160 tatatcatgt acaatact acccatctac taaataat agaataaat aaatgagtat 179220 gatcatttta gataacgatt gattttatca ttaccgctc attcttatat tctttgctta 179280 cggaacctat atttagaaac atctactaac gattttttat gcttgcatta ttaatggtat 179340 gtaatatgat tgattgtgta cgcaatacca atttgttaag tatgaatacg gggtacaaac 179400 aaactgaa atttacatt attattat gatatatatc gttatcgtta ttgttttggtc 179460 tataccatgg atatctttaa agaactaatc ttaaaacacc ctgatgaaaa tgttttgatt 179520 tctccagttt ctattttatc tactttatct attctaaatc atggagcagc tggttctaca 179580 gctgaacaac tatcaaata tagagaat tagatagaga atacacccga tgatagag 179640 gatgacaata atgacatgga cgtagatatt ccgtattgtg cgacactagc taccgcaaat 179700 aaaatacg gtagcgatag tatcgagttc cacgccctcct tcctacaaa aaaaagac 179760 gattttcaa ctgtaaactt taataatgct aaccaaaaa aggactaat caacgaatgg 179820 gttaagacga tgacaatgg taaaattaat tccttattga ctagtccgct atccattaat 179880 actcgtatga cagttgttag cgccgtccat tttaaagcaa tgtggaaata tccattttct 179940 aaacatctta catatacaga caagttttat atttctaaga atagttac cagtgttgat 180000 atgatggtgg gtaccgagaa taacttgcaa tatgtacata ttaatgaatt attcggagga 180060 ttctctatta tcgatattcc atacgaggga aacttagta tggtattat actaccggac 180120 gaatagag gtatatata catagaaaaaatatacag atgaaaaattt taaaaaatgg 180180 tgtggtatgt tatctaa aagtatagac ttgtatatgc CAagtttaa agtggaatg 180240 acgaaccgt ataatct...
Claims
1. A recombinant oncolytic virus, whose nucleotide sequence is shown in SEQ ID NO: 1, wherein the thymidine kinase gene of SEQ ID NO: 1 is replaced by a nucleotide sequence of a truncated human CD19, the recombinant oncolytic virus comprises a nucleotide sequence encoding a truncated human CD19, the truncated human CD19 comprises an extracellular domain and a transmembrane domain and lacks a functional signaling domain, and wherein the nucleotide sequence encoding the truncated CD19 is operably connected to a promoter.
2. The recombinant oncolytic virus of claim 1, wherein the promoter is a viral early promoter.
3. The recombinant oncolytic virus of claim 2, wherein the promoter is a poxvirus early promoter.
4. The recombinant oncolytic virus of claim 1, wherein the truncated human CD19 lacking a functional signaling domain comprises amino acids 22-323 of the following sequence: MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKD RPEIWEGEPPCVPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVTLAYLIFCLCSLVGILHLQRALVLRRKR.
5. Use of the recombinant oncolytic virus according to any one of claims 1 to 4 in the preparation of a medicament for treating cancer, comprising: Administering the recombinant oncolytic virus of any one of claims 1 to 4 to a patient; and simultaneously or subsequently, A population of T cells expressing a chimeric antigen receptor (CAR) targeting CD19 is administered to the patient.
6. The use of claim 5, wherein the T cell population comprises T cells transduced with a lentiviral vector encoding the CAR.
7. The use of claim 5, wherein the T cell population comprises T cells transfected with an RNA molecule encoding the CAR.
8. The use of claim 5, wherein the T cell population is administered 1-20 days after administration of the recombinant oncolytic virus.
9. The use of claim 5, wherein the T cell population is administered 5-100 days after administration of the recombinant oncolytic virus.
10. The use of claim 5, wherein the cancer is a solid tumor.
11. The use of claim 10, wherein the solid tumor is breast cancer, ovarian cancer or pancreatic cancer.
12. The use according to claim 10, wherein the solid tumor is breast cancer.
Citation Information
Patent Citations
CD19-specific chimeric T cell receptor
US7446179B2
Targeted cancer therapy
WO2017075440A1