RESTRICTED IMMUNOGLOBULIN HEAVY CHAIN MICE

Abstract

Mice having a restricted immunoglobulin heavy chain locus are provided, wherein the locus is characterized by a single polymorphic human V.sub.H gene segment, a plurality of human D.sub.H gene segments and a plurality of J.sub.H gene segments. Methods for making antibody sequences that bind an antigen (e.g., a viral antigen) are provided, comprising immunizing a mouse with an antigen of interest, wherein the mouse comprises a single human V.sub.H gene segment, a plurality of human D.sub.H gene segments and a plurality of J.sub.H gene segments, at the endogenous immunoglobulin heavy chain locus.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 USC .sctn. 119(e) of U.S. Provisional Application Ser. No. 61/658,459, filed Jun. 12, 2012, U.S. Provisional Application Ser. No. 61/597,969, filed Feb. 13, 2012 and U.S. Provisional Application Ser. No. 61/547,974, filed Oct. 17, 2011, which applications are hereby incorporated by reference in their entirety.

FIELD

[0002] Non-human animals that are genetically engineered at an immunoglobulin heavy chain variable (V) region locus (or in a transgene) to make antibodies from a restricted number of immunoglobulin heavy chain variable (V.sub.H) segments (or a single V.sub.H segment) and/or variants thereof. Non-human animals that have a human heavy chain variable domain derived from a single immunoglobulin heavy chain variable gene segment, e.g., human immunoglobulin V.sub.H1-69 gene segment or human V.sub.H1-2 gene segment. Methods for making antibody sequences in non-human animals that are useful for binding pathogens, including human pathogens.

BACKGROUND

[0003] Non-human animals, e.g., mice, have been genetically engineered to be useful tools in methods for making antibody sequences for use in antibody-based human therapeutics. Mice with humanized variable region loci (e.g., V.sub.H, D.sub.H, and J.sub.H genes, and V.sub.L and J.sub.L genes) are used to generate cognate heavy and light chain variable domains for use in antibody therapeutics. Other mice are available that generate fully human antibodies with cognate heavy and light chains.

[0004] Human antibody therapeutics are engineered based on desired characteristics with respect to certain pre-selected antigens. Humanized mice are immunized with the pre-selected antigens, and the immunized mice are used to generate antibody populations from which to identify high-affinity cognate heavy and light variable domains with desired binding characteristics. Some humanized mice, such as those having a humanization of just variable regions at endogenous mouse loci, generate populations of B cells that are similar in character and number to wild-type mouse B cell populations. As a result, an extremely large and diverse population of B cells is available in these mice from which to screen antibodies, reflecting a large number of different immunoglobulin rearrangements, to identify heavy and light variable domains with the most desirable characteristics.

[0005] But not all antigens provoke an immune response that exhibits a very large number of rearrangements from a wide selection of variable (V) segments. That is, the human humoral immune response to certain antigens is apparently restricted. The restriction is reflected in clonal selection of B cells that express only certain V segments that bind that particular antigen with sufficiently high affinity and specificity. Some such antigens are clinically significant, i.e., a number are well-known human pathogens. A presumption arises that the V segment expressed in the human immune response is a V segment that, in combination with a human D and a human J segment, is more likely to generate a useful high affinity antibody than a randomly selected V segment that has not been observed in a human antibody response to that antigen.

[0006] It is hypothesized that natural selection, over millennia, has selected the most efficient foundation or base from which to design a most effective weapon for neutralizing human pathogens--a clonally selected V segment. There is a need in the art for more and superior antibodies that bind and/or neutralize antigens such as the pathogens discussed above. There is a need to more rapidly generate useful sequences from selected V segments, including polymorphic and/or somatically mutated selected V segments and to more rapidly generate useful populations of B cells having rearrangements of the V segments with various D and J segments, including somatically mutated versions thereof, and in particular rearrangements with unique and useful CDR3s. There is a need for biological systems, e.g., non-human animals (such as, e.g., mice, rats, rabbits, etc.) that can generate therapeutically useful antibody variable region sequences from pre-selected V segments in increased number and diversity than, e.g., can be achieved in existing modified animals. There is a need for biological systems engineered to have a committed humoral immune system for clonally selecting antibody variable sequences derived from restricted, pre-selected V segments, including but not limited to cognate human heavy and light chain variable domains, useful in the manufacture of human antibody-based therapeutics against selected antigens, including certain human pathogens.

[0007] There is a need in the art for therapeutic antibodies that are capable of neutralizing viral antigens, e.g., HIV and HCV, including antigen-specific antibodies containing heavy chains derived from a single human variable segment, and for a system that produces a diverse source of antibodies from which to select therapeutic antibody sequences. There is also a need for further methods and non-human animals for making useful antibodies, including antibodies that comprise a repertoire of heavy chains derived from a single human V.sub.H segment and having a diverse set of CDR sequences, and including such heavy chains that express with cognate human light chain variable domains. Methods are needed for selecting CDRs for immunoglobulin-based binding proteins that provide an enhanced diversity of binding proteins from which to choose, and enhanced diversity of immunoglobulin variable domains, including compositions and methods for generating somatically mutated and clonally selected immunoglobulin variable domains for use, e.g., in making human therapeutics.

SUMMARY

[0008] Genetically modified immunoglobulin loci are provided that comprise a restricted number of different heavy chain variable region gene segments (i.e., V genes, V.sub.H genes, V.sub.H gene segments, or V gene segments), e.g., no more than one, two, or three different V genes; or no more than one V gene segment family member present, e.g., in a single copy or in multiple copies and/or comprising one or more polymorphisms.

[0009] Loci are provided that are capable of rearranging and forming a gene encoding a heavy chain variable domain that is derived from a V.sub.H gene repertoire that is restricted, e.g., that is a single V.sub.H gene segment or selected from a plurality of polymorphic variants of the single V.sub.H gene segment. Modified immunoglobulin loci include loci that comprise human immunoglobulin sequences are provided, e.g., a human V segment operably linked to a human or (or human/non-human chimeric) non-human immunoglobulin constant sequence (and in operable linkage with, e.g., a D and/or a J segment). Modified loci that comprise multiple copies of a single V.sub.H gene segment, including wherein one or more of the copies comprises a polymorphic variant, are provided. Modified loci that comprise multiple copies of a single V.sub.H segment, operably linked with one or more D segments and one or more J segments, operably linked to a non-human immunoglobulin constant sequence, e.g., a mouse or rat sequence, are provided. Non-human animals comprising such humanized loci are also provided.

[0010] Non-human animals are provided that have a reduced immunoglobulin heavy chain variable gene segment complexity (i.e., a limited number of heavy chain variable gene segments, or a limited heavy chain variable gene repertoire), wherein the reduced immunoglobulin heavy chain variable gene segment complexity is characterized by the presence of no more than one or no more than two heavy chain variable gene segments, and wherein the heavy chain variable genes present are operably linked to a human or non-human constant region sequence.

[0011] Non-human animals are provided that have a reduced immunoglobulin heavy chain variable gene segment complexity (e.g., a single V.sub.H gene segment, or a limited number of V.sub.H gene segments that are polymorphic variants of a single V.sub.H gene segment), wherein the reduced immunoglobulin heavy chain variable gene segment complexity is characterized by the presence of a single V.sub.H gene segment or a plurality of V.sub.H gene segments that are polymorphic forms of a single V.sub.H gene segment (e.g., V.sub.H gene segments associated with high copy number and/or polymorphism in humans), and wherein the heavy chain variable genes present are operably linked to a human or non-human constant region sequence. In various embodiments, the heavy chain variable genes present are operably linked to one or more D and/or one or more J gene segments in the germline of the non-human animal.

[0012] Non-human animals are provided that comprise an immunoglobulin heavy chain variable locus (e.g., on a transgene or as an insertion or replacement at an endogenous non-human animal heavy chain variable locus) that comprises a single V.sub.H segment operably linked to a D and/or J gene segment. In various embodiments, the single V.sub.H gene segment is operably linked to one or more D and/or one or more J gene segments at the endogenous immunoglobulin heavy chain variable gene locus of the non-human animal.

[0013] Non-human animals are provided that are modified at their immunoglobulin heavy chain variable region loci to delete all or substantially all (e.g., all functional segments, or nearly all functional segments) endogenous immunoglobulin V.sub.H segments and that comprise a human V.sub.H1-69 segment (or a human V.sub.H1-2 segment) operably linked to a D and J segment or a J segment at the endogenous immunoglobulin heavy chain variable region locus of the non-human animal.

[0014] Non-human animals are also provided that are modified at their immunoglobulin heavy chain variable region loci to render the endogenous variable region loci incapable of rearranging to form a functional heavy chain comprising endogenous variable region gene segments; wherein the non-human animals comprise a single human variable gene segment (a human V.sub.H1-2 or a human V.sub.H1-69 gene segment) operably linked to a D and a J segment or a J segment at the endogenous immunoglobulin heavy chain variable region locus of the non-human animal.

[0015] Non-human animals are provided that comprise a restricted number (e.g., no more than one, or no more than two) of heavy chain gene segments operably linked to a human or non-human constant region sequence. In one embodiment, the no more than one or no more than two heavy chain gene segments linked to the constant region sequence are on a transgene, e.g., are at a position other than an endogenous heavy chain locus.

[0016] Methods are provided for making human immunoglobulin sequences in non-human animals. In various embodiments, the human immunoglobulin sequences are derived from a repertoire of immunoglobulin V sequences that consist essentially of a single human V segment, e.g., V.sub.H1-69 or V.sub.H1-2, and one or more D and J segments or one or more J segments. Methods for making human immunoglobulin sequences in non-human animals, tissues, and cells are provided, wherein the human immunoglobulin sequences bind a pathogen.

[0017] Methods are provided for making mice characterized by a restricted immunoglobulin heavy chain locus, wherein the restriction is with respect to the number of immunoglobulin V.sub.H gene segments. In various aspects, the restriction is to one or no more than two, or a single V.sub.H gene family member (e.g., one or more V.sub.H alleles, variants, or polymorphic variants thereof). In various aspects, the heavy chain locus further comprises one or more D.sub.H gene segments and one or more J.sub.H gene segments. In various aspects, the V.sub.H, D.sub.H and J.sub.H gene segments are human. In various aspects, the V.sub.H, D.sub.H and J.sub.H gene segments are operably linked to a non-human constant region (e.g., an IgM and/or an IgG). In various aspects, the constant region is a mouse or rat constant region.

[0018] In one aspect, a method for making a mouse having a restricted immunoglobulin heavy chain locus is provided, comprising introducing a nucleic acid construct as described herein into a mouse embryonic stem (ES) cell, and isolating or identifying a mouse ES cell that comprises the nucleic acid construct.

[0019] In one embodiment, the nucleic acid construct comprises a single human V.sub.H gene segment, one or more human D.sub.H gene segments, and one or more human J.sub.H gene segments. In one embodiment, the nucleic acid construct comprises one or more site-specific recombination sites (e.g., a IoxP or a Frt site).

[0020] In one aspect, a mouse made using a targeting vector, nucleic acid sequence, or cell as described herein is provided. In various embodiments, the targeting vector, nucleic acid sequence or cell comprises a DNA sequence that contains a single human V.sub.H gene segment (or polymorphic variants thereof), one or more human D.sub.H gene segments, and one or more human J.sub.H gene segments operably linked to a non-human constant gene.

[0021] In one aspect, a method for making a mouse comprising a restricted immunoglobulin heavy chain locus is provided, comprising replacing a mouse immunoglobulin heavy chain locus with a human genomic sequence comprising a single human V.sub.H gene segment (or polymorphic variants thereof), one or more human D.sub.H gene segments, and one or more human JH gene segments, wherein the human V.sub.H, D.sub.H and J.sub.H gene segments are capable of rearranging to form a chimeric heavy chain that contains a human variable domain operably linked to a non-human constant region. In one embodiment, the non-human constant region is a mouse or rat constant region.

[0022] In various aspects, the non-human animals are rodents. In various aspects, the rodents are mice and/or rats.

[0023] In one aspect, a modified immunoglobulin heavy chain locus is provided that comprises a heavy chain V segment repertoire that is restricted with respect to the identity of the V segment, and that comprises one or more D segments and one or more J segments, or one or more J segments. In one embodiment, the heavy chain V segment is a human segment. In one embodiment, the one or more D segments are human D segments. In one embodiment, the one or more J segments are human J segments. In one embodiment, the one or more D segments and one or more J segments are human D and human J segments.

[0024] In one embodiment, the modified locus is a non-human locus. In one embodiment, the non-human locus is modified with at least one human immunoglobulin sequence.

[0025] In one embodiment, the restriction is to one V segment family member. In one embodiment, the one V segment family member is present in two or more copies. In one embodiment, the one V segment family member is present as two or more variants (e.g., two or more polymorphic forms of the V segment family member). In one embodiment, the one V segment is a human V segment family member. In one embodiment, the one V segment family member is present in a number of variants as is observed in the human population with respect to that variant. In one embodiment, the V segment family member is selected from Table 1. In one embodiment, the V segment family member is present in a number of variants as shown, for each V segment, in a number of alleles from 1 allele to the number of alleles shown in the right column of Table 1.

[0026] In one embodiment, the restriction is to a human V.sub.H1-69 gene segment. In one embodiment, the human V.sub.H1-69 gene segment is present in two or more copies. In one embodiment, the human V.sub.H1-69 gene segment is present as two or more variants (e.g., two or more polymorphic forms the human V.sub.H1-69 gene). In one embodiment, the human V.sub.H1-69 gene segment is present in a number of variants as is observed in the human population with respect to the human V.sub.H1-69 gene segment. In one embodiment, the human V.sub.H1-69 gene segment is selected from Table 2. In one embodiment, the human V.sub.H1-69 gene segment is present in a number of variants as shown, for each V.sub.H1-69 gene segment, in a number of alleles from one allele to the number of alleles shown in Table 2.

[0027] In one embodiment, the restriction is to a human V.sub.H1-2 gene segment. In one embodiment, the human V.sub.H1-2 gene segment is present in two or more copies. In one embodiment, the human V.sub.H1-2 gene segment is present as two or more variants (e.g., two or more polymorphic forms the human V.sub.H1-2 gene). In one embodiment, the human V.sub.H1-2 gene segment is present in a number of variants as is observed in the human population with respect to the human V.sub.H1-2 gene segment. In one embodiment, the human V.sub.H1-2 gene segment is selected from Table 3. In one embodiment, the human V.sub.H1-2 gene segment is present in a number of variants as shown, for each V.sub.H1-2 gene segment, in a number of alleles from one allele to the number of alleles shown in Table 3.

[0028] In one aspect, a heavy chain immunoglobulin locus is provided that comprises a single functional human V segment. In one embodiment, the single functional human V segment is selected from a V.sub.H1-2, V.sub.H1-3, V.sub.H1-8, V.sub.H1-18, V.sub.H1-24, V.sub.H1-45, V.sub.H1-46, V.sub.H1-58, V.sub.H1-69, V.sub.H2-5, V.sub.H2-26, V.sub.H2-70, V.sub.H3-7, V.sub.H3-9, V.sub.H3-11, V.sub.H3-13, V.sub.H3-15, V.sub.H3-16, V.sub.H3-20, V.sub.H3-21, V.sub.H3-23, V.sub.H3-30, V.sub.H3-30-3, V.sub.H3-30-5, V.sub.H3-33, V.sub.H3-35, V.sub.H3-38, V.sub.H3-43, V.sub.H3-48, V.sub.H3-49, V.sub.H3-53, V.sub.H3-64, V.sub.H3-66, V.sub.H3-72, V.sub.H3-73, V.sub.H3-74, V.sub.H4-4, V.sub.H4-28, V.sub.H4-30-1, V.sub.H4-30-2, V.sub.H4-30-4, V.sub.H4-31, V.sub.H4-34, V.sub.H4-39, V.sub.H4-59, V.sub.H4-61, V.sub.H5-51, V.sub.H6-1, V.sub.H7-4-1, and a V.sub.H7-81 segment.

[0029] In one embodiment, the single functional human V segment is a V.sub.H1-69 segment; in a specific embodiment, the single functional human V segment is present in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 polymorphic forms found in the human population. In one embodiment, the single functional human V segment is a V.sub.H1-2 segment; in a specific embodiment, the single functional human V segment is present in 1, 2, 3, 4, or 5 polymorphic forms found in the human population.

[0030] In one embodiment, the heavy chain immunoglobulin locus is a modified locus of a non-human animal. In one embodiment, the modified non-human immunoglobulin heavy chain locus is present in the non-human animal at a position in the genome in which the corresponding unmodified non-human locus is found in the wild-type non-human animal. In one embodiment, the modified non-human immunoglobulin heavy chain locus is present on a transgene in a non-human animal.

[0031] In one embodiment, the single functional human V gene segment is a V.sub.H1-69 gene segment. In one embodiment, the V.sub.H1-69 gene segment comprises SEQ ID NO: 34. In one embodiment, the V.sub.H1-69 gene segment is derived from SEQ ID NO: 34. In one embodiment, the V.sub.H1-69 gene segment is at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical to SEQ ID NO: 34.

[0032] In one embodiment, the single functional human V gene segment is encoded by the nucleotide sequence of SEQ ID NO: 34.

[0033] In one embodiment, the single functional human V gene segment is a V.sub.H1-2 gene segment. In one embodiment, the V.sub.H1-2 gene segment comprises SEQ ID NO: 60. In one embodiment, the V.sub.H1-2 gene segment is derived from SEQ ID NO: 60. In one embodiment, the V.sub.H1-2 gene segment is at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical to SEQ ID NO: 60.

[0034] In one embodiment, the single functional human V gene segment is encoded by the nucleotide sequence of SEQ ID NO: 60.

[0035] In one embodiment, the single functional human V segment is operably linked to one or more D segments and one or more J segments, or one or more J segments. In one embodiment, the V segment and one or more D and/or J segments are operably linked to an immunoglobulin heavy chain constant region sequence. In one embodiment the immunoglobulin heavy chain constant region sequence is selected from a C.sub.H1, a hinge, a C.sub.H2, a C.sub.H3 sequence, and a combination thereof. In one embodiment, the C.sub.H1, hinge, C.sub.H2, C.sub.H3, or combination thereof are each non-human endogenous constant sequences. In one embodiment, at least one of the C.sub.H1, hinge, C.sub.H2, C.sub.H3, or combination thereof is a human sequence. In a specific embodiment, the C.sub.H1 and/or hinge are human sequences.

[0036] In one aspect, a modified endogenous non-human immunoglobulin heavy chain locus is provided, comprising a replacement of all functional V gene segments with a single human V gene segment (or a single human V gene segment present in multiple polymorphic forms or copy number), wherein the non-human immunoglobulin heavy chain locus is incapable of rearrangement to form a heavy chain variable gene that is derived from a V gene segment other than the single human V gene segment (or one of the polymorphic forms or copies).

[0037] In one embodiment, the single human V gene segment is V.sub.H1-69. In one embodiment, the single human V gene segment is V.sub.H1-2.

[0038] In one embodiment, the locus comprises at least one human or non-human D.sub.H gene segment, and one human or non-human J.sub.H gene segment. In a specific embodiment, the locus comprises a human D.sub.H gene segment and a human J.sub.H gene segment. In a specific embodiment, the locus comprises a human J.sub.H gene segment. In another specific embodiment, the locus comprises a human V.sub.H1-69 gene segment (present as a single copy or multiple copies of different polymorphic variants), all functional human D.sub.H gene segments, and all functional human J.sub.H gene segments. In another specific embodiment, the locus comprises a human V.sub.H1-2 gene segment (present as a single copy or multiple copies of different polymorphic forms), all functional human D.sub.H gene segments, and all functional human J.sub.H gene segments. In one embodiment, the human V, D, and J gene segments (or V and J gene segments) are operably linked to a mouse constant region gene at an endogenous mouse heavy chain locus. In a specific embodiment, the mouse heavy chain locus comprises a wild-type repertoire of mouse immunoglobulin constant region sequences.

[0039] In one aspect, a genetically modified non-human animal is provided, wherein the only functional immunoglobulin heavy chain V gene segment of the non-human animal is selected from a human V.sub.H1-2, V.sub.H1-3, V.sub.H1-8, V.sub.H1-18, V.sub.H1-24, V.sub.H1-45, V.sub.H1-46, V.sub.H1-58, V.sub.H1-69, V.sub.H2-5, V.sub.H2-26, V.sub.H2-70, V.sub.H3-7, V.sub.H3-9, V.sub.H3-11, V.sub.H3-13, V.sub.H3-15, V.sub.H3-16, V.sub.H3-20, V.sub.H3-21, V.sub.H3-23, V.sub.H3-30, V.sub.H3-30-3, V.sub.H3-30-5, V.sub.H3-33, V.sub.H3-35, V.sub.H3-38, V.sub.H3-43, V.sub.H3-48, V.sub.H3-49, V.sub.H3-53, V.sub.H3-64, V.sub.H3-66, V.sub.H3-72, V.sub.H3-73, V.sub.H3-74, V.sub.H4-4, V.sub.H4-28, V.sub.H4-30-1, V.sub.H4-30-2, V.sub.H4-30-4, V.sub.H4-31, V.sub.H4-34, V.sub.H4-39, V.sub.H4-59, V.sub.H4-61, V.sub.H5-51, V.sub.H6-1, V.sub.H7-4-1, and V.sub.H7-81 gene segment. In one embodiment, the heavy chain V gene segment is a human V.sub.H1-69 gene segment. In one embodiment, the heavy chain V gene segment is a human V.sub.H1-2 gene segment.

[0040] In one aspect, a genetically modified non-human animal is provided, wherein the non-human animal comprises a single functional human V.sub.H gene segment (present as a single copy or multiple copies of different polymorphic forms), and wherein the non-human animal is substantially incapable of forming a rearranged immunoglobulin heavy chain variable domain gene that lacks the single functional human V.sub.H gene segment (or one of the polymorphic forms or copies).

[0041] In one aspect, a genetically modified non-human animal is provided, wherein the only immunoglobulin heavy chain variable region expressed in the non-human animal is derived from one of a human segment selected from a human V.sub.H1-2, V.sub.H1-3, V.sub.H1-8, V.sub.H1-18, V.sub.H1-24, V.sub.H1-45, V.sub.H1-46, V.sub.H1-58, V.sub.H1-69, V.sub.H2-5, V.sub.H2-26, V.sub.H2-70, V.sub.H3-7, V.sub.H3- 9, V.sub.H3-11, V.sub.H3-13, V.sub.H3-15, V.sub.H3-16, V.sub.H3-20, V.sub.H3-21, V.sub.H3-23, V.sub.H3-30, V.sub.H3-30-3, V.sub.H3-30-5, V.sub.H3-33, V.sub.H3-35, V.sub.H3-38, V.sub.H3-43, V.sub.H3-48, V.sub.H3-49, V.sub.H3-53, V.sub.H3-64, V.sub.H3-66, V.sub.H3-72, V.sub.H3-73, V.sub.H3-74, V.sub.H4-4, V.sub.H4-28, V.sub.H4-30-1, V.sub.H4-30-2, V.sub.H4-30-4, V.sub.H4-31, V.sub.H4-34, V.sub.H4-39, V.sub.H4-59, V.sub.H4-61, V.sub.H5-51, V.sub.H6-1, V.sub.H7-4-1, and V.sub.H7-81 gene segment. In one embodiment, the human segment is a V.sub.H1-69 segment. In one embodiment, the human segment is a V.sub.H1-2 segment. In one embodiment, the only immunoglobulin heavy chain variable region expressed by the mouse is derived from a single V segment family member, and in one embodiment the only immunoglobulin heavy chain variable region is derived from a polymorphic variant of the single V segment family member.

[0042] In one aspect, a non-human animal comprising a restricted immunoglobulin heavy chain V gene segment repertoire is provided, wherein the non-human animal further comprises one or more human immunoglobulin .kappa. light chain variable segments (V.sub..kappa.). In one embodiment, the one or more V.sub..kappa. segments are operably linked to one or more human J segments. In a specific embodiment, the J segments are human J.sub..kappa. segments. In another specific embodiment, the non-human animal does not express an immunoglobulin .lamda. light chain. In another specific embodiment, the non-human animal does not comprise a functional human or functional endogenous immunoglobulin .lamda. light chain variable locus.

[0043] In one embodiment, the non-human animal is a rodent. In one embodiment, the rodent is a mouse.

[0044] In one embodiment, the non-human animal comprises a replacement at the endogenous non-human immunoglobulin V.sub..kappa. locus of all or substantially all functional endogenous V.sub..kappa. segments with one or more functional human V.sub..kappa. segments. In a further specific embodiment, the replacement is with all or substantially all functional human immunoglobulin V.sub..kappa. segments.

[0045] In one embodiment, the non-human animal comprises a replacement at the endogenous non-human immunoglobulin V.sub..kappa. locus of all or substantially all functional endogenous V.sub..kappa. gene segments with human V.sub..kappa. gene segments selected from V.sub..kappa.4-1, V.sub..kappa.5-2, V.sub..kappa.7-3, V.sub..kappa.2-4, V.sub..kappa.1-5, V.sub..kappa.1-6, V.sub..kappa.3-7, V.sub..kappa.1-8, V.sub..kappa.1-9, V.sub..kappa.2-10, V.sub..kappa.3-11, V.sub..kappa.1-12, V.sub..kappa.1-13, V.sub..kappa.2-14, V.sub..kappa.3-15, V.sub..kappa.1-16, V.sub..kappa.1-17, V.sub..kappa.2-18, V.sub..kappa.2-19, V.sub..kappa.3-20, V.sub..kappa.6-21, V.sub..kappa.1-22, V.sub..kappa.1-23, V.sub..kappa.2-24, V.sub..kappa.3-25, V.sub..kappa.2-26, V.sub..kappa.1-27, V.sub..kappa.2-28, V.sub..kappa.2-29, V.sub..kappa.2-30, V.sub..kappa.3-31, V.sub..kappa.1-32, V.sub..kappa.1-33, V.sub..kappa.3-34, V.sub..kappa.1-35, V.sub..kappa.2-36, V.sub..kappa.1-37, V.sub..kappa.2-38, V.sub..kappa.1-39, V.sub..kappa.2-40, and a combination thereof.

[0046] In one embodiment, the non-human animal comprises a replacement at the endogenous non-human immunoglobulin J.sub..kappa. locus of all or substantially all functional endogenous non-human immunoglobulin J.sub..kappa. segments with one or more functional human immunoglobulin J.sub..kappa. segments. In a further specific embodiment, the replacement is with all or substantially all functional human immunoglobulin J.sub..kappa. segments.

[0047] In one embodiment, the non-human animal comprises a replacement at the endogenous non-human immunoglobulin J.sub..kappa. locus of all or substantially all functional endogenous non-human immunoglobulin J.sub..kappa. gene segments with human J.sub..kappa. gene segments selected from J.sub..kappa.1, J.sub..kappa.2, J.sub..kappa.3, J.sub..kappa.4, J.sub..kappa.5, and a combination thereof.

[0048] In a specific embodiment, the non-human animal comprises an immunoglobulin heavy chain variable region locus that comprises a repertoire of V segments consisting essentially of a single V segment and/or polymorphic variants thereof. In one embodiment, the single immunoglobulin heavy chain V segment is a human V.sub.H1-69 segment, and the non-human animal further comprises a replacement of all functional non-human D.sub.H segments with all functional human D.sub.H segments, and further comprises a replacement of all functional non-human J.sub.H segments with all functional human J.sub.H segments, and wherein the immunoglobulin heavy chain variable region locus is operably linked to a human or non-human constant region gene sequence. In a specific embodiment, the constant region gene sequence is an endogenous non-human constant region gene sequence. In a specific embodiment, the non-human animal rearranges segments at the non-human immunoglobulin heavy chain locus to form a gene encoding heavy chain variable region comprising a human V.sub.H1-69 sequence, a human D.sub.H sequence, a human J.sub.H sequence, and a mouse constant region sequence.

[0049] In a specific embodiment, the non-human animal comprises an immunoglobulin heavy chain variable region locus that comprises a repertoire of V segments consisting essentially of a single V segment and/or polymorphic variants thereof. In one embodiment, the single immunoglobulin heavy chain V segment is a human V.sub.H1-2 segment, and the non-human animal further comprises a replacement of all functional non-human D.sub.H segments with all functional human D.sub.H segments, and further comprises a replacement of all functional non-human J.sub.H segments with all functional human J.sub.H segments, and wherein the immunoglobulin heavy chain variable region locus is operably linked to a human or non-human constant region gene sequence. In a specific embodiment, the constant region gene sequence is an endogenous non-human constant region gene sequence. In a specific embodiment, the non-human animal rearranges segments at the non-human immunoglobulin heavy chain locus to form a gene encoding heavy chain variable region comprising a human V.sub.H1-2 sequence, a human D.sub.H sequence, a human J.sub.H sequence, and a mouse constant region sequence.

[0050] In one embodiment, a B cell is provided that comprises the rearranged gene. In a specific embodiment, the B cell is from a mouse as described that has been immunized with an antigen of interest, and the B cell encodes an antibody that specifically binds the antigen of interest. In one embodiment, the antigen of interest is a pathogen. In a specific embodiment, the pathogen is selected from an influenza virus, a hepatitis virus (e.g., hepatitis B or hepatitis C virus), and a human immunodeficiency virus. In a specific embodiment, the B cell encodes a somatically mutated, high affinity (e.g., about 10.sup.-9 K.sub.D or lower) antibody comprising a human light chain variable region (e.g., a human K light chain variable region) that specifically binds the antigen of interest.

[0051] In one aspect, a non-human animal comprising a restricted immunoglobulin heavy chain V segment repertoire is provided, wherein the non-human animal comprises one or more human .lamda. light chain variable (V.sub..lamda.) segments. In one embodiment, the one or more human V.sub..lamda. segments are operably linked to one or more human J segments. In a specific embodiment, the J segments are human J.sub..lamda. segments. In another specific embodiment, the non-human animal does not express a .kappa. light chain. In another specific embodiment, the non-human animal does not comprise a functional human or non-human .kappa. light chain variable locus.

[0052] In one embodiment, the non-human animal comprises a replacement of all or substantially all functional non-human immunoglobulin V.sub..lamda. segments with one or more functional human immunoglobulin V.sub..lamda. segments. In a further specific embodiment, the replacement is with all or substantially all functional human immunoglobulin V.sub..lamda. segments.

[0053] In one embodiment, the non-human animal comprises a replacement of all or substantially all functional non-human V.sub..lamda. segments with a fragment of cluster A of the human .lamda. light chain locus. In a specific embodiment, the fragment of cluster A of the human .lamda. light chain locus comprises human V.sub..lamda. gene segments V.sub..lamda.3-27 through V.sub..lamda.3-1.

[0054] In one embodiment, the non-human animal comprises a replacement of all or substantially all functional non-human V.sub..lamda. segments with a fragment of cluster B of the human .lamda. light chain locus. In a specific embodiment, the fragment of cluster B of the human .lamda. light chain locus comprises human V.sub..lamda. gene segments V.sub..lamda.5-52 through V.sub..lamda.1-40.

[0055] In one embodiment, the non-human animal comprises a replacement of all or substantially all functional non-human V.sub..lamda. segments with a fragment of cluster A and a fragment of cluster B of the human .lamda. light chain locus, wherein as a result of the replacement comprise human V.sub..lamda. gene segments V.sub..lamda.5-52 through V.sub..lamda.3-1.

[0056] In one embodiment, the non-human animal comprises a replacement of all or substantially all functional non-human V.sub..lamda. segments with at least 12 human V.sub..lamda. gene segments, at least 28 human V.sub..lamda. gene segments, or at least 40 human V.sub..lamda. gene segments.

[0057] In one embodiment, the non-human animal comprises a replacement of all or substantially all functional non-human immunoglobulin J.sub..lamda. gene segments with one or more functional human immunoglobulin J.sub..lamda. gene segments. In a further specific embodiment, the replacement is with all or substantially all functional human immunoglobulin J.sub..lamda. gene segments. In various embodiments, the functional human J.sub..lamda. gene segments include J.sub..lamda.1, J.sub..lamda.2, J.sub..lamda.3 and J.sub..lamda.7.

[0058] In a specific embodiment, the non-human animal comprises an immunoglobulin heavy chain variable (V.sub.H) region locus that comprises only a single V.sub.H segment, wherein the single V.sub.H segment is a human V.sub.H1-69 segment or a human V.sub.H1-2 segment, and further comprises a replacement of all functional non-human D.sub.H segments with all functional human D.sub.H segments, and further comprises a replacement of all functional non-human J.sub.H segments with all functional human J.sub.H segments, and wherein the V.sub.H region locus is operably linked to a human or non-human constant region gene sequence. In a specific embodiment, the constant region gene sequence is a non-human constant region gene sequence, e.g., an endogenous non-human constant gene sequence. In a specific embodiment, the non-human animal rearranges segments at the non-human immunoglobulin heavy chain locus to form a gene encoding an immunoglobulin heavy chain variable region comprising a human V.sub.H1-69 sequence (or a human V.sub.H1-2 sequence), a human D.sub.H sequence, a human J.sub.H sequence, and an endogenous non-human constant region sequence.

[0059] In one embodiment, a B cell is provided that comprises the rearranged gene. In a specific embodiment, the B cell is from a non-human animal as described that has been immunized with an antigen of interest, and the B cell encodes an antibody that specifically binds the antigen of interest. In one embodiment, the antigen is a human protein selected from a ligand, a cell surface receptor and an intracellular protein. In one embodiment, the antigen of interest is a pathogen. In a specific embodiment, the pathogen is selected from an influenza virus, a hepatitis virus (e.g., hepatitis B or hepatitis C virus), and a human immunodeficiency virus. In a specific embodiment, the B cell encodes a somatically mutated, high affinity (e.g., about 10.sup.<9 K.sub.D or lower) antibody comprising a human light chain variable region (e.g., a human .lamda. light chain variable region) that specifically binds the antigen of interest.

[0060] In one aspect, a non-human animal comprising a restricted immunoglobulin V.sub.H segment repertoire is provided, wherein the non-human animal comprises a human V.sub.H1-69 segment (or a human V.sub.H1-2 segment) on a transgene, wherein the human V.sub.H1-69 segment is operably linked on the transgene to a human or non-human D.sub.H segment, and/or a human or non-human J segment, and the transgene further comprises a human or non-human constant region gene, or a chimeric human/non-human constant region (e.g., a C.sub.H1, hinge, C.sub.H2, C.sub.H3 or combination thereof wherein at least one sequence is non-human, e.g., selected from hinge, C.sub.H2, and C.sub.H3 and/or hinge). In one embodiment, the non-human animal is a mouse or rat and the non-human D, J, and/or constant region gene is a mouse or rat gene or chimeric human/mouse or rat.

[0061] In one embodiment, the non-human animal comprises a transgene that comprises an immunoglobulin light chain variable region locus that comprises one or more human immunoglobulin V.sub..lamda. gene segments and J.sub..lamda. gene segments, or one or more human immunoglobulin V.sub..kappa. gene segments and J.sub..kappa. gene segments, and a human immunoglobulin .kappa. or .lamda. light chain constant region gene, such that the transgene rearranges in the non-human animal to form a rearranged immunoglobulin .kappa. or .lamda. light chain gene. In various embodiments, the human V.sub..kappa. and J.sub..kappa. gene segments are those described herein. In various embodiments, the human V.sub..lamda. and J.sub..lamda. gene segments are those described herein.

[0062] In a specific embodiment, the non-human animal comprises a transgene having an immunoglobulin heavy chain variable locus that comprises a single V segment that is a human V.sub.H1-69 segment (or a human V.sub.H1-2 segment), one or more human D segments, one or more human J segments, and a human constant gene operably linked to the heavy chain variable locus, such that the mouse expresses from the transgene a fully human antibody derived from the V.sub.H1-69 segment (or the V.sub.H1-2 segment). In one embodiment, the non-human animal does not comprise a functional endogenous immunoglobulin heavy chain variable region locus. In a specific embodiment, the non-human animal comprises a nonfunctional endogenous immunoglobulin heavy chain variable region locus that comprises a deletion of an endogenous non-human D.sub.H and/or endogenous non-human J.sub.H segment, such that the non-human animal is incapable of rearranging the endogenous immunoglobulin heavy chain variable region locus to form a rearranged non-human antibody gene. In a specific embodiment, the non-human animal comprises a deletion of a switch sequence operably linked to an endogenous mouse heavy chain constant region. In a specific embodiment, the switch sequence is a non-human (e.g., mouse) .mu. switch sequence. In another embodiment, the non-human animal further comprises a lack of a functional endogenous light chain variable locus selected from an immunoglobulin .kappa. locus and an immunoglobulin .lamda. locus. In a specific embodiment, the non-human animal comprises a deletion of a J.sub..kappa. and/or a J.sub..lamda. sequence, such that the non-human animal is incapable of rearranging an endogenous non-human immunoglobulin .kappa. light chain and/or an endogenous non-human immunoglobulin .lamda. light chain variable region to form a rearranged endogenous non-human immunoglobulin .kappa. light chain and/or a rearranged endogenous non-human immunoglobulin .lamda. light chain gene.

[0063] In one embodiment, the non-human animal comprises a deletion of an endogenous non-human immunoglobulin .kappa. light chain sequence that results in a functional knockout of the endogenous non-human immunoglobulin .kappa. light chain. In one embodiment, the non-human animal comprises a deletion of an endogenous non-human immunoglobulin .lamda. light chain sequence that results in a functional knockout of the endogenous non-human immunoglobulin .lamda. light chain.

[0064] In one aspect, the non-human animal comprises a functionally silenced endogenous immunoglobulin heavy chain variable gene locus, and comprises a restricted repertoire of human heavy chain variable gene segments (e.g., no more than one, or no more than two). In one embodiment, the functional silencing comprises a modification of an endogenous non-human heavy chain variable gene locus selected from a deletion, an insertion, an inversion, and a combination thereof.

[0065] In one aspect, a rodent is provided that comprises an immunoglobulin V.sub.H repertoire derived from no more than one human V.sub.H segment or one or more polymorphs thereof, from a D segment selected from a repertoire of one or more D segments, and from a J segment derived from a repertoire of one or more J segments. In one embodiment, the rodent rearranges the human V.sub.H segment, a human D segment, and a human J segment and forms a rearranged human heavy chain sequence that is operably linked to a human or a rodent constant region sequence. In one embodiment, the human and/or rodent constant region sequence is selected from a C.sub.H1, a hinge, a C.sub.H2, a C.sub.H3, and a combination thereof. In one embodiment, the rodent expresses an immunoglobulin light chain that comprises a human variable domain, wherein the light chain is cognate with a human heavy chain domain derived from the rearranged human heavy chain sequence. In one embodiment, the rodent does not express a polypeptide sequence selected from a non-human heavy chain variable domain, a non-human light chain variable domain, and a combination thereof.

[0066] In one embodiment, the human V.sub.H segment is present in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 or more polymorphic variants, wherein each polymorphic variant is operably linked to a D and/or J segment such that each polymorphic variant is capable for rearranging and forming a rearranged heavy chain variable domain with any of the one or more D segments and any of the one or more J segments. In one embodiment, the rodent is a mouse or a rat. In one embodiment, the repertoire of D segments comprises two or more D segments. In one embodiment, the repertoire of J segments comprises two or more J segments. In one embodiment, the D and/or J segments are human segments.

[0067] In one aspect, a nucleic acid construct is provided that comprises a sequence encoding a single human immunoglobulin V.sub.H segment and/or polymorphic variants thereof and one or more D.sub.H and one or more J sequences, wherein the construct comprises at least one homology arm homologous to a non-human immunoglobulin heavy chain variable locus, or a recombinase recognition site (e.g., a lox site). In one embodiment, the V segment is a V.sub.H1-69 segment or a V.sub.H1-2 segment.

[0068] In one aspect, a nucleic acid construct is provided; comprising a nucleic acid sequence encoding a single human immunoglobulin heavy chain V segment, wherein the single V.sub.H segment is a V.sub.H1-69 (or V.sub.H1-2) segment. In one embodiment, the construct comprises a site-specific recombinase recognition site. In one embodiment, the construct comprises a first mouse homology arm upstream of the V.sub.H1-69 (or V.sub.H1-2) segment and a second mouse homology arm downstream of the V.sub.H1-69 (or V.sub.H1-2) segment, and wherein the first mouse homology arm is homologous to a region of a mouse chromosome immediately upstream of a mouse immunoglobulin heavy chain variable region but not including a functional mouse immunoglobulin heavy chain variable segment. In one embodiment, the construct comprises SEQ ID NO: 3. In one embodiment, the construct comprises SEQ ID NO: 70.

[0069] In one aspect, the restricted single V.sub.H segment is in a non-human animal, or the restricted V.sub.H segment is at a non-human immunoglobulin heavy chain locus (e.g., in situ or in a transgene), and the non-human animal or non-human immunoglobulin heavy chain locus is selected from a mouse, rat, rabbit, pig, bovine (e.g., cow, bull, buffalo), deer, sheep, goat, chicken, cat, dog, ferret, primate (e.g., marmoset, rhesus monkey) locus or animal. In a specific embodiment, the non-human animal or locus is a mouse or a rat locus.

[0070] In one aspect, a cell or tissue is provided, wherein the cell or tissue is derived from a non-human animal as described herein, and comprises a restricted V.sub.H segment repertoire. In one embodiment, the V.sub.H segment repertoire is restricted to a single V.sub.H segment family member and/or polymorphic variants thereof. In a specific embodiment, the single V.sub.H segment is a human V.sub.H1-69 segment or a human V.sub.H1-2 segment. In one embodiment, the cell or tissue is derived from spleen, lymph node or bone marrow of the non-human animal.

[0071] In one embodiment, the cell is an ES cell. In one embodiment, the cell is a B cell. In one embodiment, the cell is a germ cell.

[0072] In one embodiment, the tissue is selected from connective, muscle, nervous and epithelial tissue. In a specific embodiment, the tissue is reproductive tissue.

[0073] In one embodiment, the cell and/or tissue derived from a mouse as described herein are isolated for use in one or more ex vivo assays. In various embodiments, the one or more ex vivo assays include measurements of physical, thermal, electrical, mechanical or optical properties, a surgical procedure, measurements of interactions of different tissue types, the development of imaging techniques, or a combination thereof.

[0074] In one embodiment, the non-human animal is a mouse.

[0075] In one aspect, a non-human embryo is provided comprising a restricted heavy chain V.sub.H segments as described herein. In one embodiment, the embryo comprises an ES donor cell that comprises the restricted V.sub.H segment, and host embryo cells.

[0076] In one embodiment, the non-human animal is a mouse.

[0077] In one aspect, a non-human cell comprising a chromosome or fragment thereof of a non-human animal as described herein. In one embodiment, the non-human cell comprises a nucleus of a non-human animal as described herein. In one embodiment, the non-human cell comprises the chromosome or fragment thereof as the result of a nuclear transfer.

[0078] In one aspect, a nucleus derived from a non-human animal as described herein is provided. In one embodiment, the nucleus is from a diploid cell that is not a B cell.

[0079] In one aspect, a pluripotent, induced pluripotent, or totipotent cell derived from a non-human animal as described herein is provided. In a specific embodiment, the cell is a mouse embryonic stem (ES) cell.

[0080] In one aspect, a non-human induced pluripotent cell comprising a restricted V.sub.H segment repertoire is provided. In one embodiment, the induced pluripotent cell is derived from a non-human animal as described herein.

[0081] In one aspect, a hybridoma or quadroma is provided, derived from a cell of a non-human animal as described herein. In one embodiment, the non-human animal is a mouse or rat.

[0082] In one aspect, a lymphocyte of a non-human animal as described herein is provided. In one embodiment, the lymphocyte is a B cell.

[0083] In one aspect, mouse cells and mouse embryos are provided, including but not limited to ES cells, pluripotent cells, and induced pluripotent cells, that comprise genetic modifications as described herein. Cells that are XX and cells that are XY are provided. Cells that comprise a nucleus containing a modification as described herein are also provided, e.g., a modification introduced into a cell by pronuclear injection.

[0084] In one aspect, an antibody variable domain sequence made in a non-human animal as described herein is provided.

[0085] In one aspect, a human therapeutic is provided, comprising an antibody variable domain comprising a sequence derived from a non-human animal as described herein.

[0086] In one aspect, a method of obtaining an antibody variable region sequence from a non-human animal is provided, wherein the antibody variable region sequence is derived from a human V.sub.H1-69 segment or a V.sub.H1-2 segment, wherein the method comprises (a) immunizing a non-human animal with an antigen of interest, wherein the non-human animal comprises a replacement at the endogenous immunoglobulin heavy chain locus of all or substantially all non-human variable segments with a single human variable segment, wherein the single human variable segment is a V.sub.H1-69 segment or a V.sub.H1-2 segment, and wherein the non-human animal is substantially incapable of forming a immunoglobulin heavy chain variable region sequence that is not derived from a human V.sub.H1-69 segment or a V.sub.H1-2 segment; (b) allowing the non-human animal to mount an immune response with respect to the antigen of interest; and, (c) identifying or isolating an immunoglobulin heavy chain variable region sequence of the non-human animal, wherein the antibody binds the antigen of interest.

[0087] In one embodiment, the single human variable segment is a V.sub.H1-69 segment.

[0088] In one embodiment, the antibody variable region sequence is derived from SEQ ID NO: 34. In one embodiment, the antibody variable region sequence is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical to SEQ ID NO: 34. In one embodiment, the antibody variable region sequence comprises SEQ ID NO: 34.

[0089] In one embodiment, the single human variable segment is a V.sub.H1-2 segment.

[0090] In one embodiment, the antibody variable region sequence is derived from SEQ ID NO: 60. In one embodiment, the antibody variable region sequence is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical to SEQ ID NO: 60. In one embodiment, the antibody variable region sequence comprises SEQ ID NO: 60.

[0091] In one embodiment, the immune response to the antigen is characterized by an antibody titer that is about 6.times.10.sup.4 to about 5.times.10.sup.5 times greater than two times background as determined in an ELISA assay. In a specific embodiment, the antibody titer is about 1.times.10.sup.5 to about 2.times.10.sup.5 times greater than two times background as determined in an ELISA assay. In a specific embodiment, the antibody titer is about 1.5.times.10.sup.5 times greater than two times background as determined in an ELISA assay. In one embodiment, the antigen is a human cell surface receptor.

[0092] In one aspect, a method for generating a repertoire of human antibody variable regions in a non-human animal is provided, wherein the human heavy chain variable regions of the repertoire are derived from the same V.sub.H gene family member and one of a plurality of D.sub.H segments and one of a plurality of J.sub.H segments, wherein the repertoire is characterized by having heavy chain immunoglobulin FR1 (framework 1), CDR1, FR2, CDR2, and FR3 sequences from a single V.sub.H gene family member. In one embodiment, the repertoire is further characterized by having a plurality of different CDR3+FR4 sequences.

[0093] In one embodiment, the single V.sub.H gene family is selected from V.sub.H family 1, 2, 3, 4, 5, 6, and 7. In a specific embodiment, the single V.sub.H gene family is V.sub.H family 1. In one embodiment, the single V.sub.H gene family member is selected from V.sub.H1-2, V.sub.H1-69, V.sub.H2-26, V.sub.H2-70, and V.sub.H3-23. In a specific embodiment, the single V.sub.H gene family member is V.sub.H1-69. In a specific embodiment, the single V.sub.H gene family member is V.sub.H1-2.

[0094] In one embodiment, the repertoire comprises heavy chain FR1, CDR1, FR2, CDR2 and FR3 sequences derived from a V.sub.H1-69 segment. In a specific embodiment, the repertoire comprises heavy chain FR1, CDR1, FR2, CDR2 and FR3 sequences derived from SEQ ID NO: 35. In a specific embodiment, the repertoire comprises heavy chain FR1, CDR1, FR2, CDR2 and FR3 sequences of SEQ ID NO: 35.

[0095] In one embodiment, the repertoire comprises heavy chain FR1, CDR1, FR2, CDR2 and FR3 sequences derived from a V.sub.H1-2 segment. In a specific embodiment, the repertoire comprises heavy chain FR1, CDR1, FR2, CDR2 and FR3 sequences derived from SEQ ID NO: 61. In a specific embodiment, the repertoire comprises heavy chain FR1, CDR1, FR2, CDR2 and FR3 sequences of SEQ ID NO: 61.

[0096] In one aspect, a biological (i.e., in vivo) system is provided for generating a plurality of different human CDR3 sequences reflecting a plurality of rearrangements of a single human V.sub.H gene segment with a plurality of human D and J segments, wherein the system generates human heavy chain variable domains characterized by having human FR1-CDR1-FR2-CDR2-FR3 sequences that are identical but for somatic hypermutations, wherein the heavy chain variable domains are characterized by being somatically hypermutated and derived from a single human V.sub.H gene segment and a plurality of human D and J segments; wherein the system comprises a genetically modified non-human animal (e.g., a rodent, e.g., a mouse or rat) as described herein.

[0097] In one embodiment, the single human V.sub.H gene segment is selected from V.sub.H1-2, V.sub.H1-69, V.sub.H2-26, V.sub.H2-70, and V.sub.H3-23. In one embodiment, the single human V.sub.H gene segment is V.sub.H1-69. In one embodiment, the single human V.sub.H gene segment is V.sub.H1-2. In one embodiment, the single human V.sub.H gene segment is identified in Table 1. In one embodiment, the single human V.sub.H gene segment is identified in Table 2. In one embodiment, the single human V.sub.H gene segment is identified in Table 3.

[0098] In one aspect, an in vivo method for generating a plurality of heavy chain CDR sequences derived from rearrangements of a single human V.sub.H gene segment with a plurality of human D and J segments is provided, wherein the method generates human heavy chain variable domains characterized by having human FR1-CDR1-FR2-CDR2-FR3 sequences that are identical but for somatic hypermutations, wherein the heavy chain variable domains are characterized by being somatically hypermutated and derived from a single human V.sub.H gene segment and a plurality of human D and J segments; wherein the system comprises a genetically modified non-human animal (e.g., a rodent, e.g., a mouse or rat) as described herein.

[0099] In one embodiment, the method comprises exposing a non-human animal as described herein to an antigen of interest, allowing the non-human animal to develop an immune response to the antigen, wherein the immune response generates the plurality of heavy chain CDR sequences derived from rearrangements of the single human V.sub.H gene segment with one of the human D and one of the human J segments, and identifying a set of heavy chain CDRs that bind the antigen. In one embodiment, the method comprises isolating from the animal a nucleic acid sequence that encodes a human V.sub.H domain that comprises the heavy chain CDRs.

[0100] In one embodiment, the heavy chain CDR sequences are derived from a rearrangement of a human V.sub.H1-69 gene segment. In one embodiment, the heavy chain CDR sequences are derived from a rearrangement of a human V.sub.H1-2 gene segment.

[0101] In one aspect, a method for generating a plurality of different CDR3 and FR4 sequences in a non-human animal is provided, comprising exposing a non-human animal that comprises an immunoglobulin heavy chain variable gene locus with a V.sub.H segment repertoire restricted to a single V.sub.H segment family member to an antigen of interest, allowing the non-human animal to develop an immune response to the antigen, wherein the immune response generates a B cell repertoire whose heavy chain variable domains are each derived from the single V.sub.H segment family member and that comprise a plurality of different CDR3 and FR4 sequences.

[0102] In one embodiment, the singe V.sub.H segment family member is human. In one embodiment, the non-human animal is selected from a mouse, a rat, and a rabbit. In one embodiment, the antigen of interest is selected from a ligand, a receptor, an intracellular protein and a secreted protein. In one embodiment, the antigen of interest is a human pathogen as described herein.

[0103] In one embodiment, the single human V.sub.H gene family member is selected from V.sub.H1-2, V.sub.H1-69, V.sub.H2-26, V.sub.H2-70, and V.sub.H3-23. In one embodiment, the single human V.sub.H gene family member is V.sub.H1-69. In one embodiment, the single human V.sub.H gene family member is V.sub.H1-2. In one embodiment, the single human V.sub.H gene family member is identified in Table 1. In one embodiment, the single human V.sub.H gene family member is identified in Table 2. In one embodiment, the single human V.sub.H gene family member is identified in Table 3.

[0104] In one aspect, a nucleotide sequence encoding an immunoglobulin variable region made in a non-human animal as described herein is provided.

[0105] In one aspect, an immunoglobulin heavy chain or immunoglobulin light chain variable region amino acid sequence of an antibody made in a non-human animal as described herein is provided.

[0106] In one aspect, an immunoglobulin heavy chain or immunoglobulin light chain variable region nucleotide sequence encoding a variable region of an antibody made in a non-human as described herein is provided.

[0107] In one aspect, an antibody or antigen-binding fragment thereof (e.g., Fab, F(ab).sub.2, scFv) made in a non-human animal as described herein is provided.

[0108] In one aspect, a mouse having a restricted immunoglobulin heavy chain locus characterized by the presence of a single human V.sub.H gene segment, one or more human D.sub.H gene segments, and one or more human J.sub.H gene segments is provided, wherein the single human V.sub.H gene segment is at an endogenous mouse locus and the V.sub.H gene segment is operably linked to the one or more human D.sub.H gene segments, the one or more human J.sub.H gene segments, and to an endogenous immunoglobulin heavy chain constant gene.

[0109] In one embodiment, the mouse further comprises a humanized immunoglobulin light chain locus comprising one or more human V.sub.L gene segments, and one or more human J.sub.L gene segments, wherein the human V.sub.L gene segments and the human J.sub.L gene segments are operably linked to a non-human immunoglobulin light chain constant region gene. In a specific embodiment, the human V.sub.L and J.sub.L gene segments are at an endogenous mouse light chain locus, and wherein the non-human immunoglobulin light chain constant region gene is a mouse gene.

[0110] In one embodiment, the humanized immunoglobulin light chain locus is on a transgene, and the constant region gene is selected from mouse, rat, and human.

[0111] In one embodiment, the human V.sub.L and J.sub.L gene segments are V.sub..kappa. and J.sub..kappa. gene segments. In one embodiment, the human V.sub.L and J.sub.L gene segments are V.sub..lamda. and J.sub..lamda. gene segments

[0112] In one aspect, a non-human animal is provided, wherein the non-human animal has a B cell repertoire that expresses immunoglobulin heavy chain variable domains derived from a single V segment family member. In one embodiment, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90, or at least 95% of the B cell repertoire of the non-human animal immunoglobulin heavy chain variable domain expressed in the B cell repertoire is derived from the same V segment family member. In a specific embodiment, the percentage is at least 90%. In one embodiment, the B cell repertoire consists essentially of peripheral (blood) B cells. In one embodiment, the B cell repertoire consists essentially of splenic B cells. In one embodiment, the B cell repertoire consists essentially of bone marrow B cells. In one embodiment, the B cell repertoire consists essentially of peripheral B cells, splenic B cells, and bone marrow B cells.

[0113] In one aspect, a genetically modified non-human animal is provided, wherein more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or more than 90% of the B cells of the non-human animal that express a heavy chain immunoglobulin variable domain express a heavy chain immunoglobulin variable domain derived from a single V.sub.H gene segment family member. In one embodiment, at least 75% of the B cells of the non-human animal that express an immunoglobulin heavy chain variable domain express an immunoglobulin heavy chain variable domain derived from the single V.sub.H gene segment family member. In a specific embodiment, the percentage is at least 90%. In one embodiment, all of the B cells that express a heavy chain domain that is derived from the single V.sub.H gene family member.

[0114] In one aspect, a genetically modified mouse is provided that makes an antigen-specific B cell population in response to immunization with an antigen of interest, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or more than 90%, of said antigen-specific B cell population expresses immunoglobulin heavy chains that are all derived from the same V.sub.H gene segment. In one embodiment, at least 75% of the antigen-specific B cell population expresses immunoglobulin heavy chains derived from the same V.sub.H gene segment. In one embodiment, all of the antigen-specific B cells express a heavy chain that is derived from the same V.sub.H gene segment.

[0115] In one aspect, a non-human animal comprising a restricted V.sub.H gene segment repertoire is provided, wherein the restriction is to a human V.sub.H1-69 gene segment or a V.sub.H1-69 gene segment that is at least about 75.5%, 76.5%, 86.7%, 87.8%, 94.9%, 96.9%, 98%, or 99% identical to a V.sub.H1-69*01 gene segment. In a specific embodiment, the restricted repertoire is selected from one or more of the V.sub.H1-69 variants of FIG. 15.

[0116] In one aspect, a non-human animal comprising a restricted V.sub.H gene segment repertoire is provided, wherein the restriction is to a human V.sub.H1-2 gene segment or a V.sub.H1-2 gene segment that is at least about 94.9%, 95.9%, 96.9%, 98%, or 99% identical to a V.sub.H1-2 gene segment. In a specific embodiment, the restricted repertoire is selected from one or more of the V.sub.H1-2 variants of FIG. 18.

[0117] In one embodiment, the non-human animal is a mouse.

[0118] In one embodiment, the mouse exhibits an immunophenotype having a characteristic of a higher ratio of mature B cells to immature B cells as compared to a wild type mouse. In a specific embodiment, the ratio is calculated from B cells harvested from spleen. In one embodiment, the mouse exhibits a population of mature B cells of about 1.times.10.sup.7. In one embodiment, the mouse exhibits a population of immature B cells of about 0.5.times.10.sup.7. In one embodiment, the mouse exhibits a ratio of mature B cells to immature B cells in the spleen of the mouse that is about 1.5-fold to about 2-fold higher than exhibited by a wild type mouse.

[0119] In one embodiment, the ratio is calculated from B cells harvested from bone marrow. In a specific embodiment, the mouse exhibits a population of mature B cells of about 3.times.10.sup.5. In one embodiment, the mouse exhibits a population of immature B cells of about 7.times.10.sup.5. In one embodiment, the mouse exhibits a ratio of mature B cells to immature B cells in the bone marrow of the mouse that is about 3-fold, or about 3.3-fold higher than exhibited by a wild type mouse.

[0120] In one embodiment, the mouse exhibits an immunophenotype having a characteristic of a higher number of pro B cells in the bone marrow as compared to a wild type mouse. In a specific embodiment, the mouse exhibits a population of pro B cells in the bone marrow of the mouse that is about 2.5-fold to about 3-fold higher than exhibited in the bone marrow of a wild type mouse. In a specific embodiment, the mouse exhibits a population of pro B cells in the bone marrow of the mouse that is about 2.75-fold higher than exhibited in the bone marrow of a wild type mouse.

[0121] In one embodiment, the mouse exhibits an immunophenotype having a characteristic selected from the group consisting of a CD19.sup.+ splenic B cell population that is about 80% of a wild-type B cell, a CD3.sup.+ splenic T cell population that is about the same as a wild type mouse, and a combination thereof.

[0122] In one embodiment, the mouse comprises a lymphocyte population whose % CD19.sup.+ B cells in spleen are about the same as a wild-type mouse. In one embodiment, the number of CD19.sup.+ B cells per spleen of the mouse is at least about 50% of the number of CD19.sup.+ B cells per spleen of a wild-type mouse.

[0123] In one embodiment, the non-human animal comprises at least about 75% to about 80% of CD19.sup.+ B cells in bone marrow as compared with a wild-type mouse.

[0124] In one embodiment, the total number of CD19.sup.+ bone cells per femur of the mouse is non less than about 30%, 40%, 50%, 60%, or 75% of the total number of CD19+ bone marrow cells in a wild-type mouse.

[0125] In one embodiment, the mouse expresses IgD and IgM at about the same level as observed in a wild-type mouse.

[0126] In one aspect, a mouse comprising a restricted human V.sub.H segment repertoire is provided, further comprising a humanized immunoglobulin light chain variable segment locus, wherein the ratio of .lamda. to .kappa. light chains expressed in the mouse is about the same as in a wild-type mouse.

[0127] In one aspect, a mouse is provided, comprising a restricted immunoglobulin heavy chain locus characterized by the presence of a single V.sub.H gene segment, one or more D.sub.H gene segments, and one or more J.sub.H gene segments, wherein the single V.sub.H gene segment is a polymorphic V.sub.H gene segment.

[0128] In one embodiment, the polymorphic V.sub.H gene segment is a human V.sub.H gene segment that is associated with a high copy number in human populations. In one embodiment, the human V.sub.H gene segment is selected from V.sub.H1-2, V.sub.H1-69, V.sub.H2-26, V.sub.H2-70, V.sub.H3-23, or a polymorphic variant thereof. In a specific embodiment, the human V.sub.H gene segment is a V.sub.H1-69 gene segment. In another specific embodiment, the human V.sub.H gene segment is a V.sub.H1-2 gene segment.

[0129] In one embodiment, the single V.sub.H gene segment is operably linked to a human, mouse, or chimeric human/mouse immunoglobulin constant region gene. In a specific embodiment, the immunoglobulin constant region gene is a mouse constant region gene. In one embodiment, the immunoglobulin constant gene comprises a human sequence selected from a human C.sub.H1, a human hinge, a human C.sub.H2, a human C.sub.H3, and a combination thereof. In one embodiment, the mouse constant gene is at an endogenous immunoglobulin heavy chain locus.

[0130] In one embodiment, the mouse further comprises a human immunoglobulin V.sub.L gene segment operably linked to a J gene segment and a light chain constant gene. In a specific embodiment, the V.sub.L gene segment and/or the J gene segment are selected from a human .kappa. gene segment and a human .lamda. gene segment. In one embodiment, the V.sub.L and/or J gene segments are human .kappa. gene segments.

[0131] In various embodiments, the mouse comprises a deletion of all or substantially all endogenous V.sub.H gene segments.

[0132] In various embodiments, the non-human animal comprises an inactivated endogenous heavy chain variable gene locus. In various embodiments, the inactivated endogenous heavy chain variable gene locus is not operably linked to an endogenous heavy chain constant region gene.

[0133] In one aspect, a mouse is provided, wherein the mouse is characterized by the expression of serum immunoglobulin, wherein greater than 80% of the serum immunoglobulin comprises a human heavy chain variable domain and a cognate human light chain variable domain, wherein the human heavy chain variable domain is derived from a V.sub.H gene segment repertoire consisting essentially of a single human V.sub.H gene segment and/or polymorphic variants thereof.

[0134] In one embodiment, the single human V.sub.H gene segment is a human V.sub.H1-69 gene segment and/or polymorphic variants thereof. In one embodiment, the single human V.sub.H gene segment is a human V.sub.H1-2 gene segment and/or polymorphic variants thereof.

[0135] In one aspect, a mouse is provided, comprising, in its germline, a replacement at an endogenous immunoglobulin heavy chain locus of all or substantially all endogenous V.sub.H gene segments with a single human V.sub.H gene segment and/or polymorphic variants thereof. In one embodiment, the single human V.sub.H gene segment is a human V.sub.H1-69 gene segment and/or polymorphic variants thereof. In one embodiment, the single human V.sub.H gene segment is a human V.sub.H1-2 gene segment and/or polymorphic variants thereof.

[0136] In one embodiment, the mouse further comprises a replacement at an endogenous immunoglobulin light chain locus of all or substantially all endogenous V.sub.L gene segments with one or more human V.sub.L gene segments. In a specific embodiment, the mouse further comprises one or more human J.sub.L gene segments operably linked to the human V.sub.L gene segments.

[0137] In one aspect, use of a mouse as described herein to make an immunoglobulin variable region nucleotide sequence is provided. In one embodiment, the sequence comprises a rearranged V.sub.H1-69 gene segment. In one embodiment, the sequence comprises a rearranged V.sub.H1-2 gene segment.

[0138] In one embodiment, the immunoglobulin variable region nucleotide sequence is at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical with a human V.sub.H1-69 gene segment. In a specific embodiment, the immunoglobulin variable region nucleotide sequence is at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical with SEQ ID NO: 34. In various embodiments, the human V.sub.H1-69 gene segment is identified from Table 2.

[0139] In one embodiment, the immunoglobulin variable region nucleotide sequence encodes an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical with SEQ ID NO: 35.

[0140] In one embodiment, the immunoglobulin variable region nucleotide sequence is at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical with a human V.sub.H1-2 gene segment. In a specific embodiment, the immunoglobulin variable region nucleotide sequence is at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical with SEQ ID NO: 60. In various embodiments, the human V.sub.H1-2 gene segment is identified from Table 3.

[0141] In one embodiment, the immunoglobulin variable region nucleotide sequence encodes an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical with SEQ ID NO: 61.

[0142] In one aspect, use of a mouse as described herein to make a fully human Fab or a fully human F(ab).sub.2 is provided. In one embodiment, the fully human Fab or fully human F(ab)2 comprises a heavy chain variable region that comprises a rearranged human V.sub.H1-69 gene segment. In one embodiment, the fully human Fab or fully human F(ab)2 comprises a heavy chain variable region that comprises a rearranged human V.sub.H1-2 gene segment.

[0143] In one aspect, use of a mouse as described herein to make an immortalized cell line is provided.

[0144] In one aspect, use of a mouse as described herein to make a hybridoma or quadroma is provided.

[0145] In one aspect, use of a mouse as described herein to make a phage library containing human heavy chain variable regions and human light chain variable regions is provided.

[0146] In one embodiment, the human heavy chain variable regions are derived from a human V.sub.H1-69 gene segment that comprises a sequence selected from SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56 and SEQ ID NO: 58.

[0147] In one embodiment, the human heavy chain variable regions are derived from a human V.sub.H1-69 gene segment that comprises a sequence selected from SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57 and SEQ ID NO: 59.

[0148] In one embodiment, the human heavy chain variable regions are all derived from a human V.sub.H1-2 gene segment that comprises a sequence selected from SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66 and SEQ ID NO: 68.

[0149] In one embodiment, the human heavy chain variable regions are derived from a human V.sub.H1-2 gene segment that comprises a sequence selected from SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67 and SEQ ID NO: 69.

[0150] In one aspect, use of a mouse as described herein to generate a variable region sequence for making a human antibody is provided, comprising (a) immunizing a mouse as described herein with an antigen of interest, (b) isolating a lymphocyte from the immunized mouse of (a), (c) exposing the lymphocyte to one or more labeled antibodies, (d) identifying a lymphocyte that is capable of binding to the antigen of interest, and (e) amplifying one or more variable region nucleic acid sequence from the lymphocyte thereby generating a variable region sequence.

[0151] In one embodiment, the lymphocyte is derived or isolated from the spleen of the mouse. In one embodiment, the lymphocyte is derived or isolated from a lymph node of the mouse. In one embodiment, the lymphocyte is derived or isolated from the bone marrow of the mouse. In one embodiment, the lymphocyte is derived or isolated from the blood of the mouse.

[0152] In one embodiment, the labeled antibody is a fluorophore-conjugated antibody. In one embodiment, the one or more fluorophore-conjugated antibodies are selected from an IgM, an IgG, and/or a combination thereof.

[0153] In one embodiment, the lymphocyte is a B cell.

[0154] In one embodiment, the one or more variable region nucleic acid sequence comprises a heavy chain variable region sequence. In one embodiment, the one or more variable region nucleic acid sequence comprises a light chain variable region sequence. In a specific embodiment, the light chain variable region sequence is an immunoglobulin .kappa. light chain variable region sequence. In one embodiment, the one or more variable region nucleic acid sequence comprises a heavy chain and a .kappa. light chain variable region sequence.

[0155] In one embodiment, use of a mouse as described herein to generate a heavy and a .kappa. light chain variable region sequence for making a human antibody is provided, comprising (a) immunizing a mouse as described herein with an antigen of interest, (b) isolating the spleen from the immunized mouse of (a), (c) exposing B lymphocytes from the spleen to one or more labeled antibodies, (d) identifying a B lymphocyte of (c) that is capable of binding to the antigen of interest, and (e) amplifying a heavy chain variable region nucleic acid sequence and a .kappa. light chain variable region nucleic acid sequence from the B lymphocyte thereby generating the heavy chain and x light chain variable region sequences.

[0156] In one embodiment, use of a mouse as described herein to generate a heavy and a .kappa. light chain variable region sequence for making a human antibody is provided, comprising (a) immunizing a mouse as described herein with an antigen of interest, (b) isolating one or more lymph nodes from the immunized mouse of (a), (c) exposing B lymphocytes from the one or more lymph nodes to one or more labeled antibodies, (d) identifying a B lymphocyte of (c) that is capable of binding to the antigen of interest, and (e) amplifying a heavy chain variable region nucleic acid sequence and a .kappa. light chain variable region nucleic acid sequence from the B lymphocyte thereby generating the heavy chain and .kappa. light chain variable region sequences.

[0157] In one embodiment, use of a mouse as described herein to generate a heavy and a .kappa. light chain variable region sequence for making a human antibody is provided, comprising (a) immunizing a mouse as described herein with an antigen of interest, (b) isolating bone marrow from the immunized mouse of (a), (c) exposing B lymphocytes from the bone marrow to one or more labeled antibodies, (d) identifying a B lymphocyte of (c) that is capable of binding to the antigen of interest, and (e) amplifying a heavy chain variable region nucleic acid sequence and a .kappa. light chain variable region nucleic acid sequence from the B lymphocyte thereby generating the heavy chain and .kappa. light chain variable region sequences. In various embodiments, the one or more labeled antibodies are selected from an IgM, an IgG, and/or a combination thereof.

[0158] In various embodiments, the antigen of interest is a pathogen that afflicts human subjects including, e.g., a viral antigen. Exemplary viral pathogens include, e.g., mainly those of the families of Adenoviridae, bacteria Picornaviridae, Herpesviridae, Hepadnaviridae, Flaviviridae, Retroviridae, Orthomyxoviridae, Paramyxoviridae, Papovaviridae, Polyomavirus, Rhabdoviridae, and Togaviridae. Such exemplary viruses typically range between 20-300 nanometers in length. In various embodiments, the antigen of interest is a viral antigen selected from a hepatitis virus (e.g., HCV, HBV, etc.), a human immunodeficiency virus (HIV), or an influenza virus (e.g., H1N1).

[0159] In various embodiments, use of a mouse as described herein to generate a heavy and .kappa. light chain variable region sequence for making a human antibody is provided, further comprising fusing the amplified heavy and light chain variable region sequences to human heavy and light chain constant region sequences, expressing the fused heavy and light chain sequences in a cell, and recovering the expressed heavy and light chain sequences thereby generating a human antibody.

[0160] In various embodiments, the human heavy chain constant regions are selected from IgM, IgD, IgA, IgE and IgG. In various specific embodiments, the IgG is selected from an IgG1, an IgG2, an IgG3 and an IgG4. In various embodiments, the human heavy chain constant region comprises a C.sub.H1, a hinge, a C.sub.H2, a C.sub.H3, a C.sub.H4, or a combination thereof. In various embodiments, the light chain constant region is an immunoglobulin .kappa. constant region. In various embodiments, the cell is selected from a HeLa cell, a DU145 cell, a Lncap cell, a MCF-7 cell, a MDA-MB-438 cell, a PC3 cell, a T47D cell, a THP-1 cell, a U87 cell, a SHSY5Y (human neuroblastoma) cell, a Saos-2 cell, a Vero cell, a CHO cell, a GH3 cell, a PC12 cell, a human retinal cell (e.g., a PER.C6.TM. cell), and a MC3T3 cell. In a specific embodiment, the cell is a CHO cell.

[0161] In one aspect, a method for generating a reverse-chimeric rodent-human antibody specific against an antigen of interest is provided, comprising the steps of immunizing a mouse as described herein with the antigen, isolating at least one cell from the mouse producing a reverse-chimeric mouse-human antibody specific against the antigen, culturing at least one cell producing the reverse-chimeric mouse-human antibody specific against the antigen, and obtaining said antibody.

[0162] In one embodiment, the reverse-chimeric mouse-human antibody comprises a human heavy chain variable domain fused with a mouse or rat heavy chain constant gene, and a human light chain variable domain fused with a mouse or rat or human light chain constant gene. In a specific embodiment, the human heavy chain variable domain contains a rearranged human V.sub.H1-69 or human V.sub.H1-2 gene segment.

[0163] In one embodiment, culturing at least one cell producing the reverse-chimeric rodent-human antibody specific against the antigen is performed on at least one hybridoma cell generated from the at least one cell isolated from the mouse.

[0164] In one embodiment, the antigen of interest is a pathogen that afflicts human subjects as described herein.

[0165] In one aspect, a method for generating a fully human antibody specific against an antigen of interest is provided, comprising the steps of immunizing a mouse as described herein with the antigen, isolating at least one cell from the mouse producing a reverse-chimeric rodent-human antibody specific against the antigen, generating at least one cell producing a fully human antibody derived from the reverse-chimeric rodent-human antibody specific against the antigen, and culturing at least one cell producing the fully human antibody, and obtaining said fully human antibody.

[0166] In various embodiments, the at least one cell isolated from the mouse producing a reverse-chimeric rodent-human antibody specific against the antigen is a splenocyte or a B cell.

[0167] In various embodiments, the antibody is a monoclonal antibody.

[0168] In various embodiments, the antibody comprises a heavy chain variable domain that contains a rearranged human V.sub.H1-69 or human V.sub.H1-2 gene segment.

[0169] In various embodiments, immunization with the antigen of interest is carried out with protein, DNA, a combination of DNA and protein, or cells expressing the antigen. In one embodiment, the antigen of interest is a pathogen that afflicts human subjects as described herein.

[0170] In one aspect, use of a mouse as described herein to make a nucleic acid sequence encoding an immunoglobulin variable region or fragment thereof is provided. In one embodiment, the nucleic acid sequence is used to make a human antibody or antigen-binding fragment thereof. In one embodiment, the mouse is used to make an antigen-binding protein selected from an antibody, a multi-specific antibody (e.g., a bi-specific antibody), an scFv, a bi-specific scFv, a diabody, a triabody, a tetrabody, a V-NAR, a V.sub.HH, a V.sub.L, a F(ab), a F(ab).sub.2, a DVD (i.e., dual variable domain antigen-binding protein), a an SVD (i.e., single variable domain antigen-binding protein), or a bispecific T-cell engager (BiTE).

[0171] In one aspect, a method for making a human antigen-binding protein is provided, comprising exposing a genetically modified non-human animal as described herein to an antigen of interest, allowing the genetically modified non-human animal to mount an immune response to the antigen, obtaining from the genetically modified non-human animal a heavy chain variable domain nucleic acid sequence encoding a human heavy chain variable domain that specifically binds the antigen of interest, cloning the heavy chain variable domain nucleic acid sequence to a human constant region sequence, and expressing in a mammalian cell an antibody comprising the human heavy chain variable domain sequence and the human constant region sequence. In one embodiment, the mammalian cell is a CHO cell. In one embodiment the genetically modified non-human animal comprises a human V.sub.H gene segment repertoire that consists essentially of a single human V.sub.H gene segment, optionally present in two or more polymorphic variants thereof, operably linked to one or more human D and/or J segments. In one embodiment, the human V.sub.H gene segment repertoire is at an endogenous non-human V.sub.H segment locus. In one embodiment, the human V.sub.H gene segment repertoire is at a locus that is not an endogenous V.sub.H segment locus. In one embodiment, the human V.sub.H gene segment rearranges with a human D segment and a human J segment to form a rearranged human VDJ gene operably linked to a constant region sequence, wherein the constant region sequence is selected from a human sequence and a rodent sequence (e.g., a mouse or rat or hamster sequence). In one embodiment, the constant region sequence comprises a sequence selected from a C.sub.H1, a hinge, a C.sub.H2, a C.sub.H3, and a combination thereof; in a specific embodiment, the constant region sequence comprises a C.sub.H1, a hinge, a C.sub.H2, and a C.sub.H3. In one embodiment, the human variable domain and the constant sequence are expressed in the mammalian cell with a cognate human light chain variable domain obtained from the same mouse (e.g., sequence obtained from the same B cell as the human variable domain sequence); in one embodiment the sequence encoding the human light chain variable domain obtained from the mouse is then fused with a sequence encoding a human light chain constant sequence, and the light chain sequence and the heavy chain sequence are expressed in the mammalian cell.

[0172] In one embodiment, the antigen of interest is a pathogen that afflicts human subjects as described herein.

[0173] In one aspect, a method for making an antibody heavy chain variable domain that binds an antigen of interest is provided, comprising expressing in a single cell (a) a first V.sub.H sequence of an immunized non-human animal as described herein, wherein the first V.sub.H sequence is fused with a C.sub.H gene sequence; and (b) a V.sub.L gene sequence of an immunized non-human animal as described herein, wherein the V.sub.L gene sequence is fused with a human C.sub.L gene sequence; maintaining the cell under conditions sufficient to express an antibody; and, isolating the antibody heavy chain variable domain. In one embodiment, the V.sub.L gene sequence is cognate with the first V.sub.H sequence.

[0174] In one embodiment, the cell comprises a second V.sub.H gene sequence of an immunized non-human animal as described herein, wherein the second V.sub.H gene sequence is fused with a C.sub.H gene sequence, wherein the first V.sub.H gene sequence encodes a V.sub.H domain that specifically binds a first epitope, and the second V.sub.H gene sequence encodes a V.sub.H domain that specifically binds a second epitope, wherein the first epitope and the second epitope are not identical.

[0175] In one embodiment, the constant region sequences are all human constant region sequences. In one embodiment, the antigen of interest is a pathogen that afflicts human subjects as described herein.

[0176] In one aspect, a method for making a human bispecific antibody is provided, comprising making the bispecific antibody using human variable region gene sequences of B cells of a non-human animal as described herein.

[0177] In one embodiment, the method comprises (a) identifying a clonally selected lymphocyte of the non-human animal, wherein the non-human animal has been exposed to an antigen of interest and allowed to develop an immune response to the antigen of interest, and wherein the lymphocyte expresses an antibody that specifically binds the antigen of interest, (b) obtaining from the lymphocyte or the antibody a nucleotide sequence that encodes a human heavy chain variable region that specifically binds the antigen of interest, and (c) employing the nucleotide sequence that encodes the human heavy chain variable region that specifically binds the antigen of interest in making the bispecific antibody. In a specific embodiment, the human heavy chain variable region comprises a rearranged V.sub.H1-2 or V.sub.H1-69 gene segment.

[0178] In one embodiment, steps (a) through (c) are performed a first time for a first antigen of interest to generate a first human heavy chain variable region sequence, and steps (a) through (c) are performed a second time for a second antigen of interest to generate a second human heavy chain variable region sequence, and wherein the first human heavy chain variable region sequence is expressed fused with a first human heavy chain constant region to form a first human heavy chain, the second human heavy chain variable region sequence is expressed fused with a second human heavy chain constant region to form a second human heavy chain, wherein the first and the second human heavy chains are expressed in the presence of a single human light chain expressed from a rearranged human V.sub..kappa.1-39 or a human V.sub..kappa.3-20 gene segment. In a specific embodiment, the single human light chain comprises a germline sequence.

[0179] In one embodiment, the method comprises (a) cloning heavy chain variable regions from B cells of a non-human animal as described herein which has been exposed to a first antigen of interest, and the same non-human animal, or a different non-human animal which is genetically the same and has been exposed to a second antigen of interest; and (b) expressing in a cell the heavy chain variable regions of (a) with the same heavy chain constant region and the same light chain to make a bispecific antibody.

[0180] In one aspect, a use of a non-human animal as described herein is provided, to obtain a nucleic acid sequence that encodes a human heavy chain variable domain. In one embodiment, the heavy chain variable domain comprises a rearranged human V.sub.H gene segment selected from V.sub.H1-2 and V.sub.H1-69.

[0181] In one aspect, a use of a non-human animal as described herein is provided, to obtain a cell that encodes a human heavy chain variable domain. In one embodiment, the heavy chain variable domain comprises a rearranged human V.sub.H gene segment selected from V.sub.H1-2 and V.sub.H1-69.

[0182] In one aspect, use of a non-human animal as described herein to make a human antibody variable domain is provided. In one embodiment, the variable domain comprises a rearranged human V.sub.H gene segment selected from V.sub.H1-2 and V.sub.H1-69.

[0183] In one aspect, use of a non-human animal as described herein to make a human antibody is provided, comprising making the antibody using human variable region gene sequences of B cells of a non-human animal as described herein. In one embodiment, the human antibody is a human bispecific antibody. In a specific embodiment, the bispecific antibody comprises one heavy chain variable domain derived from a rearranged human V.sub.H1-2 or V.sub.H1-69 gene segment. In one embodiment, the human variable region gene sequences comprise a rearranged human V.sub.H1-2 or V.sub.H1-69 gene segment.

[0184] In one aspect, use of a non-human animal as described herein is provided to select a human immunoglobulin heavy chain variable domain. In one embodiment, the heavy chain variable domain comprises a rearranged human V.sub.H gene segment selected from V.sub.H1-2 and V.sub.H1 -69.

[0185] In one aspect, use of the mouse as described herein for the manufacture of a medicament (e.g., an antigen-binding protein), or for the manufacture of a sequence encoding a variable sequence of a medicament (e.g., an antigen-binding protein), for the treatment of a human disease or disorder is provided. In one embodiment, the variable sequence of a medicament comprises a polymorphic human V.sub.H gene segment. In one embodiment, the variable sequence of a medicament comprises a human V.sub.H1-69 gene segment. In one embodiment, the variable sequence of a medicament comprises a human V.sub.H1-2 gene segment.

[0186] In one aspect, a nucleic acid construct encoding an immunoglobulin variable domain made in a mouse as described herein is provided. In one embodiment, the variable domain is a heavy chain variable domain. In a specific embodiment, the heavy chain variable domain comprises a rearranged human V.sub.H gene segment selected from V.sub.H1-2, V.sub.H1-69, V.sub.H2-26, V.sub.H2-70, or V.sub.H3-23. In another specific embodiment, the heavy chain variable domain comprises a rearranged human V.sub.H1-2 gene segment. In another specific embodiment, the heavy chain variable domain comprises a rearranged human V.sub.H1-69 gene segment.

[0187] In one embodiment, the variable domain is a light chain variable domain. In a specific embodiment, the variable domain is a .kappa. light chain variable domain that is cognate with a human heavy chain variable domain that comprises a rearranged human V.sub.H1-69 gene segment. In a specific embodiment, the variable domain is a .kappa. light chain variable domain that is cognate with a human heavy chain variable domain that comprises a rearranged human V.sub.H1-2 gene segment.

[0188] In one aspect, use of a mouse as described herein to make a nucleic acid construct encoding a human immunoglobulin variable domain is provided. In one embodiment, the variable domain is a light chain variable domain. In one embodiment, the variable domain is a .kappa. light chain variable domain that comprises a rearranged human V.sub..kappa. gene segment selected from V.sub..kappa.4-1, V.sub..kappa.5-2, V.sub..kappa.7-3, V.sub..kappa.2-4, V.sub..kappa.1-5, V.sub..kappa.1-6, V.sub..kappa.3-7, V.sub..kappa.1-8, V.sub..kappa.1-9, V.sub..kappa.2-10, V.sub..kappa.3-11, V.sub..kappa.1-12, V.sub..kappa.1-13, V.sub..kappa.2-14, V.sub..kappa.3-15, V.sub..kappa.1-16, V.sub..kappa.1-17, V.sub..kappa.2-18, V.sub..kappa.2-19, V.sub..kappa.3-20, V.sub..kappa.6-21, V.sub..kappa.1-22, V.sub..kappa.1-23, V.sub..kappa.2-24, V.sub..kappa.3-25, V.sub..kappa.2-26, V.sub..kappa.1-27, V.sub..kappa.2-28, V.sub..kappa.2-29, V.sub..kappa.2-30, V.sub..kappa.3-31, V.sub..kappa.1-32, V.sub..kappa.1-33, V.sub..kappa.3-34, V.sub..kappa.1-35, V.sub..kappa.2-36, V.sub..kappa.1-37, V.sub..kappa.2-38, V.sub..kappa.1-39, and V.sub..kappa.2-40.

[0189] In one embodiment, the variable domain is a heavy chain variable domain. In a specific embodiment, the heavy chain variable domain comprises a rearranged human V.sub.H gene segment selected from V.sub.H1-2, V.sub.H1-69, V.sub.H2-26, V.sub.H2-70, or V.sub.H3-23. In a specific embodiment, the heavy chain variable domain comprises a rearranged human V.sub.H1-69 gene segment. In a specific embodiment, the heavy chain variable domain comprises a rearranged human V.sub.H1-2 gene segment.

[0190] In one aspect, use of a mouse as described herein to make a human immunoglobulin variable domain is provided. In one embodiment, the variable domain is a light chain variable domain. In one embodiment, the variable domain is a .kappa. light chain variable domain that comprises a rearranged human V.sub..kappa. gene segment selected from V.sub..kappa.4-1, V.sub..kappa.5-2, V.sub..kappa.7-3, V.sub..kappa.2-4, V.sub..kappa.1-5, V.sub..kappa.1-6, V.sub..kappa.3-7, V.sub..kappa.1-8, V.sub..kappa.1-9, V.sub..kappa.2-10, V.sub..kappa.3-11, V.sub..kappa.1-12, V.sub..kappa.1-13, V.sub..kappa.2-14, V.sub..kappa.3-15, V.sub..kappa.1-16, V.sub..kappa.1-17, V.sub..kappa.2-18, V.sub..kappa.2-19, V.sub..kappa.3-20, V.sub..kappa.6-21, V.sub..kappa.1-22, V.sub..kappa.1-23, V.sub..kappa.2-24, V.sub..kappa.3-25, V.sub..kappa.2-26, V.sub..kappa.1-27, V.sub..kappa.2-28, V.sub..kappa.2-29, V.sub..kappa.2-30, V.sub..kappa.3-31, V.sub..kappa.1-32, V.sub..kappa.1-33, V.sub..kappa.3-34, V.sub..kappa.1-35, V.sub..kappa.2-36, V.sub..kappa.1-37, V.sub..kappa.2-38, V.sub..kappa.1-39, and V.sub..kappa.2-40.

[0191] In one embodiment, the variable domain is a heavy chain variable domain. In a specific embodiment, the heavy chain variable domain comprises a rearranged human V.sub.H gene segment selected from V.sub.H1-2, V.sub.H1-69, V.sub.H2-26, V.sub.H2-70, or V.sub.H3-23. In a specific embodiment, the heavy chain variable domain comprises a rearranged human V.sub.H1-69 gene segment. In a specific embodiment, the heavy chain variable domain comprises a rearranged human V.sub.H1-2 gene segment.

[0192] In one aspect, use of a non-human animal as described herein to make a nucleic acid sequence encoding a human heavy chain variable domain is provided. In one embodiment, the human heavy chain variable domain is characterized by having human FR1-CDR1-FR2-CDR2-FR3 sequences that are derived from a polymorphic human V.sub.H gene segment. In a specific embodiment, the human V.sub.H gene segment is selected from a human V.sub.H1-2, V.sub.H1-69, V.sub.H2-26, V.sub.H2-70, or V.sub.H3-23 gene segment. In one embodiment, the human V.sub.H gene segment is a human V.sub.H1-69 gene segment. In one embodiment, the human V.sub.H gene segment is a human V.sub.H1-2 gene segment.

[0193] In one aspect, a method for making a nucleic acid sequence encoding a human V.sub.H domain is provided, the method comprising immunizing a non-human animal as described herein with an antigen of interest, allowing the non-human animal to mount an immune response to the antigen of interest, and obtaining therefrom a nucleic acid sequence encoding a human V.sub.H domain that binds the antigen of interest. In one embodiment, the method further comprises making a nucleic acid sequence encoding a human V.sub.L domain that is cognate with the human V.sub.H domain, comprising isolating a B cell encoding the human V.sub.H domain and the human V.sub.L domain, and obtaining therefrom the sequence of the heavy and light chain variable domains. In various embodiments, the human V.sub.H domain is derived from a rearranged human V.sub.H1-69 or human V.sub.H1-2 gene segment. In various embodiments, the human V.sub.L domain is selected from a human V.sub..kappa. or a human V.sub..lamda. domain.

[0194] In one aspect, use of a non-human animal as described herein to make a human therapeutic is provided, comprising immunizing the non-human animal with an antigen of interest, allowing the non-human animal to mount an immune response, and obtaining from the animal a nucleic acid sequence encoding an immunoglobulin variable domain that binds the antigen of interest, and employing the immunoglobulin variable domain in a human therapeutic. In one embodiment, the variable domain is a heavy chain variable domain. In a specific embodiment, the heavy chain variable domain is derived from a rearranged human V.sub.H1-69 or a human V.sub.H1-2 gene segment. In one embodiment, the variable domain is a light chain variable domain. In a specific embodiment, the light chain variable domain is derived from a rearranged human V.sub..kappa. or human V.sub..lamda. gene segment.

[0195] In one aspect, a method for making a human therapeutic is provided, comprising immunizing a non-human animal as described herein with an antigen of interest, allowing the non-human animal to mount an immune response, and obtaining from the animal a nucleic acid sequence encoding an immunoglobulin variable domain that binds the antigen of interest, and employing the immunoglobulin variable domain in a human therapeutic. In one embodiment, the variable domain is a heavy chain variable domain. In a specific embodiment, the heavy chain variable domain is derived from a rearranged human V.sub.H1-69 or a human V.sub.H1-2 gene segment. In one embodiment, the variable domain is a light chain variable domain. In a specific embodiment, the light chain variable domain is derived from a rearranged human V.sub..kappa. or human V.sub..lamda. gene segment.

[0196] In one aspect, a method for making a human antigen-binding protein is provided, comprising immunizing a non-human animal as described herein with an antigen of interest, allowing the animal to mount an immune response, obtaining from the mouse a nucleic acid sequence encoding an immunoglobulin variable domain that specifically binds the antigen of interest, cloning the nucleic acid sequence in a vector suitable for expression of the nucleic acid, wherein the nucleic acid sequence is cloned in frame with a nucleic acid sequence encoding a human immunoglobulin constant region or functional fragment thereof, and inserting the vector in a mammalian cell, and maintaining the cell under conditions suitable for expressing an antigen-binding protein that comprises the immunoglobulin variable domain and the immunoglobulin constant region or functional fragment thereof. In one embodiment, the antigen-binding protein is a human antibody. In a specific embodiment, the antibody comprises a heavy chain variable domain and a light chain variable domain obtained from a mouse as described herein. In a specific embodiment, the antibody comprises a heavy chain variable domain obtained from a mouse as described herein. In various embodiments, the heavy chain variable domain is derived from a rearranged human V.sub.H1-69 or a human V.sub.H1-2 gene segment.

[0197] In one aspect, a nucleic acid sequence encoding a human antigen-binding domain made in a non-human animal as described herein is provided. In one embodiment, the nucleic acid sequence encodes a human immunoglobulin V.sub.H domain. In one embodiment, the nucleic acid sequence encodes a human immunoglobulin V.sub.H domain and a cognate human V.sub.L domain. In various embodiments, the human V.sub.H domain is derived from a rearranged human V.sub.H1-69 or a human V.sub.H1-2 gene segment.

[0198] In one aspect, a method for preparation of a human antibody is provided, comprising immunizing a non-human animal as described herein with an antigen of interest, allowing the non-human animal to mount an immune response, harvesting a lymphocyte (e.g., a B cell) from the immunized animal, fusing the lymphocyte with a myeloma cell to form a hybridoma cell, obtaining from the hybridoma cell a nucleic acid sequence that encodes a human V.sub.H domain and a human V.sub.L domain, cloning the nucleic acid sequence in frame (i.e., in operable linkage) with a human constant region sequence to create an immunoglobulin heavy chain and an immunoglobulin light chain, and expressing the heavy and light chains in a cell capable of expressing the fully human antibody. In one embodiment, the cell is a CHO cell. In various embodiments, the human V.sub.H domain is derived from a rearranged human V.sub.H1-69 gene segment or a human V.sub.H1-2 gene segment.

[0199] In one aspect, a method for preparation of a human antibody is provided, comprising immunizing a non-human animal as described herein with an antigen of interest, allowing the non-human animal to mount an immune response, harvesting a lymphocyte (e.g., a B cell) from the immunized animal, obtaining from the lymphocyte a nucleic acid sequence that encodes a human V.sub.H domain and a human V.sub.L domain, cloning the nucleic acid sequence in frame (i.e., in operable linkage) with a human constant region sequence to create an immunoglobulin heavy chain and an immunoglobulin light chain, and expressing the heavy and light chains in a cell capable of expressing the fully human antibody. In one embodiment, the lymphocyte is derived from the spleen of the non-human animal. In one embodiment, the cell is a CHO cell. In various embodiments, the human V.sub.H domain is derived from a rearranged human V.sub.H1-69 gene segment or a human V.sub.H1-2 gene segment.

[0200] In various aspects, the antigen of interest is a pathogen that afflicts human subjects as described herein. In various aspects, the antigen of interest is a virus that is capable of infecting a human. Exemplary antigens that can be employed in the methods and uses described herein include microbes or microorganisms such as a virus, bacterium, prion, or fungus or any other pathogen that causes disease in humans. A person of skill, upon reading the disclosure, will appreciate those human pathogens that will be applicable for the methods and uses described herein. The various aspects and embodiments are capable of use together, unless expressly noted otherwise or the context clearly prohibits use together.

BRIEF DESCRIPTION OF FIGURES

[0201] FIG. 1 shows a general illustration, not to scale, of a series of targeting and molecular engineering steps employed to make a targeting vector for construction of a modified heavy chain locus containing a single human V.sub.H1-69 gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at an endogenous immunoglobulin heavy chain locus.

[0202] FIG. 2 shows a general illustration, not to scale, of a series of targeting and molecular engineering steps employed to make a targeting vector for construction of a modified heavy chain locus containing a single human V.sub.H1-2 gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at an endogenous immunoglobulin heavy chain locus.

[0203] FIG. 3 shows contour plots of splenocytes gated on single lymphocytes and stained for CD19 (B cell) and CD3 (T cell) from a wild type mouse (WT) and a mouse homozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HO).

[0204] FIG. 4A shows, on the left, the percent of CD19.sup.+ B cells in spleens harvested from wild type mice (WT) and mice homozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HO). On the right, the number of CD19.sup.+ B cells per spleen is shown for both wild type mice (WT) and mice homozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HO).

[0205] FIG. 4B shows, on the left, the percent of CD19.sup.+ B cells in bone marrow harvested from femurs of wild type mice (WT) and mice homozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HO). On the right, the number of CD19.sup.+ B cells per femur is shown for both wild type mice (WT) and mice homozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HO).

[0206] FIG. 5 shows contour plots of splenocytes gated on CD19.sup.+ B cells and stained for Ig.lamda.+ and Ig.kappa.+ expression from a wild type mouse (WT) and a mouse homozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HO).

[0207] FIG. 6 shows contour plots of splenocytes gated on CD19.sup.+ B cells and stained for immunoglobulin D (IgD) and immunoglobulin M (IgM) from a wild type mouse (WT) and a mouse homozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HO).

[0208] FIG. 7 shows the total number of transitional B cells (CD19.sup.+IgM.sup.hiIgD.sup.int), mature B cells (CD19.sup.+IgM.sup.intIgD.sup.hi), and the ratio of mature to immature B cells in harvested spleens from wild type mice (WT) and mice homozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HO).

[0209] FIG. 8 shows contour plots of bone marrow gated on singlets stained for immunoglobulin M (IgM) and B220 from a wild type mouse (WT) and a mouse homozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HO).

[0210] FIG. 9 shows the total number of immature (B220.sup.intIgM.sup.+) and mature (B220.sup.hiIgM.sup.+) B cells in bone marrow isolated from the femurs of wild type mice (WT) and mice homozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HO).

[0211] FIG. 10 shows contour plots of bone marrow gated on CD19.sup.+ B cells and stained for ckit.sup.+ and CD43.sup.+ from a wild type mouse (WT) and a mouse homozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HO).

[0212] FIG. 11A shows the percent of CD19.sup.+ cells in populations of pro B (CD19.sup.+CD43.sup.+ckit.sup.+) and pre B (CD19.sup.+CD43.sup.-ckit.sup.-) cells in bone marrow harvested from the femurs of wild type mice (WT) and mice homozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HO).

[0213] FIG. 11B shows the absolute number of cells per femur in populations of pro B (CD19.sup.+CD43.sup.+ckit.sup.+) and pre B (CD19.sup.+CD43.sup.-ckit.sup.-) cells in bone marrow harvested from wild type mice (WT) and mice homozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HO).

[0214] FIG. 12 shows the relative mRNA expression (y-axis) in purified splenic B cells of V.sub.H1-69-derived heavy chains in a quantitative PCR assay using a probe specific for the human V.sub.H1-69 gene segment in mice homozygous for a replacement of the endogenous heavy chain V.sub.H, D.sub.H, J.sub.H, and a replacement of the endogenous light chain V.sub..kappa. and J.sub..kappa. gene segments with human V.sub.H, D.sub.H, J.sub.H, V.sub..kappa. and J.sub..kappa. gene segments (HK), wild type mice (WT), mice heterozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HET) and mice homozygous for a single human V.sub.H gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.H HO). Signals are normalized to expression of mouse C.sub..kappa..

[0215] FIG. 13 shows the nucleotide alignment of the second exon for each of thirteen reported alleles for the human V.sub.H1-69 gene. Lower case bases indicate germline nucleotide differences among the alleles. Complementary determining regions (CDRs) are indicated with boxes around the sequence. Dashes indicate artificial gaps for proper sequence alignment. V.sub.H1-69*01 (SEQ ID NO: 34); V.sub.H1-69*02 (SEQ ID NO: 36); V.sub.H1-69*03 (SEQ ID NO: 38); V.sub.H1-69*04 (SEQ ID NO: 40); V.sub.H1-69*05 (SEQ ID NO: 42); V.sub.H1-69*06 (SEQ ID NO: 44); V.sub.H1-69*07 (SEQ ID NO: 46); V.sub.H1-69*08 (SEQ ID NO: 48); V.sub.H1-69*09 (SEQ ID NO: 50); V.sub.H1-69*10 (SEQ ID NO: 52); V.sub.H1-69*11 (SEQ ID NO: 54); V.sub.H1-69*12 (SEQ ID NO: 56); V.sub.H1-69*13 (SEQ ID NO: 58).

[0216] FIG. 14 shows the protein alignment of the mature heavy chain variable gene sequence for each of thirteen reported alleles for the human V.sub.H1-69 gene. Lower case amino acids indicate germline differences among the alleles. Complementary determining regions (CDRs) are indicated with boxes around the sequence. Dashes indicate artificial gaps for proper sequence alignment. V.sub.H1-69*01 (SEQ ID NO: 35); V.sub.H1-69*02 (SEQ ID NO: 37); V.sub.H1-69*03 (SEQ ID NO: 39); V.sub.H1-69*04 (SEQ ID NO: 41); V.sub.H1-69*05 (SEQ ID NO: 43); V.sub.H1-69*06 (SEQ ID NO: 45); V.sub.H1-69*07 (SEQ ID NO: 47); V.sub.H1-69*08 (SEQ ID NO: 49); V.sub.H1-69*09 (SEQ ID NO: 51); V.sub.H1-69*10 (SEQ ID NO: 53); V.sub.H1-69*11 (SEQ ID NO: 55); V.sub.H1-69*12 (SEQ ID NO: 57); V.sub.H1-69*13 (SEQ ID NO: 59).

[0217] FIG. 15 shows a percent identity/percent similarity matrix for the aligned protein sequences of the mature variable gene for each of thirteen reported alleles for the human V.sub.H1-69 gene. Percent identity among the V.sub.H1-69 alleles is indicated above the shaded boxes and percent similarity is indicated below the shaded boxes. Scores for percent identity and percent similarity were scored by a ClustalW (v1.83) alignment tool using MacVector software (MacVector, Inc., North Carolina).

[0218] FIG. 16 shows the nucleotide alignment of the second exon for each of five reported alleles for the human V.sub.H1-2 gene. Lower case bases indicate germline nucleotide differences among the alleles. Complementary determining regions (CDRs) are indicated with boxes around the sequence. Dashes indicate artificial gaps for proper sequence alignment. V.sub.H1-2*01 (SEQ ID NO: 60); V.sub.H1-2*02 (SEQ ID NO: 62); V.sub.H1-2*03 (SEQ ID NO: 64); V.sub.H1-2*04 (SEQ ID NO: 66); V.sub.H1-2*05 (SEQ ID NO: 68).

[0219] FIG. 17 shows the protein alignment of the mature heavy chain variable gene sequence for each of five reported alleles for the human V.sub.H1-2 gene. Lower case amino acids indicate germline differences among the alleles. Complementary determining regions (CDRs) are indicated with boxes around the sequence. Dashes indicate artificial gaps for proper sequence alignment. V.sub.H1-2*01 (SEQ ID NO: 61); V.sub.H1-2*02 (SEQ ID NO: 63); V.sub.H1-2*03 (SEQ ID NO: 65); V.sub.H1-2*04 (SEQ ID NO: 67); V.sub.H1-2*05 (SEQ ID NO: 69).

[0220] FIG. 18 shows a percent identity/percent similarity matrix for the aligned protein sequences of the mature variable gene for each of five reported alleles for the human V.sub.H1-2 gene. Percent identity among the V.sub.H1-2 alleles is indicated above the shaded boxes and percent similarity is indicated below the shaded boxes. Scores for percent identity and percent similarity were scored by a ClustalW (v1.83) alignment tool using MacVector software (MacVector, Inc., North Carolina).

[0221] FIG. 19 shows the antibody titer from mice homozygous for human heavy and human .kappa. light chain variable gene loci (H.sub..kappa.; n=4) and mice homozygous for a single human V.sub.H1-69 gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.HHO; n=10) that were immunized with a human cell surface receptor (Antigen A).

[0222] FIG. 20 shows the antibody titer from mice homozygous for human heavy and human .kappa. light chain variable gene loci (H.sub..kappa.; n=5) and mice homozygous for a single human V.sub.H1-69 gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus (1hV.sub.HHO; n=5) that were immunized with two different influenza vaccines.

[0223] FIG. 21 shows the percentage (y-axis) of IgM-primed heavy chains having a specified amino acid length for the V.sub.H CDR3 region (x-axis) from mice homozygous for a single human V.sub.H1-69 gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus and homozygous for a replacement of the endogenous .kappa. light chain variable loci with human .kappa. light chain variable loci that were immunized with a human cell surface receptor (Antigen A).

[0224] FIG. 22 shows the percentage (y-axis) of IgG-primed heavy chains having a specified amino acid length for the V.sub.H CDR3 region (x-axis) from mice homozygous for a single human V.sub.H1-69 gene segment, twenty-seven human D.sub.H and six human J.sub.H gene segments at the endogenous immunoglobulin heavy chain locus and homozygous for a replacement of the endogenous .kappa. light chain variable loci with human .kappa. light chain variable loci that were immunized with a human cell surface receptor (Antigen A).

DETAILED DESCRIPTION

[0225] This invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention is defined by the claims.

[0226] Unless defined otherwise, all terms and phrases used herein include the meanings that the terms and phrases have attained in the art, unless the contrary is clearly indicated or clearly apparent from the context in which the term or phrase is used. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, particular methods and materials are now described. All publications mentioned are hereby incorporated by reference.

[0227] The phrase "substantial" or "substantially" when used to refer to an amount of gene segments (e.g., "substantially all" V gene segments) includes both functional and non functional gene segments and include, in various embodiments, e.g., 80% or more, 85% or more, 90% or more, 95% or more 96% or more, 97% or more, 98% or more, or 99% or more of all gene segments; in various embodiments, "substantially all" gene segments includes, e.g., at least 95%, 96%, 97%, 98%, or 99% of functional (i.e., non-pseudogene) gene segments.

[0228] The term "replacement" includes wherein a DNA sequence is placed into a genome of a cell in such a way as to replace a sequence within the genome with a heterologous sequence (e.g., a human sequence in a mouse), at the locus of the genomic sequence. The DNA sequence so placed may include one or more regulatory sequences that are part of source DNA used to obtain the sequence so placed (e.g., promoters, enhancers, 5'- or 3'-untranslated regions, appropriate recombination signal sequences, etc.). For example, in various embodiments, the replacement is a substitution of an endogenous sequence for a heterologous sequence that results in the production of a gene product from the DNA sequence so placed (comprising the heterologous sequence), but not expression of the endogenous sequence; the replacement is of an endogenous genomic sequence with a DNA sequence that encodes a protein that has a similar function as a protein encoded by the endogenous genomic sequence (e.g., the endogenous genomic sequence encodes an immunoglobulin gene or domain, and the DNA fragment encodes one or more human immunoglobulin genes or domains). In various embodiments, an endogenous gene or fragment thereof is replaced with a corresponding human gene or fragment thereof. A corresponding human gene or fragment thereof is a human gene or fragment that is an ortholog of, a homolog of, or is substantially identical or the same in structure and/or function, as the endogenous gene or fragment thereof that is replaced.

[0229] A precise, in situ replacement of six megabases of the variable regions of the mouse heavy chain immunoglobulin loci (V.sub.H-D.sub.H-J.sub.H) with a restricted human immunoglobulin heavy chain locus was performed, while leaving the flanking mouse sequences intact and functional within the hybrid loci, including all mouse constant chain genes and locus transcriptional control regions (FIG. 1 and FIG. 2). Specifically, a single human V.sub.H, 27 D.sub.H, and six JH gene segments were introduced through chimeric BAC targeting vectors into mouse ES cells using VELOCIGENE.RTM. genetic engineering technology (see, e.g., U.S. Pat. No. 6,586,251 and Valenzuela et al., 2003, High-throughput engineering of the mouse genome coupled with high-resolution expression analysis, Nat Biotechnol 21:652-659).

Non-Human Animals With Restricted Immunoglobulin V.sub.H Gene Segments

[0230] Non-human animals comprising immunoglobulin loci that comprise a restricted number of V.sub.H genes, and one or more D genes and one or more J genes, are provided, as are methods of making and using them. When immunized with an antigen of interest, the non-human animals generate B cell populations with antibody variable regions derived only from the restricted, pre-selected V.sub.H gene or set of V.sub.H genes (e.g., a pre-selected V.sub.H gene and variants thereof). In various embodiments, non-human animals are provided that generate B cell populations that express human antibody variable domains that are human heavy chain variable domains, along with cognate human light chain variable domains. In various embodiments, the non-human animals rearrange human heavy chain variable gene segments and human light chain variable gene segments from modified endogenous mouse immunoglobulin loci that comprise a replacement or insertion of the non-human unrearranged variable region sequences with human unrearranged variable region sequences.

[0231] Early work on the organization, structure, and function of the immunoglobulin genes was done in part on mice with disabled endogenous loci and engineered to have transgenic loci (randomly placed) with partial human immunoglobulin genes, e.g., a partial repertoire of human heavy chain genes linked with a human constant gene, randomly inserted into the genome, in the presence or absence of a human light chain transgene. Although these mice were somewhat less than optimal for making useful high affinity antibodies, they facilitated certain functional analyses of immunoglobulin loci. Some of these mice had as few as two or three, or even just a single, heavy chain variable gene.

[0232] Mice that express fully human immunoglobulin heavy chains derived from a single human V.sub.H5-51 gene and 10 human D.sub.H genes and six human J.sub.H genes, with human .mu. and .gamma.1 constant genes, on a randomly inserted transgene (and disabled endogenous immunoglobulin loci) have been reported (Xu and Davis, 2000, Diversity in the CDR3 Region of V.sub.H Is Sufficient for Most Antibody Specificities, Immunity 13:37-45). The fully human immunoglobulin heavy chains of these mice are mostly expressed with one of just two fully mouse .lamda. light chains derived from the endogenous mouse .lamda. light chain locus (V.sub..lamda.1-J.sub..lamda.1 or V.sub..lamda.2-J.sub..lamda.2 only), and can express no .kappa. light chain (the mice are Ig.lamda..sup.-/-). These mice exhibit severely abnormal dysfunction in B cell development and antibody expression. B cell numbers are reportedly 5-10% of wild-type, IgM levels 5-10% of wild-type, and IgG1 levels are only 0.1-1% of wild-type. The observed IgM repertoire revealed highly restricted junctional diversity. The fully human heavy chains display largely identical CDR3 length across antigens, the same J.sub.H (J.sub.H2) usage across antigens, and an initial junctional Q residue, thus reflecting a certain lack of CDR3 diversity. The fully mouse .lamda. light chains nearly all had a W96L substitution in J.sub..lamda.1 as initial junctional residue. The mice are reportedly unable to generate any antibodies against bacterial polysaccharide. Because the human variable domains couple with mouse light chains, the utility of the human variable regions is highly limited.

[0233] Other mice that have just a single human V.sub.H3-23 gene, human D.sub.H and J.sub.H genes, and mouse light chain genes have been reported, but they exhibit a limited diversity (and thus a limited usefulness) due in part to mispairing potential between human V.sub.H and mouse V.sub.L domains (see, e.g., Mageed et al., 2001, Rearrangement of the human heavy chain variable region gene V3-23 in transgenic mice generates antibodies reactive with a range of antigens on the basis of V.sub.HCDR3 and residues intrinsic to the heavy chain variable region, Clin. Exp. Immunol. 123:1-5). Similarly, mice that bear two V.sub.H genes (3-23 and 6-1) along with human D.sub.H and J.sub.H genes in a transgene containing the human .mu. constant gene (Bruggemann et al., 1991, Human antibody production in transgenic mice: expression from 100 kb of the human IgH locus, Eur. J. Immmunol. 21:1323-1326) and express them in human IgM chains with mouse light chains may exhibit a repertoire limited by mispairing (Mackworth-Young et al., 2003, The role of antigen in the selection of the human V3-23 immunoglobulin heavy chain variable region gene, Clin. Exp. Immunol. 134:420-425).

[0234] Other transgenic mice that express V.sub.H-restricted fully human heavy chains from a human transgene randomly inserted in the genome, with a limited human .lamda. repertoire expressed from a fully human randomly inserted transgene, have also been reported (see, e.g., Taylor et al., 1992, A transgenic mouse that expresses a diversity of human sequence heavy and light chain immunoglobulins, Nucleic Acids Res. 20 (23):6287-6295; Wagner et al., 1994, Antibodies generated form human immunoglobulin miniloci in transgenic mice, Nucleic Acids Res. 22 (8):1389-1393). However, transgenic mice that express fully human antibodies from transgenes randomly integrated into the mouse genome, and that comprise damaged endogenous loci, are known to exhibit substantial differences in immune response as compared with wild-type mice that affect the diversity of the antibody variable domains obtainable from such mice.

[0235] Useful non-human animals that generate a diverse population of B cells that express human antibody variable domains from a restricted V.sub.H gene repertoire and one or more D genes and one or more J genes will be capable of generating, preferably in some embodiments, repertoires of rearranged variable region genes that will be sufficiently diverse. In various embodiments, diversity includes junctional diversity, somatic hypermutation, and polymorphic diversity in V.sub.H gene sequence (for embodiments where V.sub.H genes are present in polymorphic forms). Combinatorial diversity occurs in the pairing of the V.sub.H gene with one of a plurality of cognate human light chain variable domains (which, in various embodiments, comprise junctional diversity and/or somatic hypermutations).

[0236] Non-human animals comprising a restricted human V.sub.H gene repertoire and a complete or substantially complete human V.sub.L gene repertoire will in various embodiments generate populations of B cells that reflect the various sources of diversity, such as junctional diversity (e.g., VDJ, VJ joining, P additions, N additions), combinatorial diversity (e.g., cognate V.sub.H-restricted human heavy, human light), and somatic hypermutations. In embodiments comprising a restriction of the V.sub.H repertoire to one human V.sub.H gene, the one human V.sub.H gene can be present in two or more variants. In various embodiments, the presence of two or more polymorphic forms of a V.sub.H gene will enrich the diversity of the variable domains of the B cell population.

[0237] Variations in the germline sequences of gene segments (e.g., V genes) contribute to the diversity of the antibody response in humans. The relative contribution to diversity due to V gene sequence differences varies among V genes. The degree of polymorphism varies across gene families, and is reflected in a plurality of haplotypes (stretches of sequence with coinherited polymorphisms) capable of generating further diversity as observed in V.sub.H haplotype differences between related and unrelated individuals in the human population (see, e.g., Souroujon et al., 1989, Polymorphisms in Human H Chain V Region Genes from the V.sub.HIII Gene Family, J. Immunol. 143 (2):706-711). Some have suggested, based on data from particularly polymorphic human V.sub.H gene families, that haplotype diversity in the germline is a major contributor to V.sub.H gene heterogeneity in the human population, which is reflected in the large diversity of different germline V.sub.H genes across the human population (see, Sasso et al., 1990, Prevalence and Polymorphism of Human V.sub.H3 Genes, J. Immunol. 145 (8):2751-2757).

[0238] Although the human population displays a large diversity of haplotypes with respect to the V.sub.H gene repertoire due to widespread polymorphism, certain polymorphisms are reflected in prevalent (i.e., conserved) alleles observed in the human population (Sasso et al., 1990). V.sub.H polymorphism can be described in two principle forms. The first is variation arising from allelic variation associated with differences among the nucleotide sequence between alleles of the same gene segment. The second arises from the numerous duplications, insertions, and/or deletions that have occurred at the immunoglobulin heavy chain locus. This has resulted in the unique situation in which V.sub.H genes derived by duplication from identical genes differ from their respective alleles by one or more nucleotide substitutions. This also directly influences the copy number of V.sub.H genes at the heavy chain locus.

[0239] Polymorphic alleles of the human immunoglobulin heavy chain variable gene segments (V.sub.H genes) have largely been the result of insertion/deletion of gene segments and single nucleotide differences within coding regions, both of which have the potential to have functional consequences on the immunoglobulin molecule. Table 1 sets forth the functional V.sub.H genes listed by human V.sub.H gene family and the number of identified alleles for each V.sub.H gene in the human immunoglobulin heavy chain locus. There are some findings to suggest that polymorphic V.sub.H genes have been implicated in susceptibility to certain diseases such as, for example, rheumatoid arthritis, whereas in other cases a linkage between V.sub.H and disease has been less clear. This ambiguity has been attributed to the copy number and presence of various alleles in different human populations. In fact, several human V.sub.H genes demonstrate copy number variation (e.g., V.sub.H1-2, V.sub.H1-69, V.sub.H2-26, V.sub.H2-70, and V.sub.H3-23). In various embodiments, humanized mice as described herein with restricted V.sub.H repertoires comprise multiple polymorphic variants of an individual V.sub.H family member (e.g., two or more polymorphic variants of V.sub.H1-2, V.sub.H1-69, V.sub.H2-26, V.sub.H2-70, or V.sub.H3-23, replacing all or substantially all functional mouse V.sub.H segments at an endogenous mouse locus). In a specific embodiment, the two or more polymorphic variants of mice described herein are in number up to and including the number indicated for the corresponding V.sub.H family member in Table 1 (e.g., for V.sub.H1-69, 13 variants; for V.sub.H1-2, five variants; etc.).

[0240] Commonly observed variants of particular human V.sub.H genes are known in the art. For example, one of the most complex polymorphisms in the V.sub.H locus belongs to the V.sub.H1-69 gene. The human V.sub.H1-69 gene has 13 reported alleles (Sasso et al., 1993, A fetally expressed immunoglobulin V.sub.H1 gene belongs to a complex set of alleles, Journal of Clinical Investigation 91:2358-2367; Sasso et al., 1996, Expression of the immunoglobulin V.sub.H gene 51p1 is proportional to its germline gene copy number, Journal of Clinical Investigation 97 (9):2074-2080) and exists in at least three haplotypes that carry duplications of the V.sub.H1-69 gene, which results in multiple copies of the V.sub.H gene at a given locus. These polymorphic alleles include differences in the complementarity determining regions (CDRs), which may dramatically influence antigen specificity. Table 2 sets for the reported alleles for human V.sub.H1-69 and the SEQ ID NOs for the DNA and protein sequences of the mature heavy chain variable regions. Table 3 sets forth the reported alleles for human V.sub.H1-2 genes and the SEQ ID NOs for the DNA and protein sequences of the mature heavy chain variable regions. 240

[0241] Representative genomic DNA and full-length protein sequences of a V.sub.H1-69 gene are set forth in SEQ ID NO: 1 and SEQ ID NO: 2, respectively. FIG. 13 and FIG. 14 set forth DNA and protein alignments of thirteen reported V.sub.H1-69 alleles, respectively. Representative DNA and protein sequences of a V.sub.H1-2 gene are set forth in SEQ ID NO: 60 and SEQ ID NO: 61, respectively. FIG. 16 and FIG. 17 set forth DNA and protein alignments of five reported V.sub.H1-2 alleles, respectively. FIG. 15 and FIG. 18 set forth a percent identity/similarity matrix for aligned protein sequences corresponding to thirteen reported human V.sub.H1-69 alleles and five reported human V.sub.H1-2 alleles, respectively. In various embodiments, the modified locus of the invention comprises a V.sub.H gene selected from Table 1, present in two or more copy number, wherein the copy number includes up to and including the number of alleles shown in Table 1. In one embodiment, the modified locus of the invention comprises a V.sub.H1-69 gene selected from Table 2, present in two or more copy number, wherein the copy number includes up to and including the number of alleles shown in Table 1. In one embodiment, the modified locus of the invention comprises a V.sub.H1-2 gene selected from Table 3, present in two or more copy number, wherein the copy number includes up to and including the number of alleles shown in Table 1.

[0242] Although embodiments employing a restricted human V.sub.H repertoire in a mouse are extensively discussed, other non-human animals that express a restricted human V.sub.H repertoire are also provided. Such non-human animals include any of those which can be genetically modified to express a restricted human V.sub.H repertoire as disclosed herein, including, e.g., mouse, rat, rabbit, pig, bovine (e.g., cow, bull, buffalo), deer, sheep, goat, chicken, cat, dog, ferret, primate (e.g., marmoset, rhesus monkey), etc. For example, for those non-human animals for which suitable genetically modifiable ES cells are not readily available, other methods are employed to make a non-human animal comprising the genetic modification. Such methods include, e.g., modifying a non-ES cell genome (e.g., a fibroblast or an induced pluripotent cell) and employing nuclear transfer to transfer the modified genome to a suitable cell, e.g., an oocyte, and gestating the modified cell (e.g., the modified oocyte) in a non-human animal under suitable conditions to form an embryo. Methods for modifying a non-human animal genome (e.g., a pig, cow, rodent, chicken, etc. genome) include, e.g., employing a zinc finger nuclease (ZFN) or a transcription activator-like effector nuclease (TALEN) to modify a genome to include a restricted human V.sub.H repertoire. Thus, in one embodiment a method is provided for editing a non-human animal genome to include a restricted human V.sub.H repertoire, comprising a step of editing the genome employing a ZFN or a TALEN to include no more than one, or no more than two, human V.sub.H gene segments (or polymorphic variants thereof), wherein the no more than one or no more than two human V.sub.H gene segments are operably linked to an immunoglobulin constant gene sequence. In one embodiment, the constant gene sequence is selected from a human heavy chain constant sequence and a non-human heavy chain constant sequence. In one embodiment, the constant sequence is non-human and the no more than one or no more than two human V.sub.H gene segments are operably linked to non-human constant gene sequence at an endogenous non-human immunoglobulin locus.

[0243] In one aspect, the non-human animal is a small mammal, e.g., of the superfamily Dipodoidea or Muroidea. In one embodiment, the genetically modified animal is a rodent. In one embodiment, the rodent is selected from a mouse, a rat, and a hamster. In one embodiment, the rodent is selected from the superfamily Muroidea. In one embodiment, the genetically modified animal is from a family selected from Calomyscidae (e.g., mouse-like hamsters), Cricetidae (e.g., hamster, New World rats and mice, voles), Muridae (true mice and rats, gerbils, spiny mice, crested rats), Nesomyidae (climbing mice, rock mice, with-tailed rats, Malagasy rats and mice), Platacanthomyidae (e.g., spiny dormice), and Spalacidae (e.g., mole rates, bamboo rats, and zokors). In a specific embodiment, the genetically modified rodent is selected from a true mouse or rat (family Muridae), a gerbil, a spiny mouse, and a crested rat. In one embodiment, the genetically modified mouse is from a member of the family Muridae,

[0244] In one embodiment, the non-human animal is a rodent that is a mouse of a C57BL strain. In one embodiment, the C57BL strain is selected from C57BL/A, C57BL/An, C57BL/GrFa, C57BL/KaLwN, C57BL/6, C57BL/6J, C57BL/6ByJ, C57BL/6N, C57BL/6NJ, C57BL/10, C57BL/10ScSn, C57BL/10Cr, and C57BL/OIa. In another embodiment, the mouse is a 129 strain. In one embodiment, the 129 strain is selected from the group consisting of 129P1, 129P2, 129P3, 129X1, 129S1 (e.g., 129S1/SV, 129S1/SvIm), 129S2, 129S4, 129S5, 129S9/SvEvH, 129S6 (129/SvEvTac), 129S7, 129S8, 129T1, 129T2 (see, e.g., Festing et al. (1999) Revised nomenclature for strain 129 mice, Mammalian Genome 10:836, see also, Auerbach et al. (2000) Establishment and Chimera Analysis of 129/SvEv- and C57BL/6-Derived Mouse Embryonic Stem Cell Lines). In one embodiment, the genetically modified mouse is a mix of an aforementioned 129 strain and an aforementioned C57BL strain (e.g., a C57BL/6 strain). In another embodiment, the mouse is a mix of aforementioned 129 strains, or a mix of aforementioned C57BL/6 strains. In one embodiment, the 129 strain of the mix is a 129S6 (129/SvEvTac) strain. In another embodiment, the mouse is a mix of a 129/SvEv- and a C57BL/6-derived strain. In a specific embodiment, the mouse is a mix of a 129/SvEv- and a C57BL/6-derived strain as described in Auerbach et al. 2000 BioTechniques 29:1024-1032. In another embodiment, the mouse is a BALB strain, e.g., BALB/c strain. In another embodiment, the mouse is a mix of a BALB strain (e.g., BALB/c strain) and another aforementioned strain.

[0245] In one embodiment, the non-human animal is a rat. In one embodiment, the rat is selected from a Wistar rat, an LEA strain, a Sprague Dawley strain, a Fischer strain, F344, F6, and Dark Agouti. In one embodiment, the rat strain is a mix of two or more of a strain selected from the group consisting of Wistar, LEA, Sprague Dawley, Fischer, F344, F6, and Dark Agouti.

TABLE-US-00001 TABLE 1 V.sub.H Family V.sub.H Gene Alleles V.sub.H1 1-2 5 1-3 2 1-8 2 1-18 3 1-24 1 1-45 3 1-46 3 1-58 2 1-69 13 V.sub.H2 2-5 10 2-26 1 2-70 13 V.sub.H3 3-7 3 3-9 2 3-11 4 3-13 4 3-15 8 3-16 2 3-20 1 3-21 4 3-23 5 3-30 19 3-30-3 2 3-30-5 1 3-33 6 3-35 1 3-38 2 3-43 2 3-48 4 3-49 5 3-53 4 3-64 5 3-66 4 3-72 2 3-73 2 3-74 3 V.sub.H4 4-4 7 4-28 6 4-30-1 1 4-30-2 5 4-30-4 6 4-31 10 4-34 13 4-39 7 4-59 10 4-61 8 V.sub.H5 5-51 5 V.sub.H6 6-1 2 V.sub.H7 7-4-1 5 7-81 1

TABLE-US-00002 TABLE 2 SEQ ID NO: IgHV1-69 Allele Accession Number (DNA/Protein) IgHV1-69*01 L22582 34/35 IgHV1-69*02 Z27506 36/37 IgHV1-69*03 X92340 38/39 IgHV1-69*04 M83132 40/41 IgHV1-69*05 X67905 42/43 IgHV1-69*06 L22583 44/45 IgHV1-69*07 Z29978 46/47 IgHV1-69*08 Z14309 48/49 IgHV1-69*09 Z14307 50/51 IgHV1-69*10 Z14300 52/53 IgHV1-69*11 Z14296 54/55 IgHV1-69*12 Z14301 56/57 IgHV1-69*13 Z14214 58/59

TABLE-US-00003 TABLE 3 SEQ ID NO: IgHV1-2 Allele Accession Number (DNA/Protein) IgHV1-2*01 X07448 60/61 IgHV1-2*02 X62106 62/63 IgHV1-2*03 X92208 64/65 IgHV1-2*04 Z12310 66/67 IgHV1-2*05 HM855674 68/69

Antigen-Dependent V.sub.H Gene Usage

[0246] Antigen-dependent preferential usage of V.sub.H genes can be exploited in the development of human therapeutics targeting clinically significant antigens. The ability to generate a repertoire of antibody variable domains using a particular V.sub.H gene can provide a significant advantage in the search for high-affinity antibody variable domains to use in human therapeutics. Studies on naive mouse and human V.sub.H gene usage in antibody variable domains reveal that most heavy chain variable domains are not derived from any particular single or dominantly used V.sub.H gene. On the other hand, studies of antibody response to certain antigens reveal that in some cases a particular antibody response displays a biased usage of a particular V.sub.H gene in the B cell repertoire following immunization.

[0247] Although the human V.sub.H repertoire is quite diverse, by some estimates the expected frequency of usage of any given V.sub.H gene, assuming random selection of V.sub.H genes, is about 2% (Brezinschek et al., 1995, Analysis of the Heavy Chain Repertoire of Human Peripheral B Cells Using Single-Cell Polymerase Chain Reaction, J. Immunol. 155:190-202). But V.sub.H usage in peripheral B cells in humans is skewed. In one study, functional V gene abundance followed the pattern V.sub.H3>V.sub.H4>V.sub.H1>V.sub.H2>V.sub.H5>V.sub.H6 (Davidkova et al., 1997, Selective Usage of V.sub.H Genes in Adult Human Lymphocyte Repertoires, Scand. J. Immunol. 45:62-73). One early study estimated that V.sub.H3 family usage frequency was about 0.65, whereas V.sub.H1 family usage frequency was about 0.15; these and other observations suggest that the germline complexity of the human V.sub.H repertoire is not precisely reflected in the peripheral B cell compartment in humans that have a normal germline V.sub.H repertoire, a situation that is similar to that observed in the mouse--i.e., V.sub.H gene expression is non-stochastic (Zouali and These, 1991, Probing V.sub.H Gene-Family Utilization in Human Peripheral B Cells by In Situ Hybridization, J. Immunol. 146 (8):2855-2864). According to one report, V.sub.H gene usage in humans, from greatest to least, is V.sub.H3>V.sub.H4>V.sub.H1>V.sub.H5>V.sub.H2>V.sub.H6; rearrangements in peripheral B cells reveal that V.sub.H3 family usage is higher than to be expected based on the relative number of germline V.sub.H3 genes (Brezinschek et al., 1995). According to another report V.sub.H usage in humans follows the pattern V.sub.H3>V.sub.H5>V.sub.H2>V.sub.H1>V.sub.H4>V.sub.H6, based on analysis of pokeweed mitogen-activated peripheral small immunocompetent B cells (Davidkova et al., 1997, Selective Usage of V.sub.H Genes in Adult Human B Lymphocyte Repertoires, Scand. J. Immunol. 45:62-73). One report asserts that among the most frequently used V.sub.H3 family members are 3-23, 3-30 and 3-54 (Brezinschek et al., 1995). In the V.sub.H4 family, member 4-59 and 4-4b were found relatively more frequently (Id.), as well as 4-39 and 4-34 (Brezinscheck et al., 1997, Analysis of the Human V.sub.H Gene Repertoire, J. Clin. Invest. 99 (10):2488-2501). Others postulate that the activated heavy chain repertoire is skewed in favor of high V.sub.H5 expression and lower V.sub.H3 expression (Van Dijk-Hard and Lundkvist, 2002, Long-term kinetics of adult human antibody repertoires, Immunology 107:136-144). Other studies assert that the most commonly used V.sub.H gene in the adult human repertoire is V.sub.H4-59, followed by V.sub.H3-23 and V.sub.H3-48 (Arnaout et al., 2001, High-Resolution Description of Antibody Heavy-Chain Repertoires in Humans, PLoS ONE 6 (8):108). Although usage studies are based on relatively small sample numbers and thus exhibit high variance, taken together the studies suggest that V gene expression is not purely stochastic. Indeed, studies with particular antigens have established that--in certain cases--the deck is firmly stacked against certain usages and in favor of others.

[0248] Over time, it became apparent that the observed repertoire of human heavy chain variable domains generated in response to certain antigens is highly restricted. Some antigens are associated almost exclusively with neutralizing antibodies having only certain particular V.sub.H genes, in the sense that effective neutralizing antibodies are derived from essentially only one V.sub.H gene. Such is the case for a number of clinically important human pathogens.

[0249] V.sub.H1-69-derived heavy chains have been observed in a variety of antigen-specific antibody repertoires of therapeutic significance. For instance, V.sub.H1-69 was frequently observed in heavy chain transcripts of an IgE repertoire of peripheral blood lymphocytes in young children with atopic disease (Bando et al., 2004, Characterization of V.sub.H.epsilon. gene expressed in PBL from children with atopic diseases: detection of homologous V.sub.H1-69 derived transcripts from three unrelated patients, Immunology Letters 94:99-106). V.sub.H1-69-derived heavy chains with a high degree of somatic hypermutation also occur in B cell lymphomas (Perez et al., 2009, Primary cutaneous B-cell lymphoma is associated with somatically hypermutated immunoglobulin variable genes and frequent use of V.sub.H1-69 and V.sub.H4-59 segments, British Journal of Dermatology 162:611-618), whereas some V.sub.H1-69-derived heavy chains with essentially germline sequences (i.e., little to no somatic hypermutation) have been observed among autoantibodies in patients with blood disorders (Pos et al., 2008, V.sub.H1-69 germline encoded antibodies directed towards ADAMTS13 in patients with acquired thrombotic thrombocytopenic purpura, Journal of Thrombosis and Haemostasis 7:421-428).

[0250] Further, neutralizing antibodies against viral antigens such as HIV, influenza and hepatitis C (HCV) have been found to utilize germline and/or somatically mutated V.sub.H1-69-derived sequences (Miklos et al., 2000, Salivary gland mucosa-associated lymphoid tissue lymphoma immunoglobulin V.sub.H genes show frequent use of V1-69 with distinctive CDR3 features, Blood 95 (12):3878-3884; Kunert et al., 2004, Characterization of molecular features, antigen-binding, and in vitro properties of IgG and IgM variants of 4E10, an anti-HIV type I neutralizing monoclonal antibody, Aids Research and Human Retroviruses 20 (7):755-762; Chan et al., 2001, V.sub.H1-69 gene is preferentially used by hepatitis C virus-associated B cell lymphomas and by normal B cells responding to the E2 viral antigen, Blood 97 (4):1023-1026; Carbonari et al., 2005, Hepatitis C virus drives the unconstrained monoclonal expansion of V.sub.H1-69-expressing memory B cells in type II cryoglobulinemia: A model of infection-driven lymphomagenesis, Journal of Immunology 174:6532-6539; Wang and Palese, 2009, Universal epitopes of influenza virus hemagglutinins?, Nature Structural & Molecular Biology 16 (3):233-234; Sui et al., 2009, Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses, Nature Structural & Molecular Biology 16 (3):265-273; Marasca et al., 2001, Immunoglobulin Gene Mutations and Frequent Use of V.sub.H1-69 and V.sub.H4-34 Segments in Hepatitis C Virus-Positive and Hepatitis C Virus-Negative Nodal Marginal Zone B-Cell Lymphoma, Am. J. Pathol. 159 (1):253-261).

[0251] V.sub.H usage bias is also observed in the humoral immune response to Haemophilus influenzae type b (Hib PS) in humans. Studies suggest that the V.sub.HIII family (the V.sub.HIIIb subfamily in particular, V.sub.H9.1) exclusively characterizes the human humoral response to Hib PS, with diverse D and J genes (Adderson et al., 1991, Restricted Ig H Chain V Gene Usage in the Human Antibody Response to Haemophilus influenzae Type b Capsular Polysaccharide, J. Immunol. 147 (5):1667-1674; Adderson et al., 1993, Restricted Immunoglobulin V.sub.H Usage and VDJ Combinations in the Human Response to Haemophilus influenzae Type b Capsular Polysaccharide, J. Clin. Invest. 91:2734-2743). Human J.sub.H genes also display biased usage; J.sub.H4 and J.sub.H6 are observed at about 38-41% in peripheral B cells in humans (Brezinschek et al., 1995).

[0252] V.sub.H usage in HIV-1-infected humans is reportedly biased against V.sub.H3 usage and in favor of V.sub.H1 and V.sub.H4 gene families (Wisnewski et al., 1996, Human Antibody Variable Region Gene Usage in HIV-1 Infection, J. Acquired Immune Deficiency Syndromes & Human Retroviology 11 (1):31-38). However, cDNA analysis of bone marrow from affected patients' revealed significant V.sub.H3 usage not expressed in the functional B cell repertoire, where Fabs reflecting the V.sub.H3 usage exhibited effective in vitro neutralization of HIV-1 (Id.). It might be postulated that the humoral immune response to HIV-1 infection is possibly attenuated due to the V.sub.H restriction; modified non-human animals as described herein (not infectable by HIV-1) might thus be useful for generating neutralizing antibody domains derived from particular V.sub.H genes present in the genetically modified animals described herein, but derived from different V.sub.H genes than those observed in the restricted repertoire of affected humans.

[0253] Thus, the ability to generate high affinity human antibody variable domains in V.sub.H-restricted mice, e.g., (restricted, e.g., to a V.sub.H3 family member and polymorph(s) thereof) immunized with HIV-1 might provide a rich resource for designing effective HIV-1-neutralizing human therapeutics by thoroughly mining the restricted (e.g., restricted to a V.sub.H3 family member or variant(s) thereof) repertoire of such an immunized mouse.

[0254] Restriction of the human antibody response to certain pathogens may reduce the likelihood of obtaining antibody variable regions from affected humans that can serve as springboards for designing high affinity neutralizing antibodies against the pathogen. For example, the human immune response to HIV-1 infection is clonally restricted throughout HIV-1 infection and into AIDS progression (Muller et al., 1993, B-cell abnormalities in AIDS: stable and clonally restricted antibody response in HIV-1 infection, Scand. J. Immunol. 38:327-334; Wisnewski et al., 1996). Further, V.sub.H genes are in general not present in all polymorphic forms in any particular individual; certain individuals in certain populations possess one variant, whereas individuals in other populations possess a different variant. Thus, the availability of a biological system that is restricted to a single V.sub.H gene and its variants will in various embodiments provide a hitherto unexploited source of diversity for generating antibody variable regions (e.g., human heavy and light cognate domains) based on a restricted V.sub.H gene. Thus, in one aspect, a genetically modified non-human animal is provided that comprises a plurality of polymorphic variants of no more than one, or no more than two, human V.sub.H gene segment family member. In one embodiment, the no more than one, or no more than two, human V.sub.H gene segments are operably linked to one or more human D.sub.H gene segments, one or more human J.sub.H gene segments, and a human or non-human constant region gene segment. In one embodiment the constant region is at an endogenous non-human immunoglobulin constant gene locus. In one embodiment, the non-human animal further comprises a nucleic acid sequence derived from a human V.sub.L sequence, e.g., a rearranged or unrearranged human V.sub.L gene segment or a rearranged human V.sub.L/J.sub.L sequence. In one embodiment, the nucleic acid sequence derived from the human V.sub.L sequence is at an endogenous non-human V.sub.L gene locus; in one embodiment, the nucleic acid sequence derived form the human V.sub.L sequence is on a transgene. In a specific embodiment, the non-human animal is incapable of expressing an immunoglobulin light chain variable domain that itself comprises an endogenous V.sub.L or J.sub.L gene segment, and comprises no more than one, or no more than two, light chain genes that encode rearranged human V.sub.L domains (Le., from no more than one, or no more than two, rearranged human V.sub.L/J.sub.L sequences).

[0255] Genetically modified mice that express human heavy chain variable regions with restricted V.sub.H gene segment usage are useful to generate a relatively large repertoire of junctionally diverse, combinatorially diverse, and somatically mutated high affinity human immunoglobulin heavy chain variable regions from an otherwise restricted repertoire. A restricted repertoire, in one embodiment, refers to a predetermined limitation in the number and/or identity of germline genes that results in the mouse being unable to form a rearranged heavy chain gene that is derived from any V gene other than a preselected V gene. In embodiments that employ a preselected V gene but not a preselected D and/or J gene, the repertoire is restricted with respect to the identity of the V gene but not the D and/or J gene (e.g., the repertoire consists essentially of no more than one, or no more than two, V.sub.H gene segments (and/or polymorphs thereof); and a plurality of D gene segments and a plurality of J gene segments)). The identity of the preselected V gene (and any preselected D and/or J genes) is not limited to any particular V gene.

[0256] Designing a mouse so that it rearranges a single V.sub.H gene (present as a single segment or a set of variants) with a variety of human D and J gene segments (e.g., D.sub.H and J.sub.H segments) provides an in vivo junctional diversity/combinatorial diversity/somatic hypermutation permutation machine that can be used to iterate mutations in resulting rearranged heavy chain variable region sequences (e.g., V/D/J or V/J, as the case may be). In such a mouse, the clonal selection process operates to select suitable variable regions that bind an antigen of interest that are based on a single preselected V.sub.H gene (or variants thereof). Because the mouse's clonal selection components are dedicated to selection based on the single preselected V.sub.H gene segment, background noise (e.g., a wide variety of non antigen-binding V.sub.H domains derived from many germline gene segments) is largely eradicated. With judicious selection of the V.sub.H gene segment, a relatively larger number of clonally selected, antigen-specific antibodies can be screened in a shorter period of time than with a mouse with a large diversity of V segments.

[0257] Preselecting limited repertoire and restricting a mouse to a single V segment provides a system for permuting V/D/J junctions at a rate that is in various embodiments higher than that observed in mice that otherwise have up to 40 or more V segments to recombine with D and J regions. Removal of other V segments frees the locus to form more V/D/J combinations for the preselected V segment than otherwise observed. The increased number of transcripts that result from the recombination of the preselected V with one of a plurality of D and one of a plurality of J segments will feed those transcripts into the clonal selection system in the form of pre-B cells, and the clonal selection system is thus dedicated to cycling B cells that express the preselected V region. In this way, more unique V region rearrangements derived from the preselected V segment can be screened by the organism than would otherwise be possible in a given amount of time.

[0258] In various aspects, mice are described that enhance the junctional diversity of V/D/J recombinations for the preselected V region, because all or substantially all recombinations of the immunoglobulin heavy chain variable locus will be of the preselected V segment and the D and J segments that are placed in such mice. Therefore, the mice provide a method for generating a diversity of CDR3 segments using a base, or restricted V.sub.H gene repertoire.

[0259] In one aspect, a non-human animal is provided, wherein the B cell population of the non-human animal expresses immunoglobulin heavy chains that are derived from no more than one, or no more than two human V.sub.H gene segments. In one embodiment, each of the no more than one, or no more than two, human V.sub.H gene segments are present in two or more polymorphic forms. In one embodiment, the human V.sub.H gene segment is present in three, four, five, six, seven, eight, nine, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 polymorphic forms. In one embodiment, the non-human animal expresses a human light chain variable domain derived from a human V.sub.L gene segment.

[0260] In one aspect, a method is provided for generating a B cell population in a non-human animal, wherein the B cell population expresses human heavy chains derived from a single germline human V.sub.H gene segment and two or more human D gene segments and two or more human J gene segments; the method comprising a step of immunizing a non-human animal as described herein with an antigen of interest, and allowing the non-human animal to mount an immune response to the antigen of interest, wherein the immune response comprises expressing the human heavy chains on the surface of B cells in the B cell population In one embodiment, the non-human animal is a rodent (e.g., a mouse or rat). In one embodiment, the human V.sub.H gene segment, human D.sub.H segment, and human J.sub.H segment are operably linked to a non-human constant region gene. In one embodiment, the non-human animal further comprises a nucleic acid sequence encoding a human V.sub.L domain. In one embodiment, the nucleic acid sequence encoding the human V.sub.L domain is linked to a non-human light chain constant region gene sequence.

[0261] In one aspect, a method for making a non-human animal that expresses an immunoglobulin population characterized by the immunoglobulins having heavy chains that are derived from a plurality of rearrangements of a single human V.sub.H gene segment (or sing human V.sub.H gene family member) and one of a plurality of D.sub.H gene segments and one of a plurality of J.sub.H gene segments, is provided. In one embodiment, the human V.sub.H gene segment is a human V.sub.H1-69 gene segment. In one embodiment, the human V.sub.H gene segment is a human V.sub.H1-2 gene segment.

[0262] In one aspect, a method is provided for generating a population of human immunoglobulin heavy chain variable domains whose CDR1 and CDR2 are derived from the same germline V.sub.H gene segment, and whose CDR3 are derived from the germline gene segment and two or more human D segments, and two or more human J segments; the method comprising immunizing a non-human animal as described herein with an antigen of interest, and allowing the non-human animal to mount an immune response to the antigen of interest, wherein the immune response comprises expressing the human heavy chain variable domains in the context of a light chain variable domain. In one embodiment, the non-human animal is a rodent (e.g., a mouse or rat). In one embodiment, the human V.sub.H gene segment, human D segment, and human J segment are operably linked to a non-human constant region gene. In one embodiment, the non-human animal further comprises a nucleic acid sequence encoding a human V.sub.L domain. In one embodiment, the nucleic acid sequence encoding the human V.sub.L domain is linked to a non-human light chain constant region gene sequence.

[0263] In one aspect, a genetically modified non-human animal is provided, wherein the non-human animal is incapable of expressing a non-human V.sub.H domain, and wherein each immunoglobulin heavy chain of the heavy chain population expressed in the animal comprises a human V.sub.H domain comprising a CDR1 and a CDR2 that are identical but for one or more somatic hypermutations, and wherein the heavy chain population comprises a plurality of CDR3 sequences derived from a plurality of rearrangements with a plurality of D and J gene segments.

[0264] In one aspect, a biological system for generating variation in CDR3 identity and length is provided, comprising a genetically modified non-human animal as described herein, wherein the non-human animal comprises no more than or no more than two human V.sub.H gene segments, and two or more D gene segments and one or more J gene segments, wherein the non-human animal further comprises a humanized immunoglobulin light chain locus. In various embodiments, the non-human animal in response to immunization with an antigen of interest generates an immune response that comprises expressing an immunoglobulin heavy chain population characterized by each heavy chain having CDR1s and CDR2s that differ only by somatic hypermutation, and CDR3s that differ by rearrangement and somatic hypermutation. In one embodiment, the biological system is a mouse that is genetically modified as described herein. In one embodiment, the human V.sub.H gene segment and the human V.sub.L gene segment are at endogenous mouse heavy and light immunoglobulin loci, respectively. In one embodiment, one or more of the human V.sub.H gene segment and the human V.sub.L gene segment are on transgenes (i.e., at a locus other than an endogenous immunoglobulin locus).

EXAMPLES

[0265] The following examples are provided so as to describe to those of ordinary skill in the art how to make and use methods and compositions of the invention, and are not intended to limit the scope of what the inventors regard as their invention. Unless indicated otherwise, temperature is indicated in Celsius, and pressure is at or near atmospheric. In the foregoing Examples, when the use of kits and/reagents from various suppliers is indicated, all procedures were carried out according to manufacturer's specifications.

Example 1

Construction of Restricted Heavy Chain Loci

[0266] A uniquely engineered human heavy chain locus containing a single human V.sub.H gene segment located upstream of all the human D.sub.H and J.sub.H gene segments was created by a series of homologous recombination reactions in bacterial cells (BHR) using Bacterial Artificial Chromosome (BAC) DNA. Several targeting constructs for creation of a single V.sub.H containing heavy chain locus were constructed using VELOCIGENE.RTM. genetic engineering technology (see, e.g., U.S. Pat. No. 6,586,251 and Valenzuela, D. M. et al. (2003) High-throughput engineering of the mouse genome coupled with high-resolution expression analysis. Nature Biotechnology 21 (6): 652-659).

[0267] Construction of a Human V.sub.H1-69 Restricted Heavy Chain Locus. Briefly, four modifications were performed using human BAC DNA to create a targeting construct containing a human V.sub.H1-69 gene segment with all the human D.sub.H and J.sub.H segments (FIG. 1). In the first modification, a modified human BAC containing multiple distal (5') human V.sub.H gene segments, including V.sub.H1-69, an upstream hygromycin selection cassette and a 5' mouse homology arm was targeted with a second spectinomycin cassette, which also contained a modified recombination signal sequence (RSS; BHR 1, FIG. 1, top left). This modified recombination signal sequence (RSS) introduced two point mutations (T to A and G to A) in the 3' RSS region of the human V.sub.H1-69 gene changing the RSS nonamer to the optimal consensus sequence. Thus, the first modification (BHR 1) created a human genomic fragment containing the human V.sub.H1-69 gene segment with a modified 3' RSS, a unique AsiSI restriction site about 180 bp downstream of the RSS and a spectinomycin cassette (FIG. 1, middle left).

[0268] The second modification (BHR 2) included the use of a neomycin (Neo) cassette flanked by Frt sites to delete the hygromycin cassette and 5' human V.sub.H gene segments upstream of the V.sub.H1-69 gene segment. This modification was targeted 5' to the human V.sub.H1-69 gene segment to leave intact about 8.2 kb of the promoter region of human V.sub.H1-69 and the 5' mouse homology arm (FIG. 1, bottom left).

[0269] The third modification (BHR 3) included another spectinomycin cassette flanked by uniquely engineered 5' PI-SceI and 3' AsiSI sites targeted to a human genomic fragment containing the first three functional human V.sub.H gene segments and all the human D.sub.H and J.sub.H gene segments (FIG. 1, middle right). The human genomic fragment was previously targeted with a neomycin cassette and contained 5' and 3' homology arms containing the mouse genomic sequence 5' and 3' of the endogenous heavy chain locus including the 3' intronic enhancer and the IgM gene. This modification deleted the 5' mouse genomic sequence and human V.sub.H gene segments, leaving about 3.3 kb of the V.sub.H-D.sub.H intergenic region upstream of the human D.sub.H1-1 gene segment, all of the human D.sub.H and J.sub.H segments, and the 3' mouse genomic fragment containing the 3' intronic enhancer and the IgM gene (FIG. 1, bottom right).

[0270] The fourth modification was achieved by employing the unique PI-SceI and AsiSI sites (described above) to ligate the two modified BACs from BHR 2 and BHR 3 (FIG. 1, bottom center), which yielded the final targeting construct. The final targeting construct for the creation of a modified heavy chain locus containing a single human V.sub.H gene segment and all the human D.sub.H and J.sub.H gene segments in ES cells contained, from 5' to 3', a 5' homology arm containing about 20 kb of mouse genomic sequence upstream of the endogenous heavy chain locus, a 5' Frt site, a neomycin cassette, a 3' Frt site, about 8.2 kb of the human V.sub.H1-69 promoter, the human V.sub.H1-69 gene segment with a modified 3' RSS, 27 human D.sub.H gene segments, six human J.sub.H segments, and a 3' homology arm containing about 8 kb of mouse genomic sequence downstream of the mouse J.sub.H gene segments including the 3' intronic enhancer and IgM gene (FIG. 1, bottom). The Human V.sub.H1-69 Targeting Vector (SEQ ID NO: 3) was linearized and electroporated into mouse ES cells heterozygous for a deletion of the endogenous heavy chain locus.

[0271] Construction of a Human V.sub.H1-2 Restricted Heavy Chain Locus. Using the steps described above, other polymorphic V.sub.H gene segments in the context of mouse heavy chain constant regions are employed to construct a series of mice having a restricted number immunoglobulin heavy chain V segments (e.g., 1, 2, 3, 4, or 5), wherein the V segments are polymorphic variants of a V gene family member. Exemplary polymorphic V.sub.H gene segments are derived from human V.sub.H gene segments including, e.g., V.sub.H1-2, V.sub.H2-26, V.sub.H2-70 and V.sub.H3-23. Such human V.sub.H gene segments are obtained, e.g., by de novo synthesis (e.g., Blue Heron Biotechnology, Bothell, Wash.) using sequences available on published databases. Thus, DNA fragments encoding each V.sub.H gene are, in some embodiments, generated independently for incorporation into targeting vectors, as described herein. In this way, multiple modified immunoglobulin heavy chain loci comprising a restricted number of V.sub.H gene segments are engineered in the context of mouse heavy chain constant regions. An exemplary targeting strategy for creating a restricted humanized heavy chain locus containing a human V.sub.H1-2 gene segment, 27 human D.sub.H gene segments, and six human J.sub.H gene segments is shown in FIG. 2.

[0272] Briefly, a modified human BAC clone containing three human V.sub.H gene segments (V.sub.H6-1, V.sub.H1-2, V.sub.H1-3), 27 human D.sub.H gene segments, and six human J.sub.H gene segments (see U.S. Ser. No. 13/404,075; filed 24 Feb. 2012, herein incorporated by reference) is used to create a restricted humanized heavy chain locus containing a human V.sub.H1-2 gene segment. This modified BAC clone functionally links the aforementioned human heavy chain gene segments with the mouse intronic enhancer and the IgM constant region. The restricted human V.sub.H1-2 based heavy chain locus is achieved by two homologous recombinations using the modified human BAC clone described above.

[0273] For the first homologous recombination, 205 bp of the human V.sub.H6-1 gene segment (from about 10 bp upstream (5') of the V.sub.H6-1 start codon in exon 1 to about 63 bp downstream (3') of the beginning of exon 2) in the modified human BAC clone is deleted by bacterial homologous recombination using a spectinomycin (aadA) cassette flanked by unique PI-SceI restriction sites (FIG. 2, BHR 1). This allows for subsequent removal of the aadA cassette without disrupting other human gene segments within the restricted heavy chain locus.

[0274] For the second homologous recombination, the 5' end of the modified human BAC clone including the entire human V.sub.H1-3 gene segment and about 60 bp downstream (3') of the gene segment is deleted by homologous recombination using a hygromycin cassette containing flanking 5' AsiSI and 3' AscI restriction sites (FIG. 2, BHR 2). As described above, the spectinomycin cassette is optionally removed after confirmation of the final targeting vector including deletion of the two human V.sub.H gene segments flanking the human V.sub.H1-2 gene segment (FIG. 2, bottom). An exemplary human V.sub.H1-2 targeting vector is set forth in SEQ ID NO: 70.

[0275] Employing polymorphic V.sub.H gene segments in a restricted immunoglobulin heavy chain locus represents a novel approach for generating antibodies, populations of antibodies, and populations of B cells that express antibodies having heavy chains with diverse CDRs derived from a single human V.sub.H gene segment. Exploiting the somatic hypermutation machinery of the host animal along with combinatorial association with rearranged human immunoglobulin light chain variable domains results in the engineering of unique heavy chains and unique V.sub.H/V.sub.L pairs that expand the immune repertoire of genetically modified animals and enhance their usefulness as a next generation platform for making human therapeutics, especially useful as a platform for making neutralizing antibodies specific for human pathogens.

[0276] Thus, using the strategy outlined above for incorporation of additional and/or other polymorphic V.sub.H gene segments into the mouse immunoglobulin heavy chain locus allows for the generation of novel antibody repertoires for use in neutralizing human pathogens that might otherwise effectively evade the host immune system.

[0277] Targeted ES cells described above were used as donor ES cells and introduced into an 8-cell stage mouse embryo by the VELOCIMOUSE.RTM. method (supra). Mice bearing a humanized heavy chain locus containing a single human V.sub.H gene segment, all the human D.sub.H and J.sub.H gene segments operably linked to the mouse immunoglobulin constant region genes were identified by genotyping using a modification of allele assay (Valenzuela et al., supra) that detected the presence of the neomycin cassette, the human V.sub.H gene segment and a region within the human D.sub.H and J.sub.H gene segments as well as endogenous heavy chain sequences. Table 4 sets forth the primers and probes used in this assay to confirm mice harboring a restricted heavy chain locus containing a single human V.sub.H1-69 gene segment, 27 human D.sub.H gene segments and six human J.sub.H gene segments.

[0278] Mice bearing an engineered heavy chain locus that contains a single human V.sub.H gene segment can be bred to a FLPe deletor mouse strain (see, e.g., Rodriguez, C. I. et al. (2000) High-efficiency deleter mice show that FLPe is an alternative to Cre-IoxP. Nature Genetics 25: 139-140) in order to remove any Frt'ed neomycin cassette introduced by the targeting vector that is not removed, e.g., at the ES cell stage or in the embryo. Optionally, the neomycin cassette is retained in the mice.

[0279] Pups are genotyped and a pup heterozygous for a humanized heavy chain locus containing a single human V.sub.H gene segment, all the human D.sub.H and J.sub.H segments operably linked to the endogenous mouse immunoglobulin constant genes is selected for characterizing the immunoglobulin heavy chain repertoire.

TABLE-US-00004 TABLE 4 Name SEQ ID (Region Detected) Sequence (5'-3') NO: hyg Forward: TGCGGCCGAT CTTAGCC 4 (hygromycin Reverse: TTGACCGATT CCTTGCGG 5 cassette) Probe: ACGAGCGGGT TCGGCCCATT C 6 neo Forward: GGTGGAGAGG CTATTCGGC 7 (neomycin Reverse: GAACACGGCG GCATCAG 8 cassette) Probe: TGGGCACAAC AGACAATCGG CTG 9 hIgH9T Forward: TCCTCCAACG ACAGGTCCC 10 (human D.sub.H-J.sub.H Reverse: GATGAACTGA CGGGCACAGG 11 genomic Probe: TCCCTGGAAC TCTGCCCCGA CACA 12 sequence) 77h3 Forward: CTCTGTGGAA AATGGTATGG AGATT 13 (human V.sub.H1-69 Reverse: GGTAAGCATA GAAGGTGGGT ATCTTT 14 gene segment) Probe: ATAGAACTGT CATTTGGTCC AGCAATCCCA 15 mIgHA7 Forward: TGGTCACCTC CAGGAGCCTC 16 (mouse D.sub.H-J.sub.H Reverse: GCTGCAGGGT GTATCAGGTG C 17 genomic Probe: AGTCTCTGCT TCCCCCTTGT 18 sequence) GGCTATGAGC 88710T Forward: GATGGGAAGA GACTGGTAAC ATTTGTAC 19 (mouse 3' V.sub.H Reverse: TTCCTCTATT TCACTCTTTG AGGCTC 20 genomic Probe: CCTCCACTGT GTTAATGGCT GCCACAA 21 sequence) mIgHd10 Forward: GGTGTGCGAT GTACCCTCTG AAC 22 (mouse 5' V.sub.H Reverse: TGTGGCAGTT TAATCCAGCT TTATC 23 genomic Probe: CTAAAAATGC TACACCTGGG 24 sequence) GCAAAACACC TG mIgHp2 Forward: GCCATGCAAG GCCAAGC 25 (mouse J.sub.H Reverse: AGTTCTTGAG CCTTAGGGTG CTAG 26 genomic Probe: CCAGGAAAAT GCTGCCAGAG CCTG 27 sequence)

Example 2

Characterization of Mice Expressing Heavy Chains Derived From a Single Human V.sub.H Gene Segment

[0280] Mice homozygous for a single human V.sub.H gene segment at the endogenous heavy chain locus as described in Example 1 were evaluated for expression and B cell development using flow cytometry.

[0281] Briefly, spleens and bone marrow was harvested from wild type (n=3 per group; six weeks old, male and female) and mice homozygous for a single human V.sub.H gene segment, all human D.sub.H and J.sub.H gene segments operably linked to mouse heavy chain constant regions. Red blood cells from spleens were lysed with ACK lysis buffer (Lonza Walkersville), followed by washing with complete RPMI medium.

[0282] Flow cytometry. Cells (1.times.10.sup.6) were incubated with anti-mouse CD16/CD32 (2.4G2, BD PHARMINGEN.TM.) on ice for 10 minutes, followed by labeling with the following antibody panels for 30 minutes on ice. Bone marrow panel: anti-mouse FITC-CD43 (1B11, BioLegend), PE-ckit (2B8, BIOLEGEND.RTM.), PeCy7-IgM (II/41, EBIOSCIENCE.RTM.), PerCP-Cy5.5-IgD (11-26c.2a, BIOLEGEND.RTM.), APC-eFluor 780-6220 (RA3-6B2, EBIOSCIENCE.RTM.), APC-CD19 (MB19-1, EBIOSCIENCE.RTM.). Bone marrow and spleen panel: anti-mouse FITC-Ig.kappa. (187.1, BD Biosciences), PE-Ig.lamda. (RML-42, BIOLEGEND.RTM.), PeCy7-IgM (II/41, EBIOSCIENCE.RTM.), PerCP-Cy5.5-IgD (11-26c.2a, BIOLEGEND.RTM.), Pacific Blue-CD3 (17A2, BIOLEGEND.RTM.), APC-B220 (RA3-6B2, EBIOSCIENCE.RTM.), APC-H7-CD19 (ID3, BD Biosciences). Bone marrow: immature B cells (B220.sup.intIgM.sup.+), mature B cells (B220.sup.hiIgM.sup.+), pro B cells (CD19.sup.+ckit.sup.+CD43.sup.+), pre B cells (CD19.sup.+ckit.sup.-CD43.sup.-), immature Ig.kappa..sup.+ B cells (B220.sup.intIgM.sup.+Ig.kappa..sup.+Ig.lamda..sup.-), immature Ig.lamda..sup.+ B cells (B220.sup.intIgM.sup.+Ig.kappa..sup.-Ig.lamda..sup.+), mature Ig.kappa..sup.+ B cells (B220.sup.hiIgM.sup.+Ig.kappa..sup.+Ig.lamda..sup.-), mature Ig.lamda..sup.+ B cells (B220.sup.hiIgM.sup.+Ig.kappa..sup.-Ig.lamda..sup.+). Spleen: B cells (CD19.sup.+), mature B cells (CD19.sup.+IgD.sup.hiIgM.sup.int), transitional/immature B cells (CD19.sup.+IgD.sup.intIgM.sup.hi). Bone marrow and spleen: Ig.kappa..sup.+ B cells (CD19.sup.+Ig.kappa..sup.+Ig.lamda..sup.-), Ig.lamda..sup.+ B cells (CD19.sup.+Ig.kappa..sup.-Ig.lamda..sup.+).

[0283] Following staining, cells were washed and fixed in 2% formaldehyde. Data acquisition was performed on a LSRII flow cytometer and analyzed with FLOWJO.TM. software (Tree Star, Inc.). Results for the splenic compartment are shown in FIGS. 3, 4A and 5-7. Results for the bone marrow compartment are shown in FIGS. 4B and 8-11B.

[0284] Human V.sub.H Expression. Expression of the human V.sub.H1-69 gene segment was determined for mice heterozygous and homozygous for a human V.sub.H1-69 gene segment, all human D.sub.H and J.sub.H gene segments operably linked to mouse heavy chain constant regions by a quantitative PCR assay using TAQMAN.RTM. probes.

[0285] Briefly, CD19.sup.+ B cells were purified from the spleens of groups of mice (n=3 per group) using mouse CD19 microbeads (Miltenyi Biotec) according to manufacturer's specifications. Total RNA was purified using the RNEASY.TM. Mini kit (Qiagen) and genomic RNA was removed using an RNase-free DNase on-column treatment (Qiagen). About 200 ng mRNA was reverse-transcribed into cDNA using the First Stand cDNA Synthesis kit (Invitrogen), followed by amplification with the TAQMAN.RTM. Universal PCR Master Mix (Applied Biosystems) using the ABI 7900 Sequence Detection System (Applied Biosystems). Unique primer/probe combinations were employed to specifically determine expression of human V.sub.H1-69-derived heavy chains (Table 5). Relative expression was normalized to the mouse .kappa. constant region (mC.kappa.). The results are shown in FIG. 12.

TABLE-US-00005 TABLE 5 Sequence SEQ ID Name (5'-3') NO: hIgHV1-69 Sense: AACTACGCAC AGAAGTTCCA GG 28 Anti-sense: GCTCGTGGAT TTGTCCGC 29 Probe: CAGAGTCACG ATTACC 30 mC.kappa. Sense: TGAGCAGCAC CCTCACGTT 31 Antisense: GTGGCCTCAC AGGTATAGCT 32 GTT Probe: ACCAAGGACG AGTATGAA 33

Example 3

Humoral Immune Response in Mice Expressing Heavy Chains Derived From a Single Human V.sub.H Gene Segment

[0286] The humoral immune response was determined for mice homozygous for human heavy and .kappa. light chain variable gene loci (H.sub..kappa.) and mice homozygous for a single human V.sub.H gene segment, all human D.sub.H and J.sub.H gene segments operably linked to mouse heavy chain constant regions (1hV.sub.H HO) by comparative immunization using a human cell surface receptor (Antigen A).

[0287] Immunization. Serum was collected from groups of mice prior to immunization with the above antigen. Antigen (2.35 .mu.g each) was administered in an initial priming immunization mixed with 10 .mu.g of CpG oligonucleotide (Invivogen) and 25 .mu.g of Adju-phos (Brenntag) as adjuvants. The immunogen was administered via footpad (f.p.) in a volume of 25 .mu.l per mouse. Subsequently, mice were boosted via f.p. with 2.3 .mu.g of antigen along with 10 .mu.g CpG and 25 .mu.g Adju-Phos as adjuvants on days 3, 6, 11, 13, 17, and 20 for a total of six boosts. Mice were bled on days 15 and 22 after the fourth and sixth boosts, respectively, and antisera were assayed for antibody titers to Antigen A.

[0288] Antibody titers were determined in sera of immunized mice using an ELISA assay. Ninety six-well microtiter plates (Thermo Scientific) were coated with Antigen A (1 .mu.g/ml) in phosphate-buffered saline (PBS, Irvine Scientific) overnight at 4.degree. C. The following day, plates were washed with phosphate-buffered saline containing 0.05% Tween 20 (PBS-T, Sigma-Aldrich) four times using a plate washer (Molecular Devices). Plates were then blocked with 250 .mu.l of 1% bovine serum albumin (BSA, Sigma-Aldrich) in PBS and incubated for one hour at room temperature. The plates were then washed four times with PBS-T. Sera from immunized mice and pre-immune sera were serially diluted ten-fold in 0.1% BSA PBS-T starting at 1:100 and added to the blocked plates in duplicate and incubated for one hour at room temperature. The last two wells were left blank to be used as secondary antibody control. The plates were again washed four times with PBS-T in a plate washer. A 1:5000 dilution of goat anti-mouse IgG-Fc-Horse Radish Peroxidase (HRP, Jackson Immunoresearch) conjugated secondary antibody was added to the plates and incubated for one hour at room temperature. Plates were again washed eight times with PBS-T and developed using TMB/H.sub.2O.sub.2 as substrate. The substrate was incubated for twenty minutes and the reaction stopped with 1 N H.sub.2SO.sub.4 (VWR). Plates were read on a spectrophotometer (Victor, Perkin Elmer) at 450 nm. Antibody titers were calculated using GRAPHPAD PRISM.TM. (GraphPad Software, Inc).

[0289] Serum titer was calculated as serum dilution within experimental titration range at the signal of antigen binding equivalent to two times above background. Antibody titer for the humoral immune response against a human cell surface receptor (Antigen A) is set forth in FIG. 19.

[0290] In a similar experiment, humoral immune responses were determined for mice homozygous for human heavy and .kappa. light chain variable gene loci (H.sub..kappa.) and mice homozygous for a single human V.sub.H gene segment, all human D.sub.H and J.sub.H gene segments operably linked to mouse heavy chain constant regions (1hV.sub.H HO) by comparative immunization using influenza viral vaccines FLUVIRIN.RTM. (Novartis Vaccines) and FLUMIST.RTM. (MedImmune LLC).

[0291] Briefly, serum was collected from groups of mice prior to immunization with the above antigen (as described above). Mice (n=5) homozygous for a single human V.sub.H gene segment (V.sub.H1-69), all human D.sub.H and J.sub.H gene segments operably linked to mouse heavy chain constant regions (1hV.sub.H HO) were immunized intra-nasally (i.n.) with FLUMIST.RTM. (live attenuated influenza vaccine) at 1/3 the normal dose/mouse. One normal dose of FLUMIST.RTM. contains 10.sup.6.5-7.5 FFU (fluorescent focus units) of live attenuated influenza vaccine. Therefore, each mouse was primed with 70 .mu.l FLUMIST.RTM. on day 1 followed by i.n. boost on days 3, 6, 11, 13, 17, 20 for a total of 6 boosts. No adjuvants were employed in this immunization. The mice were bled on days 15 and 22 after 4th and 6th boosts respectively and antiserum assayed for antibody titers to FLUMIST.RTM. (as described above).

[0292] In a similar manner, in immunizations with FLUVIRIN.RTM., pre-immune serum was collected from mice prior to initiation of immunization. Mice (n=5) homozygous for a single human V.sub.H gene segment (V.sub.H1-69), all human D.sub.H and J.sub.H gene segments operably linked to mouse heavy chain constant regions (1hV.sub.H HO) were immunized with FLUVIRIN.RTM. (trivalent inactivated influenza vaccine) via footpad (fp.) with 0.75 .mu.g each of hemagglutinin/mouse/boost. Mice were primed on day 1 followed by f.p. boost on days 3, 6, 11, 13, 17, 20 for a total of 6 boosts. No adjuvants were employed in this immunization. The mice were bled on days 15 and 22 after 4th and 6th boosts respectively and antiserum assayed for antibody titers to FLUVIRIN.RTM. (as described above).

[0293] Serum titer was calculated as serum dilution within experimental titration range at the signal of antigen binding equivalent to two times above background. Antibody titer for the humoral immune response against FLUMIST.RTM. and FLUVIRIN.RTM. is set forth in FIG. 20.

[0294] As shown in this Example, antibody titers generated in 1hV.sub.H HO mice were comparable to those generated in mice having a plurality of human V.sub.H gene segments (H.sub..kappa.) for both a human cell surface receptor and a viral antigen (e.g., influenza). Thus, mice having immunoglobulin heavy chain loci restricted to a single V.sub.H gene segment are capable of mounting a robust immune response to antigen in a manner comparable to mice having immunoglobulin heavy chain loci containing a plurality of human V.sub.H gene segments (e.g., 80 V.sub.H).

Example 4

Analysis of Antibody Gene Usage and CDR3 Length in Mice Having a Restricted Immunoglobulin Heavy Chain Locus

[0295] Splenocytes harvested from mice homozygous for a single human V.sub.H gene segment at the endogenous heavy chain locus and homozygous for a replacement of the endogenous .kappa. light chain variable loci with human .kappa. light chain variable loci immunized with a human cell surface receptor (Antigen A) were analyzed for heavy and light chain gene segment usage by reverse-transcriptase polymerase chain reaction (RT-PCR) on mRNA from splenic B cells.

[0296] Briefly, spleens were harvested and homogenized in 1.times.PBS (Gibco) using glass slides. Cells were pelleted in a centrifuge (500.times.g for 5 minutes), and red blood cells were lysed in ACK Lysis buffer (Gibco) for 3 minutes. Cells were washed with 1.times.PBS and filtered using a 0.7 .mu.m cell strainer. B-cells were isolated from spleen cells using MACS magnetic positive selection for CD19 (Miltenyi Biotec). Total RNA was isolated from pelleted B-cells using the RNeasy Plus Kit (Qiagen). PolyA.sup.+ mRNA was isolated from total RNA using the Oligotex.RTM. Direct mRNA mini kit (Qiagen).

[0297] Double-stranded cDNA was prepared from splenic B cell mRNA by 5' RACE using the SMARTer.TM. Pico cDNA Synthesis Kit (Clontech) with substitution of the supplied reverse transcriptase and dNTPs with Superscript.RTM. II and dNTPs (Invitrogen). V.sub.H and V.sub..kappa. antibody repertoires were amplified from the cDNA using primers specific for IgM, IgG, or Ig.kappa. constant regions and the SMARTer.TM. 5' RACE primer (Table 6). PCR products were purified using a QlAquick.RTM. PCR Purification Kit (Qiagen). A second round of PCR was done using the same 5' RACE primer and a nested 3' primer specific for the IgM, IgG, or Ig.kappa. constant regions (Table 7). Second round PCR products were purified using a SizeSelect.TM. E-Gel.RTM. system (Invitrogen). A third PCR was performed with primers that added 454 adapters and barcodes. Third round PCR products were purified using Agencourt.RTM. AMPure.RTM. XP Beads (Beckman Coulter). Purified PCR products were quantified by SYBR.RTM. qPCR using a KAPA Library Quantification Kit (KAPA Biosystems). Pooled libraries were subjected to emulsion PCR (emPCR) using a 454 GS Junior Titanium Series Lib-A emPCR Kit (Roche Diagnostics) and bidirectional sequencing using Roche 454 GS Junior instrument according to manufacturer's specifications.

[0298] Bioinformatic analysis. The 454 sequences were sorted based on the sample barcode perfect match and trimmed for quality. Sequences were annotated based on alignment of rearranged immunoglobulin sequences to human germline V(D)J segment database using local installation of Igblast (NCBI, v2.2.25+). A sequence was marked as ambiguous and removed from analysis when multiple best hits with identical score were detected. A set of perl scripts was developed to analyze results and store data in mysql database. CDR3 region was defined between conserved C codon and FGXG motif for light and WGXG motif for heavy chains. CDR3 length was determined using only productive antibodies. From the nucleic acid sequences and predicted amino acid sequences of the antibodies, gene usage was identified for IgM-primed (15,650), IgG-primed (18,967), and Ig.kappa.-primed (26,804) sequences. Results are shown in Table 8, Table 9, FIG. 21 and FIG. 22.

[0299] Table 8 sets forth the percentage of observed human D.sub.H and J.sub.H gene segments used among IgM-primed (15,650 sequences) and IgG-primed (18,967 sequences) V.sub.H1-69 derived heavy chain variable region sequences. Human D.sub.H4-4/D.sub.H4-11 and human D.sub.H5-5/D.sub.H5-18 gene segments are presented in Table 8 together due to identical sequence identity between the respective pairs of D.sub.H gene segments. Table 9 sets forth the percentage of human V.sub..kappa. and J.sub..kappa. gene segments observed among light chains (26,804 sequences) cognate with V.sub.H1-69 derived heavy chain variable regions. Percentages in Tables 8 and 9 represent rounded values and in some cases may not equal 100% when added together.

[0300] Amino acid length of the CDR3 region of IgM-primed V.sub.H1-69-derived heavy chains is shown in FIG. 21. Amino acid length of the CDR3 region of IgG-primed V.sub.H1-69-derived heavy chains is shown in FIG. 22.

[0301] As shown in Tables 8 and 9, mice according to the invention generate antigen-specific antibodies containing V.sub.H1-69-derived heavy chains, which demonstrate a variety of rearrangements of a human V.sub.H1-69 gene segment with a variety of human D.sub.H segments and human J.sub.H segments. Further, the antigen-specific antibodies contain cognate human light chains containing human V.sub..kappa. domains resulting from a variety of rearrangements of human V.sub..kappa. and J.sub..kappa. gene segments.

TABLE-US-00006 TABLE 6 Primer Sequence (5'-3') 3' Cg1 outer GGAAGGTGTG CACACCGCTG GAC (SEQ ID NO: 71) 3' Cg2ac outer GGAAGGTGTG CACACCACTG GAC (SEQ ID NO: 72) 3' Cg2b outer GGAAGGTGTG CACACTGCTG GAC (SEQ ID NO: 73) 3' Cg3 outer AGACTGTGCG CACACCGCTG GAC (SEQ ID NO: 74) 3' mIgM CH1 TCTTATCAGA CAGGGGGCTC TC (SEQ ID outer NO: 75) 3' mIg.kappa.C outer AAGAAGCACA CGACTGAGGC AC (SEQ ID NO: 76)

TABLE-US-00007 TABLE 7 Primer Sequence (5'-3') 3' mIgG1/2b AGTGGATAGA CWGATGGGGG TG (SEQ ID CH1 inner NO: 77) 3' mIgG2a/2c AGTGGATAGA CCGATGGGGC TG (SEQ ID CH1 inner NO: 78) 3' mIgG3 AAGGGATAGA CAGATGGGGC TG (SEQ ID CH1 inner NO: 79) 3' mIg.kappa.M GGAAGACATT TGGGAAGGAC TG (SEQ ID CH1 inner NO: 80) 3'mIg.kappa.C-2 GGAAGATGGA TACAGTTGGT GC (SEQ ID inner NO: 81)

TABLE-US-00008 TABLE 8 Human D.sub.H IgM IgG Human J.sub.H IgM IgG 1-1 1.2 6.0 1 7.5 1.5 1-7 39.9 9.0 2 3.3 4.2 1-14 0.5 2.3 3 22.2 12.8 1-20 2.3 1.4 4 51.5 36.4 1-26 3.5 5.7 5 10.5 9.5 2-2 1.1 3.2 6 4.9 29.4 2-8 0.7 0.6 2-15 0.3 1.2 2-21 0.7 0.3 3-3 6.3 5.2 3-9 0.6 0.6 3-10 0.9 10.3 3-16 0.9 2.0 3-22 5.1 2.7 4-4/4-11 1.5 4.0 4-17 1.5 4.7 4-23 11.5 2.4 5-12 1.1 1.8 5-5/5-18 1.3 3.2 5-24 0.3 3.3 6-6 1.8 4.5 6-13 6.1 7.4 6-19 3.0 5.1 6-25 0.1 0.6 7-27 3.3 7.3

TABLE-US-00009 TABLE 9 Human V.kappa. % Observed Human J.kappa. % Observed 1-5 3.4 1 28.1 1-6 1.3 2 25.3 1-8 0 3 12.1 1-9 1.3 4 22.5 1-12 1.0 5 11.1 1-13 0 1-16 2.5 1-17 3.6 1-22 0 1-27 0.5 1-32 0 1-33 14.3 1-35 0 1-37 0 1-39 1.6 2-4 0 2-10 0 2-14 0 2-18 0 2-19 0 2-23 0 2-24 0.7 2-26 0 2-28 0 2-29 0 2-30 1.9 2-36 0 2-38 0 2-40 1.5 3-7 0 3-11 2.7 3-15 3.9 3-20 41.2 3-25 0 3-31 0 3-34 0 4-1 13.2 5-2 0.1 6-21 0 7-3 0

Sequence CWU 1

1

811872DNAHomo sapiens 1gcaggattta gggcttggtc tctcagcatc ccacacttgt acagctgatg tggcatctgt 60gttttctttc tcatcgtaga tcaggctttg agctgtgaaa taccctgcct catgcatatg 120caaataacct gaggtcttct gagataaata tagatatatt ggtgccctga gagcatcaca 180taacaaccac attcctcctc taaagaagcc cctgggagca cagctcatca ccatggactg 240gacctggagg ttcctctttg tggtggcagc agctacaggt aaggggcttc ctagtcctaa 300ggctgaggaa gggatcctgg tttagttaaa gaggatttta ttcacccctg tgtcctctcc 360acaggtgtcc agtcccaggt gcagctggtg cagtctgggg ctgaggtgaa gaagcctggg 420tcctcggtga aggtctcctg caaggcttct ggaggcacct tcagcagcta tgctatcagc 480tgggtgcgac aggcccctgg acaagggctt gagtggatgg gagggatcat ccctatcttt 540ggtacagcaa actacgcaca gaagttccag ggcagagtca cgattaccgc ggacgaatcc 600acgagcacag cctacatgga gctgagcagc ctgagatctg aggacacggc cgtgtattac 660tgtgcgagag acacagtgtg aaaacccaca tcctgagagt gtcagaaacc ctgagggaga 720aggcagctgt gccgggctga ggagatgaca gggtttatta ggtttaaggc tgtttacaaa 780atgggttata tatttgagaa aaaaagaaca gtagaaacaa gtacatactc ctctaatttt 840aagataatta ttccattcaa gagtcgtaat at 8722118PRTHomo sapiens 2Met Asp Trp Thr Trp Arg Phe Leu Phe Val Val Ala Ala Ala Thr Gly1 5 10 15Gly Val Gln Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys 20 25 30Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr 35 40 45Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly 50 55 60Leu Glu Trp Met Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr65 70 75 80Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr 85 90 95Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala 100 105 110Val Tyr Tyr Cys Ala Arg 115399294DNAArtificial Sequencesynthetic 3aagcttatct ctctgttgct cagactcatc taggaatttc agaaatttct gttctagcat 60ctcttccagc ttttgtctcc aaccctcatt ctcttctttc tttttttttt taaattatat 120gttctctgtc tttttaaaaa actttttaaa attaggtatt tatgtcattt acatttccaa 180tgctatccca aaagtcccac ccacgctccc caacccacta tcccacccac ccactcccac 240ttcttggccc tggcattcac agtgtactga gacatataaa gtttgcacaa ccaatgggcc 300tctctttcca ctgatggccg actaggccat cttctgatac atatgcagct agagacacga 360gattctgggg gtactggtta gttcatattg ttgttccacc tatagggttg cagatccttt 420tagctccttg ggtactttct ctagctcctc cattgggggc cctgtgatcc atccaatagc 480tgactgtgag catccacttc tgtgtttgct aggccccaga tagtctcaca agagacagct 540atatctgggt cctttcagca aaatcttgct agtgtatgca acggtgtcag agtttggaag 600ctgattatgg gatggatccc cggatatggc attctctagt tggttcatcc ttttgtctca 660gctccaaact ttgtctctgt aactccttcc atgggtgttt tgttcccagt tctaaggagg 720ggcaaagtat ccacactttg gtcttcattc ttcttgagtt tcatgtgttt tgcaaattgt 780atcttatatc ttgggtattc taagtttctg ggctaatatc cacttatcag tgagtacaca 840ttgtgtgagt tcttttgtga ttgggttacc tcactcagta tgatgccctc caggtccatc 900catttgccta ggaatttcat aaattcattc tttttaatag ctcagtagta ctccattgtg 960tagatgtacc acattttctg tattcattcc tctgttgagg ggcatctggg ttctttccag 1020cttctggcta ttataaataa ggctgctatg aacatagtgg agcatgtgac cttcttaccg 1080gttgggacat cttctggata tatgcccagg agaggtattg ctggatcttc cggtagtact 1140atgtccaatt ttctgaggaa ctgacaaact gatttccaga gtggttagta ccagcttgca 1200atcccaccaa caatgagagg agtgttcgtc tttctccaca tcctcaccag catgctgctg 1260tcacctgaat ttttgatgct tagccattct gactggtgtg aggtggaatc tcagggttgt 1320tttgatttgt atttccctga tgattaagga tgctgaacat tttctcaggt gcttctcagc 1380cattcagtat tctttaggtg agaattcttt gtttagctct aagccccatt tttttaatgg 1440ggttatttga ttttctggag tccaccttct tgagtttttt tttccatttt ttattacata 1500atttcctcaa ttacatttcc aatgctatcc caaaagtccc ccataccctc ccccccccaa 1560ttccctaccc accccttccc atttttttgg ccctggcgtt cccctgtact ggggcatata 1620aagtttgtgt gtccaatggg cttctctttc cagtgatggc tgactaggcc atcttttgat 1680acatatgcag ctagagtcaa gagctcccgg gtactggtta gttcataatg ttgttccacc 1740tatagggttg cagatccctt tagcttcttg ggtactttct ctagctcctc cattgggagc 1800cctgtgatcc atccaatagc tgactgtgag catccacttc tgtgtttgct aggccccggc 1860atagtctcac aagagacagc tacatctggg tccttttgat aaaatcttgc tagtgtatgc 1920aagggtgtca gcatttggaa gctgattatg gggtggatcc ctggatatgg cagtctctac 1980atggtccatc cttttgtctc agctccaaac tttgtctctg taacttcttc catgagtgtt 2040ttgttcccaa ttctaaggag gggcatagtg tccacacttc attcttcatt cttcttgagt 2100ttcatgtgtt tagcaaattg tatcttatat cttgggtatc ctaggttttg ggctaatatc 2160cacttatcag tgagtacata ttgtgtgagt tcctttgtaa atgtgttacc tcactcagga 2220tgacgccctc caggtccatc catttggcta ggaatttcat aaattcattc tttttaatag 2280ctgagtagta ctccattgtg taaatgtacc acattttctg tactcattcc tctgttgagg 2340ggcatctggg ttctttatag gttctggcta ttataaataa ggttgctatg aacatagtgg 2400agcatgtgtc cttcttaccg gttgagacat cttctggata tatgcccagg cgaggtattg 2460ctggatcctc cggtagtact atgtccaatt ttctgaggaa ctgccagact gatttccaga 2520gtggttgtac aagcctgcac tctcaccaac aatggaggag tgttcctctt tctccacatc 2580cacgccagca tctgctgtca cctgaatttt tgatcttagc cattctgact ggtgtgaggt 2640ggaatctcag ggttgttttg atttgcattt ccctgatgat taaggatgtt gaacattttt 2700ttcaggtgct tctctgccat tcggtattcc tcaggtgaga attctttgtt cagttctgag 2760ccccattttt taatggggtt atttgatttt ctgaagtcca ccttcttgag ttctttatat 2820atgttggata ttagtcccct atctgattta cgataggtaa agatcctttc ccaatctgtt 2880ggtggtcttt ttctcttatt gacggtgtct tttgccttgc agaaactttg gagtgagttc 2940tttatatata ttggatatta gtcccctatc tgatttagga taggtaaaga tcctttccca 3000atctgttggt gacctttttg tcttattgac ggtgtctttt gccttgcaga atctttgcaa 3060ttttatgagg tcgcatttgt caattctcga tcttacagca caagtcattg ctgttctgtt 3120caggaatttt tcctctgtgc ccatatcttc gaggctttta cctgctttct cctctatatg 3180tttgagtgtc tctggtttaa tgtggagttc cttaatccac ttagatttga ccttagtaca 3240aggagatagg aatggatcaa ttcgcattct tctacatgat aaccgctagt tgtgccagca 3300ccatttgttg ataatgctgt cttttttcca ctggatggtt tttgctccct tgtctaagat 3360caagtgacca taggtgtgtg ggttcatttc tgggtcttca attctatttc attggtctac 3420ttgtctgttg ttataccagt accatgcaga ttttatcaca attgctctgt agtagagttt 3480taggtcaggc atggtgatta caccagaggt tttttttatc cttgagcaga gtttttgcta 3540tcctaggttt tgtgttattt cagatgaatt tgcagattgc cctttccagt tcgttgaaga 3600attgagttgg aattttgatg gggattgcat tgaatctgta gattgctttg gcaatatagc 3660catttttact atattgatcc tgccaatcca tgagcatggg agatctttcc atcttctcaa 3720atcttcttta atttctttct tcagagactt gaagttcttg tcatacagat ctttcacttc 3780cttagttaga gtcacgctaa ggtattttat attatttgtg actattgaga agggtgttgt 3840ttccctaatt tctttctcag cctgtttatc ctttgtgtac agaaaagcca ttgacttgtg 3900ttagttaatc tcatatccag ctacttcact gaagcggttt atcaggttta ggagttctct 3960ggtgtaattt ttagggtcac tcatatatac tatcatatca tctgcaaaaa gtgacatttt 4020gacttcttcc tttccaattt gtatcccctt gatctccttt tgttgtcgaa ttgctctggc 4080aaggacatca agtactatat tgaataggta gggagaaaat cggcaccctt gtctagtccc 4140tgattttagt aggattgctt caagtttctc accatttact ttgatgttgg ctactggttt 4200gctgttgaat gctttttatc atgtttaggt atgggccttg aattcctgat ctttccaaga 4260cttttatcat gaaagggtgt tggattttgt caaatgcttt ctccagcctt tcattctgag 4320gttgtgtctg tctttttccc tgagatgggt ttcctgtaag cagcaaaatg ttgggtcctg 4380tttgtgtagc ccgtctgtta ttctatgtct ttttattggg gagttgagtc cattgatatt 4440aagatatatt aaggaaaagt aattgttgct tcctattatt tttgttttta aagttggcat 4500tctgttcttg tggctgtctt cttttaggtt tgttgaagga ttcctttctt gctttttcta 4560ggtcgtggtt tccatccttg tattcatttt ttttctgtta ttatcctttg aaggactgga 4620ttcatggata gataatgtgt gaatttggtt ttgtcttgga atacttttgt ttctccatct 4680acggtaattg agagtttggc tgggtatagt agcctgggct ggcaattgtg ttgtcttagt 4740gtctatataa tgtctgtcca ggatcttctg gctttcatag tctgtggtga aaaatctggt 4800gtaattctga taggcttgcc tttatatgtt acttgaattt ttcacttact gcttttaata 4860ttctttcttt atttagtgca tttgttgttc tgattattat gtgtcgggag gaatttcttt 4920tctggtccag tctatttgga gttctgtagg cttcttgtat gttcacgggc atctctttct 4980ttaggtttgg gaagttttct tctataattt tgttgaagat atttgctggc ccttcaagtt 5040gaaaatgttc attctcatct actcctatta ttcgtatggt tggtcttctc attgtgtcct 5100ggatttcctg gatgttttga gttaggatct ttttgcattt tccattttct ttgattgttg 5160tgcagatgtt ctctatggaa tcttctgcac ctgatattct ctcttccatc tcttgtagtc 5220tgttgctgat gctcgcatct atggttccag atttctttcc tagggtttct atctccagtg 5280ttgccccact ttgggttttc tgtatagtgt ctacttccct ttttagatct agtatggttt 5340tgttcatttc catcacctgt ttgggtgtgt tttcctgttt ttctttaaag acttgcaact 5400ctttagcaga gttctcctgt atttaagtga gttattaaag tccttcttga tgtccagtac 5460cataattgtg agatatgcct ttaaatccaa gtctaggttt ttgggtgtgt tggggtgccc 5520tggactggct gagttgggag tgctgcattc tgatgatggt gagtggtctt ggtttctgct 5580agtaagattc ttacatctgc ctttcgccat ctggtaatct ctggagtcag ttgttaaagt 5640tgtctctggt taaagcttgt tcctctcgtg attctgttat tctcttccag cagacctggg 5700agactagctc tttcctgagt ttcagtggtc agagcactct ctgcaggcag gatttcctct 5760ttcagggaag gtgcacagat atctggtgtt cagatttgcc tcctggcaga agatgatggc 5820ctgaaacagg acctgtccca gaagctgtta gcttctgtag tcaacactgt cacctgtgca 5880gactagtctc ggtggagtcc gggaaccaag atgtctcctg cagatgctct ggcattccct 5940tctgggccgg gtgatcacct ctcctctggc agggaaggtg ccctggtgtc tggaacccga 6000aaagggggct gcctcagaag ctctgtggct actgcctgtc ccagaagctg ttagcttctg 6060tagtccacac tctcacctgt gcagactagt cttggtggag tctgggaacc aagatgtctc 6120ccgcagatgc tccagccatt ctcctctttc tgttgcttat tttgacctat gaaatcctgg 6180acatatagtt ctagtgttgc ttgtaatctc ttttctaagc caaggaattt tttttatcta 6240gggcacaatc ttttgagaag acatattaaa tcaagagaat aaatattgca agaccaataa 6300atgataaggt atctattttc tttaaatcca tcgctgtcaa accattcaaa atatcctcac 6360ataaagccaa aaagatattt attgtgtttc ccatcttagt tgagttcaag tcaatatttt 6420ggtgccattt tgttgcagta aatctctaac acaaatatgc ctgggcaatg aaaacacaac 6480tcagttaata tgaatacaga ttgttcagat ctaccactac actaccatct tcttcatcta 6540agagacccct tagaacttgc agtttctcca ggccttgtgc ttctgcgctg cttttcttct 6600tcttcctctt ctacattgct tctctcataa acctacttct ttttttccct ccttctgttc 6660catcttccct tttatctgcc caatcattag ctctccttta ttttacaaat taaggtgtga 6720agccggtttc taggaaatca cctgagtgct gacttgttcc ttgttcagag ccacgcacag 6780gagaacagaa ttaacatcaa atataattat ccccagggct atccacaaca cgtgcatcct 6840ataagatcac cacggactaa tgctggtctt caattacaac ataaacaaca aaaaccccac 6900atatatgtgg aaacaaatcg aactatacaa agaatcaatg aaaccaggag cttgttcttt 6960gagaaaaatc aacaagatag ataaaccctt agccagacta accagagggc acagagacag 7020tatccaaatt aataaagtca gaaatgaaag gaagacataa caatgaaata tatcttaaaa 7080taattaatct gtttgtagac tattagcagt tgaaaatatt aaaatcatgt tctacaaacg 7140tggaattatt attgataatt ttctcactgt gcttgaaatt agcattttct taatgtttaa 7200cttcaaagag tttttgctat tttgaaatat taaacatata cttactgata aaataatttc 7260cctcctaaca acactgataa tcttttttta agtaaactga ttattagaca atgtacacag 7320atatataatg tgttttaaat actctcccac tgtcaggtgg tatcatatag ggcctttgaa 7380tatattttta aatgtattat ttgtaatatt ttatggtctc tcctatgctt atttctgaaa 7440gaatattttg tatgttttga aacaatttag tatttaacat tagatatagg atcctcagtt 7500atggatagta ttaaatattc attaatgata tttttaaggt ataaaaggat atgaatataa 7560aagtttaaca aattttatgt attatttgat tctaaaaata ctcaatatta ttaatatgtt 7620tgatgtttaa aatgcattta aataataaaa acatttaaaa aaataaaatc aagaaatgag 7680gttctaagca gaggtcaagg aaaatgagga atagaaaaat agtaaaaatc aatatgtcca 7740tttattcaag gaaagctcct acatagacat tgcaccagat tagcaaatat tatggtcctc 7800atattagttt aagttaggag actatgctta tgttatctat ttacattcta aggagcctag 7860acatttgtga atggattaca ttataagagg aggatgtcta cttaagtagg catgaacgcc 7920tgtgcattgc accctatgag ttccatcagc attccatgat tggagtatga agaacagcat 7980tatagacatt acccagaacc ttagtggttc tagaatgcca agataaaaca atctaacctt 8040ctggatagta gggataaatg ttcctatatc atcagaattc actggtgccc tgaggatgtt 8100accctgctaa ctgacaattc acaggacatc acatggattc tgataagttg cagaaaagag 8160gagatgcatt caattggtcc tcctccttct aagctgcaat attaggtgca tccaatttgt 8220gaacttcaat ttagattaca atagacatga ataatctgaa ttcatgtagt acatattttt 8280gttttaatat gagttaccat tgttcagaaa attaaataca catgatcaca tattcctaca 8340tagtgctgtt agtttttcac atctctggga caatattcca aatatctcct tcattagtga 8400aaatatcaac tactgtaaag cttagctaac atgcctttgc aggaataaga acatcctgga 8460ttgaaagcta cacagggaga tgtaaaactt tctaagcaca cacattctcc atccattagg 8520atcatggtcc atgagatttt tctctctctc ttcttcccat taaatgcatg tacatgcagg 8580ttgggaaaca gattgtgttg cagaatacat ttgcttgatt tccacttcct tctcaatgca 8640aatatttttg aagtgttaat tttgctgtga gtaccacagt ggttcttgct ctttctgttg 8700actcctgtct gtgaatgttc caggaattca cacatggaca cacgtggggc tgcatctgag 8760ctccagactc actgttgtcc ttctgtcctc agctgctctg gcccaggcac agcctcgtga 8820attcaacaaa gaccctgatc tctcttgttt acacctcatt acaaatggga actgttagag 8880gtggacccaa ctgcatttcc atgaggaaag cacatgagtt tgagagggtc gttgatgata 8940aggtagaaac aactttaatt cataggctga gatatcagtc atcacctcca gataaacaag 9000agccatttct tcctgcatct gagccctgta agcacactag ctttaggaat atgttactgc 9060tgaagtcaga ttgggcaact tcatagtata caatagaaaa tctacctgca gatgagttca 9120gaaccagcag ggggcacaat ggggccaaga atccctagca gagagatgtg gtgtgtgtgc 9180aggggactct gcatcctctg tggtttcctt tcttaactta catgtacctg tagtgattga 9240catgtaacgt ttccacgctc aaacactgtg aagatacttt gctaaacact tcaaagattt 9300atgttttctt gatgtgtgca tgtgtgtatt cttttttgtt tttagacaca gggtttctct 9360gtgtagtcct ggctgccctg gaactcactc tgtagaccag gctggcctcg aactcagaaa 9420tctgcctgct tctgcctccc aagtgctgaa gttaaagaca tgtgccacca ttgcctggcc 9480atgtgtgtat tcttgatgca ctcttctgtt gacagataca cagtttattt ccataattta 9540tttattgtga tggtgctgca ataatcactt atgtacaaat gtttctgaag tatatttagt 9600tttggtcatt tgggtgatta tttttttctt tctagtatat agcattttgg aaaggtagat 9660attaattgta tgtatgggaa ggaggctgta aattctaata acttagctgc ttttgaaatt 9720tgtcctcaat tctatcatcc ttgtaaccac cttaaatcca tctattagcc ttgtcacaag 9780tgagccactg tctcaggctg caaatctttt tatagattag gtcgtgatgt tacatccaca 9840gcctctgcac aatgctcagg ggtgggatat gggatgaatt ccctcagaca gcattaggac 9900ttggatctca gcagactgat tcttgaccca aatgtctctt cttctctagc aggagtaagt 9960ccttatctaa gatgtactct gctcatgaat atgcaaatca attgagtcta tggtggtaaa 10020tatagggatg tctacacccc tcaaaaactt aagatcactg tcgtcttcac agtcacagga 10080gtacacagga catcaccatg tgttggagct gtatcatcct cttcctgtta gcaacagctg 10140cacgtaaggg gcttacagta gcaggcttga ggtctggcca tacactcatg tgacaatgac 10200atccactctg tccttccctt cacaggtgtg cactcccagg tccagctgca gcagtctggg 10260gctgagctgg tgaggcctgg ggcctcagtg aagatttcct gcaaggcttt tggctacacc 10320ttcacaaacc atcatataaa ctgggtgaag cagaggcctg gacagggcct ggactggatt 10380ggatatatta atccttataa tgattatact agctacagaa ccagaagttc aagggcaagg 10440ccacattgac tgtagacaaa tcctccagca cagcctatat ggagcttagc agcctgacat 10500ctgaggactc tgcagtctat tactgtgcaa gacacagtgc tacaaacaca tcctgagtgt 10560gtcagaaacc ctggaggaga agcaagcaga gctggaatgg agatgacaga aagattatca 10620tttagacttg ctcagaaaga gaaattttga atgcccattt attgcctctt ccttacagta 10680ctatagtgcc tgtttttgtt gacattttca aactaatttc caaagtcact accacaattt 10740acaatcacat aaaaagcaag caaggataac attattttct gtgcttactt gccatttata 10800ttcttgctta ttctcatctc actgaggtca tattgggaca ttaaatttct ggggttactt 10860tttattaaaa atttttcatt attcattcac tttacatcct tctagtcttc ctctcacaca 10920tgccctatcc ctttctcctc tgagaggatg gagccctccc taccctcgta tccccttacc 10980caggcacatc aagtgtctgc agtactagga atattctctg tcaatgctgc cagacaaggc 11040agacaagtta ggggatcagg attcacagga aggcaacagc ttgagggaca gcccccactg 11100aagttattgg tggattcaca tgaagactga gttgcacatc tgctacatat attcaggggt 11160cctatttaca gctcaagtag actcttgttg gtggtttagt ctcttagaac cccaagtgtc 11220caggttagtt gactctgtgg gtcttccttt ggagttccta tcccctccag atccctcagt 11280tcttctccca actcttccat aagacacccg taggtccatc caatgtttgg ttttgggttt 11340ttctgcatct gcttcagtca gctgctgggt ggagcatctc tgaggataat tatgagaagc 11400tcttatgtgc aagcataaca ggatatcatt attagtgtca gggactggtg cttggccatg 11460ggatgggtct caagtttggt cagttatttg gccattccca cagtctctga taatctttgt 11520ccctgcattt cttgtagaca ggaaaaatat tgggttgaaa gttttgtggg tgggttggcg 11580tctctattgc tccactgggc ttctttctgg atataggagt ttgcctcttc aggttccata 11640ttcccaaagt agtgtgtcac actaaggtca ctcccataca gagggacact cattctcttg 11700ccacgtctct gtccaccttc attggacctg aggttcctga atcatacaga actgcatgtg 11760tgcaaccaca cagaacaagg ctatctatca gaggcctacc ataccaggac catcaaggtt 11820caccttactc ccaatactga ctacaaaaag aacatcaagg accaatgcag tctatatgga 11880taaacacact tgaaagaaca caaacaagat tgagggcaac atgacacctc caaagcatac 11940ctaaccgagt acagcatgcc ctggatatcc taacacaatc aaaacacaag aaagttacct 12000taaatccagt cttataaagg tgatgaaggc ctttaaatag gaaatgaatt aatccttagg 12060ataatacagg acaatacatt cgaacagata gaggtcttta ggaggaaaga aataaatccc 12120tcaaagacat acatgaaaat acaattaaac aggtgaaagt aataactaca atggtgtaag 12180acctaaaaat ggaaatagaa gcaataaagt aacacaaact tagaatcttg aaggtggaaa 12240acctagagaa caggaatact agatgcaagg atgatatctt ctaggtccat ccatttgctt 12300gcacaattta tcatgtcctt gcttttaata gttgaacagt atttcattgt ttaaatgaac 12360cacatgttct gtctccattc tctggatgag ggggtgagca agtttttcca cattctggct 12420attacaaata gagctgctat gaacctagta gaaaacatat cctgtgtatg gtggagagtt 12480ttggagtata tcaccaagag tgttatagct gggtcttcat gtagaactat tcctaatttt 12540ctgagaaatc ccaagtcaga tttctagaat ggttgttcaa gtgttcactc caaccatcaa 12600tggaggactg ttttccttgc cagcatgtgc tgtattttga gtttttgatc ctagccagtt 12660ttatcctgca tttcacactt agatatggac tatggtacag gacagagaga aaccaacctt 12720ctactcacca ggatattcta cctgctacca atttatttat ttatttattt atttatttat 12780ttatttattt atttatttat attagagaac aacaccatgc agtttagaag aagtactaag 12840acgtcagtga tgttatactg tgcctaacct tgcattgtac aatctcagct ttcaggtaag 12900acagtgcatg actcttatgc agtgccaact gttttctgat tgtatttatg gtctattgcc 12960taggaatgac ctcctctcaa ataaacatgg tcaaaagccc atggcctgag atgacagagc 13020ccctagtaga ccctagttgt atttctgaag tttagatatc ataatgactt ataaatactt 13080atgtttatac aatagattag agctgctctc agccatgacc aaggagcttc tgtgttcaat 13140gaataatgat tgatgcagac attcgtgagt ggtcaaagtg gtgagaatga ttagagagtc 13200ctcagccaca caagcgttaa tgatatgaac tttccaatat attaactgta ttaatgaata 13260aatgcagaca tcatatgaga tctcattagt agttcttagg tattgcattt ttatatacaa 13320ttatgcatat cagtacatta tagtgtataa aggaaattgt ctagcataat

agagaaaaat 13380aggacagtca agaaacaaaa gagtagaaat tatgggtgaa atatgcagtg tgaaatattt 13440acatgaaaat tttaaccata tgtaaaattg ttatttttgt ttttcagaat gagtttgctc 13500attctttgac atttttattc ctgtgtgaaa tatatcagga tcatatgtat cccattctga 13560tggtctgact tccactggga atttccaata tatctcttcc aactaactga ccagtttctt 13620tttttcttat tttctctctt tctcgttttg ttttgctttg ttttgttttt caagacaggg 13680tttctctgtg tagctctggc tgtcctggaa ctcactttgt agatcaggct ggcttcgagc 13740tcataaatcc acttgcctct gcctcctgag tgctgggatt aaaggagtgg ctaccacgcc 13800cggctagttt ttttttttct tataagaaca acatttactg gatggtcact tacatattca 13860gaggttcagt caattattat caaggcagaa gcatggcagt ggtccagtag tcatggcact 13920ggggaaggag ctgagagatc tacatcttgc tccaaaggga aagaggaata gtctgacttc 13980catgtgtttc agaggagggt ttcatttccc acccccacag tgacacactt cctccaacac 14040ggccacacct cctaatattg ccactcttgg atcaagcata ttcacaccac aaaggaaagt 14100ttagagataa acattaagaa aattaatgaa gtcattttat cttatatgct caacatgact 14160agtacttaaa accataattt tacatgtaca atatttcatg gcataacata ttttttatat 14220ttttattaga tattttcttt atttatattt caaatgtgat accctttccc aattcccctc 14280caaaaatccc ctatgccttc ccctcatagc cagctcccaa acccacccac tcctgctttc 14340tggtcctggc attcccctat actggggcat aaaaccttca caggaccaag tgcctcttct 14400ccattgatgg ccaattaggc catcctctgc tacatatgca gctagagcca tgagttccac 14460catgtgtttt ctttgattgg tggtttagtt ccagggagct ctgggggtat tggttagttc 14520atattgttcc tcctatgggg ctgcaaaccc tttcagcccc ttgggtattt tttctagctc 14580cttcattggg gaccctgtgc tccatccaat ggatgagtga gcctccactt ttgtatttgt 14640caggaactgg cagagtctct caggagacaa ttatatcagg ctcctgtcag caaaatctcg 14700ttggcatctg caatagtgtc tgggtttggt ggttgtttat gggatggatt tctgggtggg 14760gcagtctctg gattgtcatt cctttagtct ctgcttccac ctttgtcttt gtaactccat 14820ccatgggtat tttgttcccc cttcaaagaa ggatcaaaat atccacactt tagtcttcct 14880tcttcttgag tctcatgtgt ttttcaaatt gtatcttggg tattctgagc ttctaggcta 14940atatccactt atcagtgagt gattatcatg tctgttcttt tgtgattgag ttacctcact 15000tagcatgata tcctccaggt ctatccattt gtctaagaat ttcataaagt cattgtcttt 15060aatagctgca tcgtactcaa ttgtgtaaat gcaccacatt ttctttatcc attcctctgt 15120tgagggacac ttggtttttc ccagcttctg gttattataa ataaggctgc tatgaacata 15180gtggaacatg tgtccttagt acatgttgga acatcttctg ggtatatgcc caggagtggt 15240attgctggat cttctggtgg tactatgtcc aaatttttgg ggaaccatca aactgatttc 15300ctgagtggtt gtacaagctt gcaatcccac accagcaata gtggaatgtt catctttgtc 15360caagtccttg ccagcatctg ctgtcacctg agtttttgat cttagccatt cttactggtg 15420tgaggtggaa tcttggggtt gttttgattt gcatttccct gatgtttaag ggttttgaac 15480atttttaggt gcttattaga catttggtat tcctcagttt agaaatcttt gtttagctct 15540gtaccacatt tttgaatagg gttatttggt tttctggagt ctaacttctt gagttctttg 15600tacatattgg atattagccc tctatcagat ttagaattag taaggatctt tccccaaact 15660gttggtggtt cttttgtctt attgacagtg tactttgcct tagagaagct ttgcaatttt 15720atgaggtccc atttgtcaat tcttgatctt atagtacaag ccattggtct tttgttcagg 15780aatttttccc atgtgtccat atgttcaagg catttcccca ctttctccac tacaagtttt 15840agtgtctctg gttttatgtg gaggtccttg atccacttag atttgagctt tgtacaagga 15900gataagaatg gatagattca cattcttcta catgctctct gccagttgag ctagcaccat 15960ttgttgaaaa tgctgtcttt tttttccccc actggatggt ttttagctct tttggccaag 16020atcaagtgac cattggtgtg tgggttcatt tcttggtctt caattctagt tcactgactt 16080acctgtttgt cactgtacaa ggaccatgca gcttttttca caattgctct gtagtacagc 16140ttgaggtctg ggatggtgat tctaccagag agattctttt actgttgtga ataatttttg 16200ctatcatagg atattttttt atttcagatg aatttacaaa ttgctctttc taactctgtg 16260aacaattgag ttggaatttt gattgtgatt gctttgaata ctcaagatat aatttacaaa 16320acacatgaaa cttaacaagg actactaaag tgcagatact tcgatccttc ttagaagggg 16380gaacaaaata cccatagatg gagttacaga gacaaagttc ggagcagaga ctataggaac 16440gaccatccag aggtccacct ggggatccat catgtaaaca accacccaaa acagacacta 16500ttgtggatgc caagaagaac ttgctgacag gagtctgata tagctgtctc ttgagaggct 16560ctgccagggc ctcagaaagt ggaggctcac agccatccat tggatggagc acagggtccc 16620caatgaagga gctagagaaa gtactcaagg agctgaaggg gtttgcagcc ccataggagg 16680aacaacaata tgaactaacc agtaccccca gagctccctg ggactaaacc accaatcaaa 16740gaaaacacat ggagggactt gaagctcttg ctgcatttat agcagaggat ggcctagatg 16800gtcatcaatg ggaggagagg tcaatggtcc tgggaaggtt ccatgcccca gtatagggga 16860atgccagggc caggaagcag gagtgggtgg gctggggatc agggaggggg agatgatagg 16920gcattttcag tggggaaact aggaaagagg ataacattta aaatataaat aaagaaaata 16980tctaattaaa aaggattacc tatgtgcatg ggagctcatg agcagcaggg gtcactctaa 17040ggccaataat ccacatagag cgatgagctg tgtgtgaaca ggactctgta tcctctgtgg 17100tttcctttct taagtgtatt aactgatctg tccagctgtg attgacatgt gatgtctcca 17160tgctcaagcc cagtaaagat tctctgttaa ataccttaca gacttatgtt tacttgtttt 17220tatttgcttt tcatattttt ttaaaaagtc atacaatgta ttctaataac tcattctccc 17280atctccaatt tattctaagt ttttcttaac tcatccaacc acacactttt taattctgat 17340aaagcacccc cccccccaaa aaaaaaccca accaaccaaa aaaaaaaaaa gccaaggaat 17400ttaaaagggg attgaaagca aataaaaact aaacaaaaaa gtaaaaacta cacacacaca 17460cacacacaca cacacacaca cacacacaca cacacactca cacacacaca cacacaccac 17520acacacacac acccatgcac gaacacacac acacacacac acacacacac acacacacac 17580acacacacac acacatggaa tccagtaaaa ccacaactct ttacccatga tacacaggaa 17640aatataagtc aaacaaacag aatggaagaa ggtggtatta taaaaatgtc tgcacaaata 17700ccattaagtt cattttcttg ttggctacca actgctaagc ctgtctccct tgattaattg 17760tgcttatcat cccctatgaa ctccattgga ggacactaat ttttccttct gtctccagga 17820attgaagtgt tgcagaactc tcagtagctt tatttacctg cacaatacag cctctaatcc 17880aaccagtgaa aattaccaca tgagagactt ccaaatgaaa gaacaggtaa agttgtctac 17940tggcaagctt agtaatatca tgtaaatgcc ttagaattta atgacatatg tcatcctctg 18000aggttaataa atccattttg gtgcatatat accctgaact caccactaac ataatacaac 18060aattaaaaaa ttccaacatg gatgcagagg aatccctgag ggacatttgt tgatttgtga 18120gcacaatata attatttttt gggggggaaa tgtctgaatg ttaactcttt accagtgata 18180atctattcta ttaatgtgta cataggtagc actaattaaa atcactgtgt tatcaggtaa 18240tgaaacagag gaagtaggat gctgggaaac agacttttgg aaggtcccaa gggaaaccac 18300agggacctag tggtgataga ttatggtgag agtcctgaga gtggtcatag attatagcat 18360atttcatatg caattgaaaa tttcaaagaa tgaaaatcct tatgaaatat agaaataaca 18420actttactta tgtacatata cttcatagta caatttttac actgtgcata tttctcctgt 18480aacatctggt tcctcctatt ttcctttatt ctcctagaca atttcactga tacaatctca 18540tgtttttgta taaatagttg tatataacta ttaaatacat aagctgttaa tgagtcttca 18600ttaatgtctg tgattttttt attgtcttaa ttaatactat tatctctaat tgcatccaca 18660ttttcaaaag caatgtaaat ttcttactca tttctgttca aaaacttctg ttgttgtatc 18720attaccatgc cttagtgata aaatcctttc ttgacacatc tatagctatt gctataattt 18780agttattgat gatcctcctg caataatcat tgataggtaa atattttaag cacttttact 18840tttagtcatt ttagtgagat ttgaagtagt atataacctg ttggaaaggc aaatattaat 18900tccatatatg tgaaagaaga cgctaaaact aaaaacatta gccactttta gatatcttct 18960ccttcttctt cttcttcttc ttcttcttct tcttcttctt cttcttcttc ttcttcttct 19020tcttcttctt cttcttttct tcttcttctt ctccttctcc ttctccttct ccttctcctt 19080ctcctcttcc tcctccttcc ttccttcctt ccttccttcc ttccttcctt ccttccttcc 19140ttccttcctt ccttccttcc ttccttcctt ccttccttcc ttccttcctt ccttccttcc 19200ttcctttctt tctttctttc tttctttctt tctttctttc tttctttctt tctttctttc 19260tttctttctt tctttctttc tttctttctt ctcctcctcc ttctttttcc ttctccttcc 19320ccttcacctt ccccttcctt cctctttccc ttccccttct ccttctcctc aatctacaat 19380ctgttaacat attaacatgt cccagagtag agcaacagac tcaggtcaaa catctactga 19440gaaatttgcc catgtagtta acatctacag catctgtcta ggggttacaa aaagtctatg 19500ggatacaatt cctcagaaag gaataggatt tggacctgag catactgctg cctaacacat 19560gaaatggcag ttcttctcca gctggactag gtccttaact aagaaatgca ctgctcatga 19620atatgcaaat tacccaagtc tatggcagta aatacagaga tgtccacacc ctgaagacaa 19680cctatgaaca atgttctctc cacagtccct gaagacactg attctaggac cgaagttcct 19740attccgaagt tcctattctc tagaaagtat aggaacttct cgcgcgtctg gcctccgagg 19800cctccgcgcc gggttttggc gcctcccgcg ggcgcccccc tcctcacggc gagcgctgcc 19860acgtcagacg aagggcgcag cgagcgtcct gatccttccg cccggacgct caggacagcg 19920gcccgctgct cataagactc ggccttagaa ccccagtatc agcagaagga cattttagga 19980cgggacttgg gtgactctag ggcactggtt ttctttccag agagcggaac aggcgaggaa 20040aagtagtccc ttctcggcga ttctgcggag ggatctccgt ggggcggtga acgccgatga 20100ttatataagg acgcgccggg tgtggcacag ctagttccgt cgcagccggg atttgggtcg 20160cggttcttgt ttgtggatcg ctgtgatcgt cacttggtga gtagcgggct gctgggctgg 20220ccggggcttt cgtggccgcc gggccgctcg gtgggacgga agcgtgtgga gagaccgcca 20280agggctgtag tctgggtccg cgagcaaggt tgccctgaac tgggggttgg ggggagcgca 20340gcaaaatggc ggctgttccc gagtcttgaa tggaagacgc ttgtgaggcg ggctgtgagg 20400tcgttgaaac aaggtggggg gcatggtggg cggcaagaac ccaaggtctt gaggccttcg 20460ctaatgcggg aaagctctta ttcgggtgag atgggctggg gcaccatctg gggaccctga 20520cgtgaagttt gtcactgact ggagaactcg gtttgtcgtc tgttgcgggg gcggcagtta 20580tggcggtgcc gttgggcagt gcacccgtac ctttgggagc gcgcgccctc gtcgtgtcgt 20640gacgtcaccc gttctgttgg cttataatgc agggtggggc cacctgccgg taggtgtgcg 20700gtaggctttt ctccgtcgca ggacgcaggg ttcgggccta gggtaggctc tcctgaatcg 20760acaggcgccg gacctctggt gaggggaggg ataagtgagg cgtcagtttc tttggtcggt 20820tttatgtacc tatcttctta agtagctgaa gctccggttt tgaactatgc gctcggggtt 20880ggcgagtgtg ttttgtgaag ttttttaggc accttttgaa atgtaatcat ttgggtcaat 20940atgtaatttt cagtgttaga ctagtaaatt gtccgctaaa ttctggccgt ttttggcttt 21000tttgttagac gtgttgacaa ttaatcatcg gcatagtata tcggcatagt ataatacgac 21060aaggtgagga actaaaccat gggatcggcc attgaacaag atggattgca cgcaggttct 21120ccggccgctt gggtggagag gctattcggc tatgactggg cacaacagac aatcggctgc 21180tctgatgccg ccgtgttccg gctgtcagcg caggggcgcc cggttctttt tgtcaagacc 21240gacctgtccg gtgccctgaa tgaactgcag gacgaggcag cgcggctatc gtggctggcc 21300acgacgggcg ttccttgcgc agctgtgctc gacgttgtca ctgaagcggg aagggactgg 21360ctgctattgg gcgaagtgcc ggggcaggat ctcctgtcat ctcaccttgc tcctgccgag 21420aaagtatcca tcatggctga tgcaatgcgg cggctgcata cgcttgatcc ggctacctgc 21480ccattcgacc accaagcgaa acatcgcatc gagcgagcac gtactcggat ggaagccggt 21540cttgtcgatc aggatgatct ggacgaagag catcaggggc tcgcgccagc cgaactgttc 21600gccaggctca aggcgcgcat gcccgacggc gatgatctcg tcgtgaccca tggcgatgcc 21660tgcttgccga atatcatggt ggaaaatggc cgcttttctg gattcatcga ctgtggccgg 21720ctgggtgtgg cggaccgcta tcaggacata gcgttggcta cccgtgatat tgctgaagag 21780cttggcggcg aatgggctga ccgcttcctc gtgctttacg gtatcgccgc tcccgattcg 21840cagcgcatcg ccttctatcg ccttcttgac gagttcttct gaggggatcc gctgtaagtc 21900tgcagaaatt gatgatctat taaacaataa agatgtccac taaaatggaa gtttttcctg 21960tcatactttg ttaagaaggg tgagaacaga gtacctacat tttgaatgga aggattggag 22020ctacgggggt gggggtgggg tgggattaga taaatgcctg ctctttactg aaggctcttt 22080actattgctt tatgataatg tttcatagtt ggatatcata atttaaacaa gcaaaaccaa 22140attaagggcc agctcattcc tcccactcat gatctataga tctatagatc tctcgtggga 22200tcattgtttt tctcttgatt cccactttgt ggttctaagt actgtggttt ccaaatgtgt 22260cagtttcata gcctgaagaa cgagatcagc agcctctgtt ccacatacac ttcattctca 22320gtattgtttt gccaagttct aattccatca gacctcgacc tgcagcccct agagaagttc 22380ctattccgaa gttcctattc tctagaaagt ataggaactt cctagggttt caccggttaa 22440atggcatgtc ccctgttagt ggttcatgca agcagaagct gtatcctgtt tgacaaagat 22500tcagcatgaa aggtcctgct acctaaaaaa aaatagacag atgagattta attaacctaa 22560ataatttttt tcacaacaac agagtgaata cgcaatttac agaatgacag aaaacttttg 22620cacactttgc ctgtgacagg gaactaatat gaagaatttg caaggaactc aaacaactct 22680acaacaacaa cagcaacaag aaccaaataa ctccgttaaa atgagcaaag gacatgagta 22740gacattttca aaagaacaca tagaaatgga taataaatat ataaacaata ctcaacatca 22800ctaaccatca gggaaatgca aattaaaacc acaataagat atcatcttcc accagtcaca 22860atgactatta ctaaaaactc aaataatatc agatgttgct gaggatggga aatgaaggca 22920actcttagac attgttgatg aggatgtaga tgagtacaac ctctgtggaa aatggtatgg 22980agatttccca gaaaactaga aatagaactg tcatttggtc cagcaatccc actactgggt 23040aactacccaa aggaaaataa actattattt caaaaagata cccaccttct atgcttacca 23100taaaactact ctcaatagca catatgtcaa actgagtgtc tgccaaccga tgattttata 23160aaagaatata gcatgtatgc acaattcaat actagtcagc cacaataagg aatgaaactg 23220tgtcttttgc agcaagatgc atagaagtgg gggacaatat aattagtgaa ctaactcaca 23280aacagaatgt cacatgtcac acattattac ttgtaagtgg gaggtaaaca gcgtgtacac 23340aaggatttgt agagagaaat tacacacatt ggagacttac aaggatgggc gggcagaagg 23400tgggagcatg atgagtcatt acataacagg cacaatataa aataattaag aattgaccaa 23460tgatcttaaa attaaaatgt agaatatgat caataaatga acttgatatt agttgacctc 23520attaaattta aaaacttttt ctactcaaat gactgtaaga aaatgaatgc ccggttacag 23580atgagaaact gtttgcgagt caaataacca ccaatgtaac tataataaga aacttcagaa 23640ctcaactgtg aataaaaaag aaacaactga tggataaatt aggcaagggt ttctacagac 23700atttcgtcaa agaagatgtg cagatgacac tgaagcatat aaacaggatc tcaacaggat 23760tttccgttag agaaattcaa atcaagcccg caaagagaca ccactgtaca ctttttaaaa 23820tggctgaaat taagaagaaa tacagataac atcaatgctg gtgagcatac caggttgcta 23880gaggctaaaa cattgctaac aggaatgcaa aatgaaacag atactcagga aaataatttt 23940tagttttctc taaaatcaaa cataccctta acacctgaat atttgcatca gagaaaaaca 24000atcttacatt cacgcataac ttctattcaa atattcaaga tatcgtgtgt atgtgtgtta 24060gaaagtaaaa ataacataaa tgtctcaaaa tttgaatagg tgaagaacta ggaagcatct 24120ataaattgaa taccaccagc aataaaaaaa taacaagtga ccgatacata aactattaca 24180ggtgaactcc agacattgtg ctaagtgaga gaagccagtc tcaaagatca aagggacaca 24240gctgtaagca ccacggtcat cctcaggtgt cagtggtttg ggctggactt tctgtgtctc 24300tttcctgacc agacccagat attgagctcc accacttgca gatggaaaat cctattttca 24360accatgcagt gaggtttgaa ctgcttcaca gactgaacga aacaaacacg ggctcctttg 24420aacagcgtcc ggcatttgtt ccaaccacaa gagaacgtcc ctcagctctc ccacctcctc 24480ggttctctcc tgcaagccag cagccctgca gtttagcctg catctcccgt gcatccaccc 24540atctccctcc aagcaccttc ccccacaccc tccactgttt ctgagagcac aggcaggctt 24600tgaacttttc cgcattctgt tgttattgaa gttaggatgt ttaggaccaa cttaaggatc 24660atattttatg actgaattcc agtgcccctt ctctcctggg acagagtgca taaccaagtt 24720tctgcaggtg gagacgaagt tgagcttttt tcttcctcag cctaggagat gagcgctaat 24780tggagggttg gcagaagctt cccaccatcc cagcactttg gttctggtgg ggcggaatcg 24840gtgccatagg gcagagctag aaaccgcgga ctgaatgttc ccagtggcac tggacccagg 24900gcagagcctc catccacgag tggggctcta tggaagaagt gagtctctgg ctctcagtag 24960ctctcgtcca gcactgaacc tcagcatcat gtgctgtgtg cagggtcaga gggccaacgt 25020actggcccct gggaaagcgt ttcctctggt gggagttggt agaaggtgtc ctgtcttctt 25080ggctgcatct gtccgcagtg gagtttacat catgctgagc tgggatgtgg aaggaaggaa 25140gagcatctta gatcaaatat gatgactggc cttactgagt tttctagatt ttcctgaata 25200aatgtttctt cactcactgt gtgctgttag agtctttcca aacctgtaat ttcccaaaat 25260aattttcact ggtctcatga gggcatggat tcattgagcc cctcatgctg tcaaagagaa 25320atagaactgt tttttttttt cacttcatag cgaacatcca tgggttatca aataatgggc 25380tggcttttct tccaacactt tacagacacc atcaattttc ttcttgctta taaggtttta 25440accagaagaa tgctgtcatg gtcttttctg ttcttttgga aggaatgccc cctctactca 25500cctccacttg tctgcctgta tttctatttg tctttggttt tcaacaattt taataagatt 25560tacctaaatg tgtgtggggg gagcatgggg tgttattctg ctgttctgtg ttctctgaga 25620tgcatggatt caccatttac tctgtctcca tttttgtgaa aacaattaga aaaaaagtca 25680gtatgagccc agaaacaagc ctccctgaag tgggcacagg accacctggg ggcgctcagg 25740acccactgaa cacaagagcc agccccaggg caggtgcaga tgcgggttaa gttctggttt 25800cctgtcaacc ctgtggcttc ctctccataa aacagtttcc tttgtggcat atctctggat 25860tccttatcct gttcttcctg tgaagtctct gaagaagaaa catttgtcgt aacaagagaa 25920aaactttctc acatgcacca aaggcagagt cacctacagt cacttactcc tgtttctcaa 25980tgtcaataag ttaccaatgc ttctgaagtt aatcagctaa atctataaaa ggtgcggtgt 26040ttaactcagc attacagccc agctcaacag aactccaaag gtcagccagc agcagccagg 26100aaaaagtgca tgctgggcat tggggcagag ggagttacca tccagtgcaa gagaagaaag 26160cccccgtggt ggtcattgtc aggactccaa tcccacagtt ccaattgtag gtgatgccag 26220gcaaaggaag agagacccca ccaatggtta gtgtggatgt cgagtttgat gtttccacac 26280tcacactcca ggtgaatatg aaaagattta ttagctctat ttctgaggtg tctgctgaga 26340gcagcacagt cctctcaaga aattacagat tggaatttcc tcagtagagc aggaaaggag 26400gctggctcag ggctttataa tgatttggtg gtggggtcgg cggggggggg ggggcgtttc 26460tactcaggag aaggagcttg tgtgatttaa acctcacact gacatcacat gagggagctt 26520ccatgatttc ttactagatt tcccatgtgt gggggacaag gatgagggag aataaacctt 26580aattcatcag catcaaggca ccaaaaatag gacctgacac tttattctcc ctagcagctt 26640aagaaaatga gtgaaaaaga gagataagag tccacccatg tgctgaaaag catagctctt 26700ggtaaagacg agaaaaaggc actcctacga agaaggggtt gggcagaagc tttatgctga 26760agggtttggc taaagagaca taatcaacag gttacaggag gggctactga tgttcatgga 26820ggtggtcctc acacatgcat actgaacaaa catgtctgta acgtatgacc cctgttcact 26880taccagtgga gacttagcat ttaaattcat tccagtcagg ccctatgtgc aaacagcaga 26940agcagagaca caaaggtact cagggtgcag cctctgtgaa cggccagagc caggccatgg 27000tcagcggtct cggattagga gaaagttcct gatatcactg tagtgttcaa tcaaagctgg 27060ggttatggtt tgtggaacag gggtcagttc atcagggggt gggctgcaat tgtcttcata 27120gtgcttgtct cagtgccggt gcttactgag ccactagaga aaaaggttta attgagcttc 27180tttaaaatca acattttgaa ttatttatca gacgtttcaa atatgtcatg ttgtttagat 27240tctattgctg gagagttaag gtgatatttg gggttttgta actctgtttt ttcatacttc 27300ctgaattgct tatctgtttg cttttcatta gctaaactat cgcttcttct tattttttaa 27360ttcattctga ttttgatgaa tatttaattc cctttagaat gtgaatataa tgtacattgt 27420gtgggtattt tgattttggt tcttggttta cttagtggca aagactctgt aagagttcct 27480tgtctataga tagccattat ttagtggctt tctgaaatgg tggttttagt accaaagtac 27540tggacttgtg agtaggctca ctgccccctg caggtcctag atagtggagg cctcaggaac 27600tgtttctcat ttggaatgcc tttgtttcag cagattttgt gttgggttgt taagttcacc 27660ctccacatta gtagatgtcc ttacagatta gagctgactc tggtagaagc agttgagtgc 27720atgcttgata tctgtgcaca gggagaagct ctctgttgcc tcaggcgatg gactggtcta 27780tgaaatgcac agtgacctga gttccctgct cagcccctga gaggtggacc aagctggaca 27840cacatgagcc accgagcctg gcaagcaaaa gcgccagcct tgatggaaat ggcgagctga 27900gcggcatcta ctcagtgtgg tttcttttgt tattaagagc tttagtgtgg tggctgtttc 27960aaattcccgt tgtagtagta atatactggg tatgtgagca ggcccgtggt cttttgcggg 28020gttggaatca ccgaagtaat gagaagctaa tctcattttc aactgctgta cactggtggt 28080attgagtttg tatgaggtca tgcagtttga acgtcaggcc agtaggtggt gctcgcaggt 28140aagagccggc tatggtggca gcagaagggt ttatgcttta ctggtgatta aagtgggaaa 28200cttggcgtgt tccagatctt agagaaaaga tttttagtta tttctcattc aacctgatac 28260tacctgaaag tctctcgaat gtaactttta ttttgtcgag atgggttctt tctataccca 28320ttttttatgt tttttttgtg aaaggatgtt gtttcatcaa atgcgttttc agcatcaatt 28380gaaaaaagtt atatgtggat taaagatcaa aatgtaaaac ctaacactat

aaaacctctg 28440gataataaca taggaaacag aatttaggag gtaagaactg acaaaggttt tataatgaaa 28500atgctagaag tagttgcaac aaaattgaaa attgacaaat gggacctaag taaattaaag 28560aacttctgta cagcaaaaga cactatcgac agagtaaaca ggcaacctac agaatgggaa 28620ataaaatatt tgcagcctat acatctgaca aaggtccgac acttagtata tacatggaaa 28680tttaacaaac atacaagaaa taaaaagtga ccaaaggaca tgaaaagaca cttcaaaaaa 28740gacctacatg tggccaacaa gcataggaaa aaatgctgaa tatcactatc attagagaaa 28800tacatatcaa aacctcaatg aggtaccgtc tcacatcagt caggatggct aatcttaaaa 28860aaaaaataac agatttttaa ggttacagaa aaaaggggaa atttatacac ttttggcggg 28920aatataaatg agttcaacca ttgtggaaag cagtgtggtg atccctccaa taacctaaaa 28980cagaagtttc atttgaccca acaatcctac aactggacat atacctaaag gaatataaac 29040atgtaggttc actgcagcac tatccacaat agcatagaca tggaatttac ctaaatcccc 29100atcactggca gaatgataga gaaaaatgtg gtacatacaa ccatggaata ctatgcagct 29160aaggaaagaa tgaaactatg tcctttgtag gaacatgatg gaactggcag tcaatactct 29220tagaaaacta attcaggaac agaaaaccag atattatata ttctccctta tttgttggag 29280ataaataaaa gcaaatattc ttccagggcc tgagtcttcc ttattcaaca agtcattcta 29340aattaagtgt tcagcaagtt gctgatactc atctaaatat tctatttcat ctgggccact 29400tacatcactc aaaaagcaat gagagctata tttctaaggg gggttctagg ataataaata 29460cctgaatagt gagaatatga aggatatgga aactgggcca cttatatcac tcaaaaagga 29520atgagagcta tatttataag gggggttcta ggataataaa tacctgaata gtgagaatat 29580gaaggatatg gaaactgggc cacttatatc actcaaaaag caatgaaagc tatatttaca 29640aggggggttc taggataata aatatctgaa tagtgagaat atgaaggata tggatggttt 29700ttttttaact caatgggcac ataactgtgg gagatactat attcctatga agaaggtatt 29760cagacttcag agataagtaa tgtttcctac attgtgcttg tgacttggaa gcagtggatt 29820gaagagtgtg ataagtgccc agaccaagca gaacagaaat cagcatgtaa agatgatgat 29880ctatggatat gatctaaaac catgtaaata cttcaaataa ttctatttaa tgcagtttga 29940aataaaacac aaacttattc aaaatacaaa ttacttggta attattttgg gagctatgag 30000ttcaccaaga aactcaaatt cctatttcta tttcaacccc tgattcctac tgtcaatggg 30060agggaagtct cagaaccaat cacacatcag acggcaaatc tgtcaaccaa gagtctttcc 30120actgaaggac ctgggaggtc aggaccctca ggaaagtgct ggggaccctg tcttgggagt 30180gcccagcaga tctcagaact ctccatgggt cctgctggac actcatgtag ggtaacgagt 30240ggccaccttt tcagtgttac cagtgagctc tgagtgttcc taatgggacc aggatgggtc 30300taggtgcctg ctcaatgtca gagacagcaa tggtcccaca aaaaacccag gtaatcttta 30360ggccaataaa atgtgggttc acagtgagga gtgcatcctg gggttggggt ttgttctgca 30420gcgggaagag cgctgtgcac agaaagctta gaaatggggc aagagatgct tttcctcagg 30480caggatttag ggcttggtct ctcagcatcc cacacttgta cagctgatgt ggcatctgtg 30540ttttctttct catcctagat caggctttga gctgtgaaat accctgcctc atgcatatgc 30600aaataacctg aggtcttctg agataaatat agatatattg gtgccctgag agcatcacat 30660aacaaccaca ttcctcctct gaagaagccc ctgggagcac agctcatcac catggactgg 30720acctggaggt tcctctttgt ggtggcagca gctacaggta aggggcttcc tagtcctaag 30780gctgaggaag ggatcctggt ttagttaaag aggattttat tcacccctgt gtcctctcca 30840caggtgtcca gtcccaggtg cagctggtgc agtctggggc tgaggtgaag aagcctgggt 30900cctcggtgaa ggtctcctgc aaggcttctg gaggcacctt cagcagctat gctatcagct 30960gggtgcgaca ggcccctgga caagggcttg agtggatggg agggatcatc cctatctttg 31020gtacagcaaa ctacgcacag aagttccagg gcagagtcac gattaccgcg gacaaatcca 31080cgagcacagc ctacatggag ctgagcagcc tgagatctga ggacacggcc gtgtattact 31140gtgcgagaga cacagtgtga aaacccacat cctgagagtg acaaaaaccc tgagggagaa 31200ggcagctgtg ccgggctgag gagatgacag gggttattag gtttaaggct gtttacaaaa 31260tgggttatat atttgagaaa aaaagaacag tagaaacaag tacatactct aattttaaga 31320taaatattcc attcaagagt cgtaatataa gccaaattca cagagtggaa aaggcgcgat 31380cgcggagcag gggatcctta gatattggtt ggggttatct caccttaggt ctgaatatgg 31440ggttgtctta gactgttttg tgctgttaga atagaatacc caagactggg aaatttatac 31500tgaacggaaa tttatttctc acagttctag aggctgtgaa gtccaagagc acaggtgcca 31560gagcaagtcc aagagcaagg gaaagtccaa agcaagtcca ggagcatctg gcgaggacct 31620tcttgctgtg tcatcacatg gcggaaggca agaaagagag caagaggggg ccgaactcac 31680ccttttataa cagcaccaat cccacccatg aggtggggac cttatgacct aatcactctt 31740catactgtta caatggcaat gaaatttcaa catgagtttt ggaggagaga agcattcaaa 31800ccacagcaag ggtgctccta cctcctctct cagggcatct gcagaaagag ctgcaactgc 31860acgtccttcc tccgtccatc ctccatccct tcccaatgtc cgtgcatatc ctgtgaccca 31920ggaggtctgg catagggggt gctcctgcct taggtctgag gccctgtctg aagaggggta 31980ggtgaggagg ccatctgatg gtctgggcca agacagtcac aggacgcatc atttatcatc 32040aaggaggctg agggttgagt ctccaggtcc agggaactcc ccacaaagtg ggaaccctgc 32100ccagctccac acagcctctg ctgggggacc ctgctctggt gcagagcctg gggacaggtc 32160ttgagctcag ccagagtctg cctccctgtc atttaggaac taaaccaagc ggcaggatgc 32220tggagcccag cccccatctg accttacagg gccaaggctg gggccctggg ttcccctcaa 32280ggcgcagcag gactggagcc ccaggcagtg caggagtggc caaagctggg gcttcctcca 32340gagcccccaa gcatcacggc accaagaagg gtaggaccct ggcctgagga attggcacca 32400aagccccaga aactaccctg gacaccatgg agagaggcct ggaggggaag caccaggcac 32460tgcctcccct tctgatccca cctgaggtgg ctgccaagcc cagagagccg ctctgatgtc 32520ccccagccct gcagcccagg gatacctgta ctgtgcccct gggggacccc tggccagtct 32580gtgcaaagaa gtcaccaccc tacactcaga gacagtgggg gtcctcgtcc cacatcctca 32640gagcatggcc cggctgctgc agggatggtc tcctggtcct cagagcatgg cccggctgct 32700gcagggatgg tctcctggtc ctcagagcat ggcccagctg ctgcagggat ggtctcctgg 32760aggcccccca gtgctctatt gtcagggctc cctccacccc cccgcaccaa gagagagcca 32820gaccccagca aggcttccag tggcttcagg tcacacccct aggctgaccc cagccccatt 32880aacacctgcc tgagaaagct ccacgcacca gaactgaccg tctgctccaa ctcttgacct 32940cccgttctca gggcgtctgc tgaaaaggct gcaactgcac atccttcctc cgtccgttcc 33000cgatgtccgt gtgtctcctg tggccaggaa ggtctttctc gggacctgag agccgctccc 33060tgaagtgtcc ccattgggaa ggatggggcc tgtgtctcca ggctctggga ggacagaatc 33120ctgacctcaa cagtggccgg cacggacaca actggcccca tcccggggac gctgaccagc 33180gctgggcaac ttttcccttc cccgacgact gagccccgag caccctccct gctcccctac 33240cacctccctt tacaaggctg tggcctctgc acagatgata atggagcttg gctcattccc 33300ctagagtcgg tagggagtta aggacaaaac tcagtttcct ccacctgaac tcaagtctgc 33360ctatgtttac ctaatcacac ctggtggaca gtttggacaa acttgcacac tcagagacac 33420agacacttct agaaatcatt atctccctgc cccggggacc ccactccagc agaagtctgc 33480taggcactgg cctgggccct cctgctgtcc taggaggctg ctgacctcct gcctggctcc 33540tgtccccagg tccagagtca gagcagactc cagggacgct gcaggctagg aagccgcccc 33600ctccaggcca gggtctagtg caggtgccca ggacaagaaa gattgtgaat gcaggaatga 33660ctgggccaca cccctcccgt gcacgccccc tcttgccctg caccccacag cccagccccc 33720cgtgctggat gcccccccac agcagaggtg ctgttctgtg atcccctggg aaagacgccc 33780tcaacctcca ccctgtccca cggcccaagg aagacaagac acaggccctc tcctcacagt 33840ctccccacct ggctcctgct gggaccctca aggtgtgaac agggaggatg gttgtctggg 33900tggcccctag gagcccagat cttcactcta cagaccccaa cccaagcacc cccttctgca 33960gggcccagct catccccctc ctcctccctc tgctctcctc tcgtcgcctc tacgggaaat 34020ccgggactca gcagtaaccc tcaggaagca gggcccaggc gccgtttaat aggaggcttc 34080ctcacaatga aacttttaga aagccttgac tacaatgatg accttggtgt ggctgtgaac 34140actgtcagct cccacagctg ctgcagcaaa aaatgtccat agacagggtg ggggcccggg 34200gtcgtctgct gtcctgctca gcccacagca cgcatggagg atctgaggtg ccacacctga 34260cgcccaggcc agaacatgcc tccctccagg gtgacctgcc atgtcctgca ttgctggagg 34320gacaggggca gcctatgagg atctggggcc aggagatgaa tcctattaac ccagaggaaa 34380actaacagga cccaagcacc ctccccgttg aagctgacct gcccagaggg gcctgggccc 34440accccacaca ccggggcgga atgtgtacag gccccggtct ctgtgggtgt tccgctaact 34500ggggctccca gtgctcaccc cacaactaaa gcgagcccca gcctccagag cccccgaagg 34560agatgccgcc cacaagccca gcccccatcc aggaggcccc agagctcagg gcgccggggc 34620agattctgaa cagccccgag tcacggtggg tacaactgga acgaccaccg tgagaaaaac 34680tgtgtccaaa actgtctcct ggcccctgct ggaggccgcg ccagagaggg gagcagccgc 34740cccgaaccta ggtcctgctc agctcacacg acccccagca cccagagcac aacggagtcc 34800ccattgaatg gtgaggacgg ggaccagggc tccagggggt catggaaggg gctggacccc 34860atcctactgc tatggtccca gtgctcctgg ccagaactga ccctaccacc gacaagagtc 34920cctcagggaa acgggggtca ctggcacctc ccagcatcaa ccccaggcag cacaggcata 34980aaccccacat ccagagccga ctccaggagc agagacaccc cagtaccctg ggggacaccg 35040accctgatga ctccccactg gaatccaccc cagagtccac caggaccaaa gaccccgccc 35100ctgtctctgt ccctcactca ggacctgctg cggggcgggc catgagacca gactcgggct 35160tagggaacac cactgtggcc ccaacctcga ccaggccaca ggcccttcct tcctgccctg 35220cggcagcaca gactttgggg tctgtgcaga gaggaatcac agaggcccca ggctgaggtg 35280gtgggggtgg aagaccccca ggaggtggcc cacttccctt cctcccagct ggaacccacc 35340atgaccttct taagataggg gtgtcatccg aggcaggtcc tccatggagc tcccttcagg 35400ctcctccccg gtcctcacta ggcctcagtc ccggctgcgg gaatgcagcc accacaggca 35460caccaggcag cccagaccca gccagcctgc agtgcccaag cccacattct ggagcagagc 35520aggctgtgtc tgggagagtc tgggctcccc accgcccccc cgcacacccc acccacccct 35580gtccaggccc tatgcaggag ggtcagagcc ccccatgggg tatggactta gggtctcact 35640cacgtggctc ccctcctggg tgaaggggtc tcatgcccag atccccacag cagagctggt 35700caaaggtgga ggcagtggcc ccagggccac cctgacctgg accctcaggc tcctctagcc 35760ctggctgccc tgctgtccct gggaggcctg gactccacca gaccacaggt ccagggcacc 35820gcccataggt gctgcccaca ctcagttcac aggaagaaga taagctccag acccccaaga 35880ctgggacctg ccttcctgcc accgcttgta gctccagacc tccgtgcctc ccccgaccac 35940ttacacacgg gccagggagc tgttccacaa agatcaaccc caaaccggga ccgcctggca 36000ctcgggccgc tgccacttcc ctctccattt gttcccagca cctctgtgct ccctccctcc 36060tccctccttc aggggaacag cctgtgcagc ccctccctgc accccacacc ctggggaggc 36120ccaaccctgc ctccagccct ttctcccccg ctgctcttcc tgcccatcca gacaaccctg 36180gggtcccatc cctgcagcct acaccctggt ctccacccag acccctgtct ctccctccag 36240acacccctcc caggccaacc ctgcacatgc aggccctccc cttttctgct gccagagcct 36300cagtttctac cctctgtgcc taccccctgc ctcctcctgc ccacaactcg agctcttcct 36360ctcctggggc ccctgagcca tggcactgac cgtgcactcc cacccccaca ctgcccatgc 36420cctcaccttc ctcctggaca ctctgacccc gctcccctct tggacccagc cctggtattt 36480ccaggacaaa ggctcaccca agtcttcccc atgcaggccc ttgccctcac tgcccggtta 36540cacggcagcc tcctgtgcac agaagcaggg agctcagccc ttccacaggc agaaggcact 36600gaaagaaatc ggcctccagc accctgatgc acgtccgcct gtgtctctca ctgcccgcac 36660ctgcagggag gctcggcact ccctgtaaag acgagggatc caggcagcaa catcatggga 36720gaatgcaggg ctcccagaca gcccagccct ctcgcaggcc tctcctggga agagacctgc 36780agccaccact gaacagccac ggagcccgct ggatagtaac tgagtcagtg accgacctgg 36840agggcagggg agcagtgaac cggagcccag accataggga cagagaccag ccgctgacat 36900cccgagcccc tcactggcgg ccccagaaca ccgcgtggaa acagaacaga cccacattcc 36960cacctggaac agggcagaca ctgctgagcc cccagcacca gccctgagaa acaccaggca 37020acggcatcag agggggctcc tgagaaagaa aggaggggag gtctccttca ccagcaagta 37080cttcccttga ccaaaaacag ggtccacgca actcccccag gacaaaggag gagccccctg 37140tacagcactg ggctcagagt cctctcccac acaccctgag tttcagacaa aaaccccctg 37200gaaatcatag tatcagcagg agaactagcc agagacagca agaggggact cagtgactcc 37260cgcggggaca ggaggatttt gtgggggctc gtgtcactgt gaggatattg tagtagtacc 37320agctgctata cccacagtga cacagcccca ttcccaaagc cctgctgtaa acgcttccac 37380ttctggagct gaggggctgg ggggagcgtc tgggaagtag ggcctagggg tggccatcaa 37440tgcccaaaac gcaccagact cccccccaga catcacccca ctggccagtg agcagagtaa 37500acagaaaatg agaagcagct gggaagcttg cacaggcccc aaggaaagag ctttggcggg 37560tgtgcaagag gggatgcggg cagagcctga gcagggcctt ttgctgtttc tgctttcctg 37620tgcagatagt tccataaact ggtgttcaag atcgatggct gggagtgagc ccaggaggac 37680agtgtgggaa gggcacaggg aaggagaagc agccgctatc ctacactgtc atctttcaag 37740agtttgccct gtgcccacaa tgctgcatca tgggatgctt aacagctgat gtagacacag 37800ctaaagagag aatcagtgaa atggatttgc agcacagatc tgaataaatt ctccagaatg 37860tggagccaca cagaagcaag cacaaggaaa gtgcctgatg caagggcaaa gtacagtgtg 37920taccttcagg ctgggcacag acactctgaa aagccttggc aggaactccc tgcaacaaag 37980cagagccctg caggcaatgc cagctccaga gccctccctg agagcctcat gggcaaagat 38040gtgcacaaca ggtgtttctc atagccccaa actgagaatg aagcaaacag ccatctgaag 38100gaaaacaggc aaataaacga tggcaggttc atgaaatgca aacccagaca gccagaagga 38160caacagtgag ggttacaggt gactctgtgg ttgagttcat gacaatgctg agtaattgga 38220gtaacaaagg aaagtccaaa aaatactttc aatgtgattt cttctaaata aaatttacag 38280ccggcaaaat gaactatctt cttaagggat aaactttcca ctaggaaaac tataaggaaa 38340atcaagaaaa ggatgatcac ataaacacag tggtcgttac ttctactggg gaaggaagag 38400ggtatgaact gagacacaca gggttggcaa gtctcctaac aagaacagaa caaatacatt 38460acagtacctt gaaaacagca gttaaaattc taaattgcaa gaagaggaaa atgcacacag 38520ctgtgtttag aaaattctca gtccagcact gttcataata gcaaagacat taacccaggt 38580tggataaata aacgatgaca caggcaattg cacaatgata cagacataca ttcagtatat 38640gagacattga tgatgtatcc ccaaagaaat gactttaaag agaaaaggcc tgatatgtgg 38700tggcactcac ctccctgggc atccccggac aggctgcagg cacactgtgt ggcagggcag 38760gctggtacct gctggcagct cctggggcct gatgtggagc aggcacagag ccgtatcccc 38820ccgaggacat atacccccaa ggacggcaca gttggtacat tccggagaca agcaactcag 38880ccacactccc aggccagagc ccgagaggga cgcccatgca cagggaggca gagcccagct 38940cctccacagc cagcagcacc cgtgcagggg ccgccatctg gcaggcacag agcatgggct 39000gggaggaggg gcagggacac caggcagggt tggcaccaac tgaaaattac agaagtctca 39060tacatctacc tcagccttgc ctgacctggg cctcacctga cctggacctc acctggcctg 39120gacctcacct ggcctagacc tcacctctgg gcttcacctg agctcggcct cacctgactt 39180ggaccttgcc tgtcctgagc tcacatgatc tgggcctcac ctgacctggg tttcacctga 39240cctgggcttc acctgacctg ggcctcatct gacctgggcc tcactggcct ggacctcacc 39300tggcctgggc ttcacctggc ctcaggcctc atctgcacct gctccaggtc ttgctggaac 39360ctcagtagca ctgaggctgc aggggctcat ccagggttgc agaatgactc tagaacctcc 39420cacatctcag ctttctgggt ggaggcacct ggtggcccag ggaatataaa aagcctgaat 39480gatgcctgcg tgatttgggg gcaatttata aacccaaaag gacatggcca tgcagcgggt 39540agggacaata cagacagata tcagcctgaa atggagcctc agggcacagg tgggcacgga 39600cactgtccac ctaagccagg ggcagacccg agtgtccccg cagtagacct gagagcgctg 39660ggcccacagc ctcccctcgg tgccctgcta cctcctcagg tcagccctgg acatcccggg 39720tttccccagg cctggcggta ggtttggggt gaggtctgtg tcactgtggt attacgattt 39780ttggagtggt tattataccc acagtgtcac agagtccatc aaaaacccat ccctgggaac 39840cttctgccac agccctccct gtggggcacc gccgcgtgcc atgttaggat tttgactgag 39900gacacagcac catgggtatg gtggctaccg cagcagtgca gcccgtgacc caaacacaca 39960gggcagcagg cacaacagac aagcccacaa gtgaccaccc tgagctcctg cctgccagcc 40020ctggagacca tgaaacagat ggccaggatt atcccatagg tcagccagac ctcagtccaa 40080caggtctgca tcgctgctgc cctccaatac cagtccggat ggggacaggg ctggcccaca 40140ttaccatttg ctgccatccg gccaacagtc ccagaagccc ctccctcaag gctgggccac 40200atgtgtggac cctgagagcc ccccatgtct gagtaggggc accaggaagg tggggctggc 40260cctgtgcact gtccctgccc ctgtggtccc tggcctgcct ggccctgaca cctgggcctc 40320tcctgggtca tttccaagac agaagacatt cccaggacag ctggagctgg gagtccatca 40380tcctgcctgg ccgtcctgag tcctgcgcct ttccaaacct cacccgggaa gccaacagag 40440gaatcacctc ccacaggcag agacaaagac cttccagaaa tctctgtctc tctccccagt 40500gggcaccctc ttccagggca gtcctcagtg atatcacagt gggaacccac atctggatcg 40560ggactgcccc cagaacacaa gatggcccac agggacagcc ccacagccca gcccttccca 40620gacccctaaa aggcgtccca ccccctgcat ctgccccagg gctcaaactc caggaggact 40680gactcctgca caccctcctg ccagacatca cctcagcccc tcctggaagg gacaggagcg 40740cgcaagggtg agtcagaccc tcctgccctc gatggcaggc ggagaagatt cagaaaggtc 40800tgagatcccc aggacgcagc accactgtca atgggggccc cagacgcctg gaccagggcc 40860tgcgtgggaa aggcctctgg gcacactcag gggctttttg tgaagggtcc tcctactgtg 40920tgactacagt aactaccaca gtgatgaacc cagcagcaaa aactgaccgg actcccaagg 40980tttatgcaca cttctccgct cagagctctc caggatcaga agagccgggc ccaagggttt 41040ctgcccagac cctcggcctc tagggacatc ttggccatga cagcccatgg gctggtgccc 41100cacacatcgt ctgccttcaa acaagggctt cagagggctc tgaggtgacc tcactgatga 41160ccacaggtgc cctggcccct tccccaccag ctgcaccaga ccccgtcatg acagatgccc 41220cgattccaac agccaattcc tggggccagg aatcgctgta gacaccagcc tccttccaac 41280acctcctgcc aattgcctgg attcccatcc cggttggaat caagaggaca gcatccccca 41340ggctcccaac aggcaggact cccacaccct cctctgagag gccgctgtgt tccgtagggc 41400caggctgcag acagtccccc tcacctgcca ctagacaaat gcctgctgta gatgtcccca 41460cctggaaaat accactcatg gagcccccag ccccaggtac agctgtagag agagtctctg 41520aggcccctaa gaagtagcca tgcccagttc tgccgggacc ctcggccagg ctgacaggag 41580tggacgctgg agctgggccc atactgggcc acataggagc tcaccagtga gggcaggaga 41640gcacatgccg gggagcaccc agcctcctgc tgaccagagg cccgtcccag agcccaggag 41700gctgcagagg cctctccagg gggacactgt gcatgtctgg tccctgagca gccccccacg 41760tccccagtcc tgggggcccc tggcacagct gtctggaccc tctctattcc ctgggaagct 41820cctcctgaca gccccgcctc cagttccagg tgtggttatt gtcagggggt gtcagactgt 41880ggtggataca gctatggtta ccacagtggt gctgcccata gcagcaacca ggccaagtag 41940acaggcccct gctgtgcagc cccaggcctc cagctcacct gcttctcctg gggctctcaa 42000ggctgctgtt ttctgcactc tcccctctgt ggggagggtt ccctcagtgg gagatctgtt 42060ctcaacatcc cacggcctca ttcctgcaag gaaggccaat ggatgggcaa cctcacatgc 42120cgcggctaag atagggtggg cagcctggcg gggacaggac atcctgctgg ggtatctgtc 42180actgtgccta gtggggcact ggctcccaaa caacgcagtc cttgccaaaa tccccacggc 42240ctcccccgct aggggctggc ctgatctcct gcagtcctag gaggctgctg acctccagaa 42300tggctccgtc cccagttcca gggcgagagc agatcccagg ccggctgcag actgggaggc 42360caccccctcc ttcccagggt tcactgcagg tgaccagggc aggaaatggc ctgaacacag 42420ggataaccgg gccatccccc aacagagtcc accccctcct gctctgtacc ccgcaccccc 42480caggccagcc catgacatcc gacaacccca caccagagtc actgcccggt gctgccctag 42540ggaggacccc tcagccccca ccctgtctag aggactgggg aggacaggac acgccctctc 42600cttatggttc ccccacctgg ctctggctgg gacccttggg gtgtggacag aaaggacgct 42660tgcctgattg gcccccagga gcccagaact tctctccagg gaccccagcc cgagcacccc 42720cttacccagg acccagccct gcccctcctc ccctctgctc tcctctcatc accccatggg 42780aatccagaat ccccaggaag ccatcaggaa gggctgaggg aggaagtggg gccactgcac 42840caccaggcag gaggctctgt ctttgtgaac ccagggaggt gccagcctcc tagagggtat 42900ggtccaccct gcctatggct cccacagtgg caggctgcag ggaaggacca gggacggtgt 42960gggggagggc tcagggcccc gcgggtgctc catcttggat gagcctatct ctctcaccca 43020cggactcgcc cacctcctct tcaccctggc cacacgtcgt ccacaccatc ctaagtccca 43080cctacaccag agccggcaca gccagtgcag acagaggctg gggtgcaggg gggccgactg 43140ggcagcttcg gggagggagg aatggaggaa ggggagttca gtgaagaggc ccccctcccc 43200tgggtccagg atcctcctct gggacccccg gatcccatcc cctccaggct ctgggaggag 43260aagcaggatg ggagaatctg tgcgggaccc tctcacagtg gaatacctcc acagcggctc 43320aggccagata caaaagcccc tcagtgagcc ctccactgca gtgctgggcc tgggggcagc 43380cgctcccaca caggatgaac ccagcacccc gaggatgtcc tgccaggggg agctcagagc 43440catgaaggag caggatatgg gacccccgat acaggcacag acctcagctc

cattcaggac 43500tgccacgtcc tgccctggga ggaacccctt tctctagtcc ctgcaggcca ggaggcagct 43560gactcctgac ttggacgcct attccagaca ccagacagag gggcaggccc cccagaacca 43620gggatgagga cgccccgtca aggccagaaa agaccaagtt gcgctgagcc cagcaaggga 43680aggtccccaa acaaaccagg aagtttctga aggtgtctgt gtcacagtgg agtatagcag 43740ctcgtcccac agtgacactc gccaggccag aaaccccatc ccaagtcagc ggaatgcaga 43800gagagcaggg aggacatgtt taggatctga ggccgcacct gacacccagg ccagcagacg 43860tctcctgtcc acggcaccct gccatgtcct gcatttctgg aagaacaagg gcaggctgaa 43920gggggtccag gaccaggaga tgggtccgct ctacccagag aaggagccag gcaggacaca 43980agccccctcc ccattgaggc tgacctgccc agagggtcct gggcccaccc aacacaccgg 44040ggcggaatgt gtgcaggcct cggtctctgt gggtgttccg ctagctgggg ctcacagtgc 44100tcaccccaca cctaaaacga gccacagcct ccggagcccc tgaaggagac cccgcccaca 44160agcccagccc ccacccagga ggccccagag cacagggcgc cccgtcggat tctgaacagc 44220cccgagtcac agtgggtata actggaacta ccactgtgag aaaagcttcg tccaaaacgg 44280tctcctggcc acagtcggag gccccgccag agaggggagc agccacccca aacccatgtt 44340ctgccggctc ccatgacccc gtgcacctgg agccccacgg tgtccccact ggatgggagg 44400acaagggccg ggggctccgg cgggtcgggg caggggcttg atggcttcct tctgccgtgg 44460ccccattgcc cctggctgga gttgaccctt ctgacaagtg tcctcagaga gtcagggatc 44520agtggcacct cccaacatca accccacgca gcccaggcac aaaccccaca tccagggcca 44580actccaggaa cagagacacc ccaataccct gggggacccc gaccctgatg actcccgtcc 44640catctctgtc cctcacttgg ggcctgctgc ggggcgagca cttgggagca aactcaggct 44700taggggacac cactgtgggc ctgacctcga gcaggccaca gacccttccc tcctgccctg 44760gtgcagcaca gactttgggg tctgggcagg gaggaacttc tggcaggtca ccaagcacag 44820agcccccagg ctgaggtggc cccaggggga accccagcag gtggcccact acccttcctc 44880ccagctggac cccatgtctt ccccaagata ggggtgccat ccaaggcagg tcctccatgg 44940agcccccttc aggctcctct ccagacccca ctgggcctca gtccccactc taggaatgca 45000gccaccacgg gcacaccagg cagcccaggc ccagccaccc tgcagtgccc aagcccacac 45060cctggaggag agcagggtgc gtctgggagg ggctgggctc cccaccccca cccccacctg 45120cacaccccac ccacccttgc ccgggccccc tgcaggaggg tcagagcccc catgggatat 45180ggacttaggg tctcactcac gcacctcccc tcctgggaga aggggtctca tgcccagatc 45240cccccagcag cgctggtcac aggtagaggc agtggcccca gggccaccct gacctggccc 45300ctcaggctcc tctagccctg gctgccctgc tgtccctggg aggcctgggc tccaccagac 45360cacaggtcta gggcaccgcc cacactgggg ccgcccacac acagctcaca ggaagaagat 45420aagctccaga cccccaggcc cgggacctgc cttgctgcta cgacttcctg ccccagacct 45480cgttgccctc ccccgtccac ttacacacag gccaggaagc tgttcccaca cagaccaacc 45540ccagacgggg accacctggc actcaggtca ctgccatttc cttctccatt cacttccaat 45600gcctctgtgc ttcctccctc ctccttcctt cgggggagca ccctgtgcag ctcctccctg 45660cagtccacac cctggggaga cccgaccctg cagcccacac cctggggaga cctgaccctc 45720ctccagccct ttctcccccg ctgctcttgc cacccaccaa gacagccctg gggtcctgtc 45780cctacagccc ccacccagtt ctctacctag acccgtcttc ctccctctaa acacctctcc 45840caggccaacc ctacacctgc aggccctccc ctccactgcc aaagaccctc agtttctcct 45900gcctgtgccc acccccgtgc tcctcctgcc cacagctcga gctcttcctc tcctagggcc 45960cctgagggat ggcattgacc gtgccctcgc acccacacac tgcccatgcc ctcacattcc 46020tcctggccac tccagcccca ctcccctctc aggcctggct ctggtatttc tgggacaaag 46080ccttacccaa gtctttccca tgcaggcctg ggcccttacc ctcactgccc ggttacaggg 46140cagcctcctg tgcacagaag cagggagctc agcccttcca caggcagaag gcactgaaag 46200aaatcggcct ccagcgcctt gacacacgtc tgcctgtgtc tctcactgcc cgcacctgca 46260gggaggctcg gcactccctc taaagacgag ggatccaggc agcagcatca caggagaatg 46320cagggctacc agacatccca gtcctctcac aggcctctcc tgggaagaga cctgaagacg 46380cccagtcaac ggagtctaac accaaacctc cctggaggcc gatgggtagt aacggagtca 46440ttgccagacc tggaggcagg ggagcagtga gcccgagccc acaccatagg gccagaggac 46500agccactgac atcccaagcc actcactggt ggtcccacaa caccccatgg aaagaggaca 46560gacccacagt cccacctgga ccagggcaga gactgctgag acccagcacc agaaccaacc 46620aagaaacacc aggcaacagc atcagagggg gctctggcag aacagaggag gggaggtctc 46680cttcaccagc aggcgcttcc cttgaccgaa gacaggatcc atgcaactcc cccaggacaa 46740aggaggagcc ccttgttcag cactgggctc agagtcctct ccaagacacc cagagtttca 46800gacaaaaacc ccctggaatg cacagtctca gcaggagagc cagccagagc cagcaagatg 46860gggctcagtg acacccgcag ggacaggagg attttgtggg ggctcgtgtc actgtgagga 46920tattgtacta atggtgtatg ctatacccac agtgacacag ccccattccc aaagccctac 46980tgcaaacgca ttccacttct ggggctgagg ggctggggga gcgtctggga aatagggctc 47040aggggtgtcc atcaatgccc aaaacgcacc agactcccct ccatacatca cacccaccag 47100ccagcgagca gagtaaacag aaaatgagaa gcaagctggg gaagcttgca caggccccaa 47160ggaaagagct ttggcgggtg tgtaagaggg gatgcgggca gagcctgagc agggcctttt 47220gctgtttctg ctttcctgtg cagagagttc cataaactgg tgttcgagat caatggctgg 47280gagtgagccc aggaggacag cgtgggaaga gcacagggaa ggaggagcag ccgctatcct 47340acactgtcat ctttcgaaag tttgccttgt gcccacactg ctgcatcatg ggatgcttaa 47400cagctgatgt agacacagct aaagagagaa tcagtgagat ggatttgcag cacagatctg 47460aataaattct ccagaatgtg gagcagcaca gaagcaagca cacagaaagt gcctgatgca 47520aggacaaagt tcagtgggca ccttcaggca ttgctgctgg gcacagacac tctgaaaagc 47580cctggcagga actccctgtg acaaagcaga accctcaggc aatgccagcc ccagagccct 47640ccctgagagc ctcatgggca aagatgtgca caacaggtgt ttctcatagc cccaaactga 47700gagcaaagca aacgtccatc tgaaggagaa caggcaaata aacgatggca ggttcatgaa 47760atgcaaaccc agacagccac aagcacaaaa gtacagggtt ataagcgact ctggttgagt 47820tcatgacaat gctgagtaat tggagtaaca aagtaaactc caaaaaatac tttcaatgtg 47880atttcttcta aataaaattt acaccctgca aaatgaactg tcttcttaag ggatacattt 47940cccagttaga aaaccataaa gaaaaccaag aaaaggatga tcacataaac acagtggtgg 48000ttacttctgc tggggaagga agagggtatg aactgagata cacagggtgg gcaagtctcc 48060taacaagaac agaacgaata cattacagta ccttgaaaac agcagttaaa cttctaaatt 48120gcaagaagag gaaaatgcac acagttgtgt ttagaaaatt ctcagtccag cactgttcat 48180aatagcaaag acattaaccc aggtcggata aataagcgat gacacaggca attgcacaat 48240gatacagaca tatatttagt atatgagaca tcgatgatgt atccccaaat aaacgacttt 48300aaagagataa agggctgatg tgtggtggca ttcacctccc tgggatcccc ggacaggttg 48360caggctcact gtgcagcagg gcaggcgggt acctgctggc agttcctggg gcctgatgtg 48420gagcaagcgc agggccatat atcccggagg acggcacagt cagtgaattc cagagagaag 48480caactcagcc acactcccca ggcagagccc gagagggacg cccacgcaca gggaggcaga 48540gcccagcacc tccgcagcca gcaccacctg cgcacgggcc accaccttgc aggcacagag 48600tgggtgctga gaggaggggc agggacacca ggcagggtga gcacccagag aaaactgcag 48660acgcctcaca catccacctc agcctcccct gacctggacc tcactggcct gggcctcact 48720taacctgggc ttcacctgac cttggcctca cctgacttgg acctcgcctg tcccaagctt 48780tacctgacct gggcctcaac tcacctgaac gtctcctgac ctgggtttaa cctgtcctgg 48840aactcacctg gccttggctt cccctgacct ggacctcatc tggcctgggc ttcacctggc 48900ctgggcctca cctgacctgg acctcatctg gcctggacct cacctggcct ggacttcacc 48960tggcctgggc ttcacctgac ctggacctca cctggcctcg ggcctcacct gcacctgctc 49020caggtcttgc tggagcctga gtagcactga gggtgcagaa gctcatccag ggttggggaa 49080tgactctaga agtctcccac atctgacctt tctgggtgga ggcagctggt ggccctggga 49140atataaaaat ctccagaatg atgactctgt gatttgtggg caacttatga acccgaaagg 49200acatggccat ggggtgggta gggacatagg gacagatgcc agcctgaggt ggagcctcag 49260gacacaggtg ggcacggaca ctatccacat aagcgaggga tagacccgag tgtccccaca 49320gcagacctga gagcgctggg cccacagcct cccctcagag ccctgctgcc tcctccggtc 49380agccctggac atcccaggtt tccccaggcc tggcggtagg tttagaatga ggtctgtgtc 49440actgtggtat tacgatattt tgactggtta ttataaccac agtgtcacag agtccatcaa 49500aaacccatgc ctggaagctt cccgccacag ccctccccat ggggccctgc tgcctcctca 49560ggtcagcccc ggacatcccg ggtttcccca ggctgggcgg taggtttggg gtgaggtctg 49620tgtcactgtg gtattactat ggttcgggga gttattataa ccacagtgtc acagagtcca 49680tcaaaaaccc atccctggga gcctcccgcc acagccctcc ctgcagggga ccggtacgtg 49740ccatgttagg attttgatcg aggagacagc accatgggta tggtggctac cacagcagtg 49800cagcctgtga cccaaacccg cagggcagca ggcacgatgg acaggcccgt gactgaccac 49860gctgggctcc agcctgccag ccctggagat catgaaacag atggccaagg tcaccctaca 49920ggtcatccag atctggctcc gaggggtctg catcgctgct gccctcccaa cgccagtcca 49980aatgggacag ggacggcctc acagcaccat ctgctgccat caggccagcg atcccagaag 50040cccctccctc aaggctgggc acatgtgtgg acactgagag ccctcatatc tgagtagggg 50100caccaggagg gaggggctgg ccctgtgcac tgtccctgcc cctgtggtcc ctggcctgcc 50160tggccctgac acctgagcct ctcctgggtc atttccaaga cagaagacat tcctggggac 50220agccggagct gggcgtcgct catcctgccc ggccgtcctg agtcctgctc atttccagac 50280ctcaccgggg aagccaacag aggactcgcc tcccacattc agagacaaag aaccttccag 50340aaatccctgc ctctctcccc agtggacacc ctcttccagg acagtcctca gtggcatcac 50400agcggcctga gatccccagg acgcagcacc gctgtcaata ggggccccaa atgcctggac 50460cagggcctgc gtgggaaagg cctctggcca cactcgggct ttttgtgaag ggccctcctg 50520ctgtgtgact acagtaacta ccatagtgat gaacccagtg gcaaaaactg gctggaaacc 50580caggggctgt gtgcacgcct cagcttggag ctctccagga gcacaagagc cgggcccaag 50640gatttgtgcc cagaccctca gcctctaggg acacctgggt catctcagcc tgggctggtg 50700ccctgcacac catcttcctc caaatagggg cttcagaggg ctctgaggtg acctcactca 50760tgaccacagg tgacctggcc cttccctgcc agctatacca gaccctgtct tgacagatgc 50820cccgattcca acagccaatt cctgggaccc tgaatagctg tagacaccag cctcattcca 50880gtacctcctg ccaattgcct ggattcccat cctggctgga atcaagaagg cagcatccgc 50940caggctccca acaggcagga ctcccgcaca ccctcctctg agaggccgct gtgttccgca 51000gggccaggcc ctggacagtt cccctcacct gccactagag aaacacctgc cattgtcgtc 51060cccacctgga aaagaccact cgtggagccc ccagccccag gtacagctgt agagacagtc 51120ctcgaggccc ctaagaagga gccatgccca gttctgccgg gaccctcggc caggccgaca 51180ggagtggacg ctggagctgg gcccacactg ggccacatag gagctcacca gtgagggcag 51240gagagcacat gccggggagc acccagcctc ctgctgacca gaggcccgtc ccagagccca 51300ggaggctgca gaggcctctc cagggagaca ctgtgcatgt ctggtaccta agcagccccc 51360cacgtcccca gtcctggggg cccctggctc agctgtctgg gccctccctg ctccctggga 51420agctcctcct gacagccccg cctccagttc caggtgtggt tattgtcagg cgatgtcaga 51480ctgtggtgga tatagtggct acgattacca cagtggtgcc gcccatagca gcaaccaggc 51540caagtagaca ggcccctgct gcgcagcccc aggcatccac ttcacctgct tctcctgggg 51600ctctcaaggc tgctgtctgt cctctggccc tctgtgggga gggttccctc agtgggaggt 51660ctgtgctcca gggcagggat gattgagata gaaatcaaag gctggcaggg aaaggcagct 51720tcccgccctg agaggtgcag gcagcaccac ggagccacgg agtcacagag ccacggagcc 51780cccattgtgg gcatttgaga gtgctgtgcc cccggcaggc ccagccctga tggggaagcc 51840tgtcccatcc cacagcccgg gtcccacggg cagcgggcac agaagctgcc aggttgtcct 51900ctatgatcct catccctcca gcagcatccc ctccacagtg gggaaactga ggcttggagc 51960accacccggc cccctggaaa tgaggctgtg agcccagaca gtgggcccag agcactgtga 52020gtaccccggc agtacctggc tgcagggatc agccagagat gccaaaccct gagtgaccag 52080cctacaggag gatccggccc cacccaggcc actcgattaa tgctcaaccc cctgccctgg 52140agacctcttc cagtaccacc agcagctcag cttctcaggg cctcatccct gcaaggaagg 52200tcaagggctg ggcctgccag aaacacagca ccctccctag ccctggctaa gacagggtgg 52260gcagacggct gtggacggga catattgctg gggcatttct cactgtcact tctgggtggt 52320agctctgaca aaaacgcaga ccctgccaaa atccccactg cctcccgcta ggggctggcc 52380tggaatcctg ctgtcctagg aggctgctga cctccaggat ggctccgtcc ccagttccag 52440ggcgagagca gatcccaggc aggctgtagg ctgggaggcc acccctgccc ttgccggggt 52500tgaatgcagg tgcccaaggc aggaaatggc atgagcacag ggatgaccgg gacatgcccc 52560accagagtgc gccccttcct gctctgcacc ctgcaccccc caggccagcc cacgacgtcc 52620aacaactggg cctgggtggc agccccaccc agacaggaca gacccagcac cctgaggagg 52680tcctgccagg gggagctaag agccatgaag gagcaagata tggggccccc gatacaggca 52740cagatgtcag ctccatccag gaccacccag cccacaccct gagaggaacg tctgtctcca 52800gcctctgcag gtcgggaggc agctgacccc tgacttggac ccctattcca gacaccagac 52860agaggcgcag gccccccaga accagggttg agggacgccc cgtcaaagcc agacaaaacc 52920aaggggtgtt gagcccagca agggaaggcc cccaaacaga ccaggaggtt tctgaaggtg 52980tctgtgtcac agtggggtat agcagcagct ggtaccacag tgacactcac ccagccagaa 53040accccattcc aagtcagcgg aagcagagag agcagggagg acacgtttag gatctgagac 53100tgcacctgac acccaggcca gcagacgtct cccctccagg gcaccccacc ctgtcctgca 53160tttctgcaag atcaggggcg gcctgagggg gggtctaggg tgaggagatg ggtcccctgt 53220acaccaagga ggagttaggc aggtcccgag cactctcccc attgaggctg acctgcccag 53280agagtcctgg gcccacccca cacaccgggg cggaatgtgt gcaggcctcg gtctctgtgg 53340gtgttccgct agctggggct cacagtgctc accccacacc taaaatgagc cacagcctcc 53400ggagcccccg caggagaccc cgcccacaag cccagccccc acccaggagg ccccagagct 53460cagggcgccc cgtcggattc cgaacagccc cgagtcacag cgggtataac cggaaccacc 53520actgtcagaa tagctacgtc aaaaactgtc cagtggccac tgccggaggc cccgccagag 53580agggcagcag ccactctgat cccatgtcct gccggctccc atgaccccca gcacgcggag 53640ccccacagtg tccccactgg atgggaggac aagagctggg gattccggcg ggtcggggca 53700ggggcttgat cgcatccttc tgccgtggct ccagtgcccc tggctggagt tgacccttct 53760gacaagtgtc ctcagagaga caggcatcac cggcgcctcc caacatcaac cccaggcagc 53820acaggcacaa accccacatc cagagccaac tccaggagca gagacacccc aataccctgg 53880gggaccccga ccctgatgac ttcccactgg aattcgccgt agagtccacc aggaccaaag 53940accctgcctc tgcctctgtc cctcactcag gacctgctgc cgggcgaggc cttgggagca 54000gacttgggct taggggacac cagtgtgacc ccgaccttga ccaggacgca gacctttcct 54060tcctttcctg gggcagcaca gactttgggg tctgggccag gaggaacttc tggcaggtcg 54120ccaagcacag aggccacagg ctgaggtggc cctggaaaga cctccaggag gtggccactc 54180cccttcctcc cagctggacc ccatgtcctc cccaagataa gggtgccatc caaggcaggt 54240gctccttgga gccccattca gactcctccc tggaccccac tgggcctcag tcccagctct 54300ggggatgaag ccaccacaag cacaccaggc agcccaggcc cagccaccct gcagtgccca 54360agcacacact ctggagcaga gcagggtgcc tctgggaggg gctgagctcc ccaccccacc 54420cccacctgca caccccaccc acccctgccc agcggctctg caggagggtc agagccccac 54480atggggtatg gacttagggt ctcactcacg tggctcccat catgagtgaa ggggcctcaa 54540gcccaggttc ccacagcagc gcctgtcgca agtggaggca gaggcccgag ggccaccctg 54600acctggtccc tgaggttcct gcagcccagg ctgccctgct gtccctggga ggcctgggct 54660ccaccagacc acaggtccag ggcaccgggt gcaggagcca cccacacaca gctcacagga 54720agaagataag ctccagaccc ccagggccag aacctgcctt cctgctactg cttcctgccc 54780cagacctggg cgccctcccc cgtccactta cacacaggcc aggaagctgt tcccacacag 54840aacaacccca aaccaggacc gcctggcact caggtggctg ccatttcctt ctccatttgc 54900tcccagcgcc tctgtcctcc ctggttcctc cttcggggga acagcctgtg cagccagtcc 54960ctgcagccca caccctgggg agacccaacc ctgcctgggg cccttccaac cctgctgctc 55020ttactgccca cccagaaaac tctggggtcc tgtccctgca gtccctaccc tggtctccac 55080ccagacccct gtgtatcact ccagacaccc ctcccaggca aaccctgcac ctgcaggccc 55140tgtcctcttc tgtcgctaga gcctcagttt ctcccccctg tgcccacacc ctacctcctc 55200ctgcccacaa ctctaactct tcttctcctg gagcccctga gccatggcat tgaccctgcc 55260ctcccaccac ccacagccca tgccctcacc ttcctcctgg ccactccgac cccgccccct 55320ctcaggccaa gccctggtat ttccaggaca aaggctcacc caagtctttc ccaggcaggc 55380ctgggctctt gccctcactt cccggttaca cgggagcctc ctgtgcacag aagcagggag 55440ctcagccctt ccacaggcag aaggcactga aagaaatcgg cctccagcac cttgacacac 55500gtccgcccgt gtctctcact gcccgcacct gcagggaggc tccgcactcc ctctaaagac 55560aagggatcca ggcagcagca tcacgggaga atgcagggct cccagacatc ccagtcctct 55620cacaggcctc tcctgggaag agacctgcag ccaccaccaa acagccacag aggctgctgg 55680atagtaactg agtcaatgac cgacctggag ggcaggggag cagtgagccg gagcccatac 55740catagggaca gagaccagcc gctgacatcc cgagctcctc aatggtggcc ccataacaca 55800cctaggaaac ataacacacc cacagcccca cctggaacag ggcagagact gctgagcccc 55860cagcaccagc cccaagaaac accaggcaac agtatcagag ggggctcccg agaaagagag 55920gaggggagat ctccttcacc atcaaatgct tcccttgacc aaaaacaggg tccacgcaac 55980tcccccagga caaaggagga gccccctata cagcactggg ctcagagtcc tctctgagac 56040accctgagtt tcagacaaca acccgctgga atgcacagtc tcagcaggag aacagaccaa 56100agccagcaaa agggacctcg gtgacaccag tagggacagg aggattttgt gggggctcgt 56160gtcactgtga ggatattgta gtggtggtag ctgctactcc cacagtgaca cagacccatt 56220cccaaagccc tactgcaaac acacccactc ctggggctga ggggctgggg gagcgtctgg 56280gaagtagggt ccaggggtgt ctatcaatgt ccaaaatgca ccagactccc cgccaaacac 56340caccccacca gccagcgagc agggtaaaca gaaaatgaga ggctctggga agcttgcaca 56400ggccccaagg aaagagcttt ggcgggtgtg caagagggga tgcaggcaga gcctgagcag 56460ggccttttgc tgtttctgct ttcctgtgca gagagttcca taaactggtg ttcaagatca 56520gtggctggga atgagcccag gagggcagtc tgtgggaaga gcacagggaa ggaggagcag 56580ccgctatcct acactgtcat ctttcaaaag tttgccttgt gaccacacta ttgcatcatg 56640ggatgcttaa gagctgatgt agacacagct aaagagagaa tcagtgagat gaatttgcag 56700catagatctg aataaactct ccagaatgtg gagcagtaca gaagcaaaca cacagaaagt 56760gcctgatgca aggacaaagt tcagtgggca ccttcaggca ttgctgctgg gcacagacac 56820tctgaaaagc cttggcagga tctccctgcg acaaagcaga accctcaggc aatgccagcc 56880ccagagccct ccctgagagc gtcatgggga aagatgtgca gaacagctga ttatcataga 56940ctcaaactga gaacagagca aacgtccatc tgaagaacag tcaaataagc aatggtaggt 57000tcatgcaatg caaacccaga cagccagggg acaacagtag agggctacag gcggctttgc 57060ggttgagttc atgacaatgc tgagtaattg gagtaacaga ggaaagccca aaaaatactt 57120ttaatgtgat ttcttctaaa taaaatttac accaggcaaa atgaactgtc ttcttaaggg 57180ataaactttc ccctggaaaa actacaagga aaattaagaa aacgatgatc acataaacac 57240agttgtggtt acttctactg gggaaggaag agggtatgag ctgagacaca cagagtcggc 57300aagtctccaa gcaagcacag aacgaataca ttacagtacc ttgaatacag cagttaaact 57360tctaaatcgc aagaacagga aaatgcacac agctgtgttt agaaaattct cagtccagca 57420ctattcataa tagcaaagac attaacccag gttggataaa taaatgatga cacaggcaat 57480tgcacaatga tacagacata catttagtac atgagacatc gatgatgtat ccccaaagaa 57540atgactttaa agagaaaagg cctgatgtgt ggtggcactc acctccctgg gatccccgga 57600caggttgcag gcacactgtg tggcagggca ggctggtaca tgctggcagc tcctggggcc 57660tgatgtggag caagcgcagg gctgtatacc cccaaggatg gcacagtcag tgaattccag 57720agagaagcag ctcagccaca ctgcccaggc agagcccgag agggacgccc acgtacaggg 57780aggcagagcc cagctcctcc acagccacca ccacctgtgc acgggccacc accttgcagg 57840cacagagtgg gtgctgagag gaggggcagg gacaccaggc agggtgagca cccagagaaa 57900actgcagaag cctcacacat ccacctcagc ctcccctgac ctggacctca cctggtctgg 57960acctcacctg gcctgggcct cacctgacct ggacctcacc tggcctgggc ttcacctgac 58020ctggacctca cctggcctcc ggcctcacct gcacctgctc caggtcttgc tggaacctga 58080gtagcactga ggctgcagaa gctcatccag ggttggggaa tgactctgga actctcccac 58140atctgacctt tctgggtgga ggcatctggt ggccctggga atataaaaag ccccagaatg 58200gtgcctgcgt gatttggggg caatttatga acccgaaagg acatggccat ggggtgggta 58260gggacatagg gacagatgcc agcctgaggt ggagcctcag gacacagttg gacgcggaca 58320ctatccacat aagcgaggga cagacccgag tgttcctgca gtagacctga gagcgctggg 58380cccacagcct cccctcggtg ccctgctgcc tcctcaggtc agccctggac atcccgggtt 58440tccccaggcc agatggtagg tttgaagtga ggtctgtgtc actgtggtat tatgattacg 58500tttgggggag ttatcgttat acccacagca tcacacggtc catcagaaac

ccatgccaca 58560gccctccccg caggggaccg ccgcgtgcca tgttacgatt ttgatcgagg acacagcgcc 58620atgggtatgg tggctaccac agcagtgcag cccatgaccc aaacacacag ggcagcaggc 58680acaatggaca ggcctgtgag tgaccatgct gggctccagc ccgccagccc cggagaccat 58740gaaacagatg gccaaggtca ccccacagtt cagccagaca tggctccgtg gggtctgcat 58800cgctgctgcc ctctaacacc agcccagatg gggacaaggc caaccccaca ttaccatctc 58860ctgctgtcca cccagtggtc ccagaagccc ctccctcatg gctgagccac atgtgtgaac 58920cctgagagca ccccatgtca gagtaggggc agcagaaggg cggggctggc cctgtgcact 58980gtccctgcac ccatggtccc tcgcctgcct ggccctgaca cctgagcctc ttctgagtca 59040tttctaagat agaagacatt cccggggaca gccggagctg ggcgtcgctc atcccgcccg 59100gccgtcctga gtcctgcttg tttccagacc tcaccaggga agccaacaga ggactcacct 59160cacacagtca gagacaaaga accttccaga aatccctgtc tcactcccca gtgggcacct 59220tcttccagga cattcctcgg tcgcatcaca gcaggcaccc acatctggat caggacggcc 59280cccagaacac aagatggccc atggggacag ccccacaacc caggccttcc cagaccccta 59340aaaggcgtcc caccccctgc acctgcccca gggctaaaaa tccaggaggc ttgactcccg 59400cataccctcc agccagacat cacctcagcc ccctcctgga ggggacagga gcccgggagg 59460gtgagtcaga cccacctgcc ctcgatggca ggcggggaag attcagaaag gcctgagatc 59520cccaggacgc agcaccactg tcaatggggg ccccagacgc ctggaccagg gcctgcgtgg 59580gaaaggccgc tgggcacact caggggcttt ttgtgaaggc ccctcctact gtgtgactac 59640ggtgactacc acagtgatga aactagcagc aaaaactggc cggacaccca gggaccatgc 59700acacttctca gcttggagct ctccaggacc agaagagtca ggtctgaggg tttgtagcca 59760gaccctcggc ctctagggac accctggcca tcacagcgga tgggctggtg ccccacatgc 59820catctgctcc aaacaggggc ttcagagggc tctgaggtga cttcactcat gaccacaggt 59880gccctggccc cttccccgcc agctacaccg aaccctgtcc caacagctgc cccagttcca 59940acagccaatt cctggggccc agaattgctg tagacaccag cctcgttcca gcacctcctg 60000ccaattgcct ggattcacat cctggctgga atcaagaggg cagcatccgc caggctccca 60060acaggcagga ctcccgcaca ccctcctctg agaggccgct gtgttccgca gggccaggcc 60120ctggacagtt cccctcacct gccactagag aaacacctgc cattgtcgtc cccacctgga 60180aaagaccact cgtggagccc ccagccccag gtacagctgt agagagactc cccgagggat 60240ctaagaagga gccatgcgca gttctgccgg gaccctcggc caggccgaca ggagtggaca 60300ctggagctgg gcccacactg ggccacatag gagctcacca gtgagggcag gagagcacat 60360gccggggagc acccagcctc ctgctgacca gaggcccgtc ccagagccca ggaggctgca 60420gaggcctctc cagggggaca ctgtgcatgt ctggtccctg agcagccccc cacgtcccca 60480gtcctggggg cccctggcac agctgtctgg accctccctg ttccctggga agctcctcct 60540gacagccccg cctccagttc caggtgtggt tattgtcagg gggtgtcaga ctgtggtgga 60600tacagctatg gttaccacag tggtgctgcc catagcagca accaggccaa gtagacaggc 60660ccctgctgtg cagccccagg cctccacttc acctgcttct cctggggctc tcaaggtcac 60720tgttgtctgt actctgccct ctgtggggag ggttccctca gtgggaggtc tgttctcaac 60780atcccagggc ctcatgtctg cacggaaggc caatggatgg gcaacctcac atgccgcggc 60840taagataggg tgggcagcct ggcgggggac agtacatact gctggggtgt ctgtcactgt 60900gcctagtggg gcactggctc ccaaacaacg cagtcctcgc caaaatcccc acagcctccc 60960ctgctagggg ctggcctgat ctcctgcagt cctaggaggc tgctgacctc cagaatgtct 61020ccgtccccag ttccagggcg agagcagatc ccaggccggc tgcagactgg gaggccaccc 61080cctccttccc agggttcact ggaggtgacc aaggtaggaa atggccttaa cacagggatg 61140actgcgccat cccccaacag agtcagcccc ctcctgctct gtaccccgca ccccccaggc 61200cagtccacga aaaccagggc cccacatcag agtcactgcc tggcccggcc ctggggcgga 61260cccctcagcc cccaccctgt ctagaggact tggggggaca ggacacaggc cctctcctta 61320tggttccccc acctgcctcc ggccgggacc cttggggtgt ggacagaaag gacacctgcc 61380taattggccc ccaggaaccc agaacttctc tccagggacc ccagcccgag caccccctta 61440cccaggaccc agccctgccc ctcctcccct ctgctctcct ctcatcaccc catgggaatc 61500cggtatcccc aggaagccat caggaagggc tgaaggagga agcggggccg tgcaccaccg 61560ggcaggaggc tccgtcttcg tgaacccagg gaagtgccag cctcctagag ggtatggtcc 61620accctgcctg gggctcccac cgtggcaggc tgcggggaag gaccagggac ggtgtggggg 61680agggctcagg gccctgcggg tgctcctcca tcttcggtga gcctccccct tcacccaccg 61740tcccgcccac ctcctctcca ccctggctgc acgtcttcca caccatcctg agtcctacct 61800acaccagagc cagcaaagcc agtgcagaca aaggctgggg tgcagggggg ctgccagggc 61860agcttcgggg agggaaggat ggagggaggg gaggtcagtg aagaggcccc cttcccctgg 61920gtccaggatc ctcctctggg acccccggat cccatcccct cctggctctg ggaggagaag 61980caggatggga gaatctgtgc gggaccctct cacagtggaa tatccccaca gcggctcagg 62040ccagacccaa aagcccctca gtgagccctc cactgcagtc ctgggcctgg gtagcagccc 62100ctcccacaga ggacagaccc agcaccccga agaagtcctg ccagggggag ctcagagcca 62160tgaaagagca ggatatgggg tccccgatac aggcacagac ctcagctcca tccaggccca 62220ccgggaccca ccatgggagg aacacctgtc tccgggttgt gaggtagctg gcctctgtct 62280cggaccccac tccagacacc agacagaggg gcaggccccc caaaaccagg gttgagggat 62340gatccgtcaa ggcagacaag accaaggggc actgacccca gcaagggaag gctcccaaac 62400agacgaggag gtttctgaag ctgtctgtat cacagtgggg tatagcagtg gctggtacca 62460cagtgacact cgccaggcca gaaaccccgt cccaagtcag cggaagcaga gagagcaggg 62520aggacacgtt taggatctga ggccgcacct gacacccagg gcagcagacg tctcccctcc 62580agggcaccct ccaccgtcct gcgtttcttc aagaataggg gcggcctgag ggggtccagg 62640gccaggcgat aggtcccctc taccccaagg aggagccagg caggacccga gcaccgtccc 62700cattgaggct gacctgccca gacgggcctg ggcccacccc acacaccggg gcggaatgtg 62760tgcaggcccc agtctctgtg ggtgttccgc tagctggggc ccccagtgct caccccacac 62820ctaaagcgag ccccagcctc cagagccccc taagcattcc ccgcccagca gcccagcccc 62880tgcccccacc caggaggccc cagagctcag ggcgcctggt cggattctga acagccccga 62940gtcacagtgg gtataactgg aacgaccacc gtgagaaaaa ctgtgtccaa aactgactcc 63000tggcagcagt cggaggcccc gccagagagg ggagcagccg gcctgaaccc atgtcctgcc 63060ggttcccatg acccccagca cccagagccc cacggtgtcc ccgttggata atgaggacaa 63120gggctggggg ctccggtggt ttgcggcagg gacttgatca catccttctg ctgtggcccc 63180attgcctctg gctggagttg acccttctga caagtgtcct cagaaagaca gggatcaccg 63240gcacctccca atatcaaccc caggcagcac agacacaaac cccacatcca gagccaactc 63300caggagcaga gacaccccaa cactctgggg gaccccaacc gtgataactc cccactggaa 63360tccgccccag agtctaccag gaccaaaggc cctgccctgt ctctgtccct cactcagggc 63420ctcctgcagg gcgagcgctt gggagcagac tcggtcttag gggacaccac tgtgggcccc 63480aactttgatg aggccactga cccttccttc ctttcctggg gcagcacaga ctttggggtc 63540tgggcaggga agaactactg gctggtggcc aatcacagag cccccaggcc gaggtggccc 63600caagaaggcc ctcaggaggt ggccactcca cttcctccca gctggacccc aggtcctccc 63660caagataggg gtgccatcca aggcaggtcc tccatggagc ccccttcaga ctcctcccgg 63720gaccccactg gacctcagtc cctgctctgg gaatgcagcc accacaagca caccaggaag 63780cccaggccca gccaccctgc agtgggcaag cccacactct ggagcagagc agggtgcgtc 63840tgggaggggc taacctcccc accccccacc ccccatctgc acacagccac ctaccactgc 63900ccagaccctc tgcaggaggg ccaagccacc atggggtatg gacttagggt ctcactcacg 63960tgcctcccct cctgggagaa ggggcctcat gcccagatcc ctgcagcact agacacagct 64020ggaggcagtg gccccagggc caccctgacc tggcatctaa ggctgctcca gcccagacag 64080cactgccgtt cctgggaagc ctgggctcca ccagaccaca ggtccagggc acagcccaca 64140ggagccaccc acacacagct cacaggaaga agataagctc cagaccccag ggcgggacct 64200gccttcctgc caccacttac acacaggcca gggagctgtt cccacacaga tcaaccccaa 64260accgggactg cctggcacta gggtcactgc catttccctc tccattccct cccagtgcct 64320ctgtgctccc tccttctggg gaacaccctg tgcagcccct ccctgcagcc cacacgctgg 64380ggagacccca ccctgcctcg ggccttttct acctgctgca cttgccgccc acccaaacaa 64440ccctgggtac gtgaccctgc agtcctcacc ctgatctgca accagacccc tgtccctccc 64500tctaaacacc cctcccaggc caactctgca cctgcaggcc ctccgctctt ctgccacaag 64560agcctcaggt tttcctacct gtgcccaccc cctaacccct cctgcccaca acttgagttc 64620ttcctctcct ggagcccttg agccatggca ctgaccctac actcccaccc acacactgcc 64680catgccatca ccttcctcct ggacactctg accccgctcc cctccctctc agacccggcc 64740ctggtatttc caggacaaag gctcacccaa gtcttcccca tgcaggccct tgccctcact 64800gcctggttac acgggagcct cctgtgcgca gaagcaggga gctcagctct tccacaggca 64860gaaggcactg aaagaaatca gcctccagtg ccttgacaca cgtccgcctg tgtctctcac 64920tgcctgcacc tgcagggagg ctccgcactc cctctaaaga tgagggatcc aggcagcaac 64980atcacgggag aatgcagggc tcccagacag cccagccctc tcgcaggcct ctcctgggaa 65040gagacctgca gccaccactg aacagccacg gaggtcgctg gatagtaacc gagtcagtga 65100ccgacctgga gggcagggga gcagtgaacc ggagcccata ccatagggac agagaccagc 65160cgctaacatc ccgagcccct cactggcggc cccagaacac cccgtggaaa gagaacagac 65220ccacagtccc acctggaaca gggcagacac tgctgagccc ccagcaccag ccccaagaaa 65280cactaggcaa cagcatcaga gggggctcct gagaaagaga ggaggggagg tctccttcac 65340catcaaatgc ttcccttgac caaaaacagg gtccacgcaa ctcccccagg acaaaggagg 65400agccccctgt acagcactgg gctcagagtc ctctctgaga caggctcagt ttcagacaac 65460aacccgctgg aatgcacagt ctcagcagga gagccaggcc agagccagca agaggagact 65520cggtgacacc agtctcctgt agggacagga ggattttgtg ggggttcgtg tcactgtgag 65580catattgtgg tggtgactgc tattcccaca gtgacacaac cccattccta aagccctact 65640gcaaacgcac ccactcctgg gactgagggg ctgggggagc gtctgggaag tatggcctag 65700gggtgtccat caatgcccaa aatgcaccag actctcccca agacatcacc ccaccagcca 65760gtgagcagag taaacagaaa atgagaagca gctgggaagc ttgcacaggc cccaaggaaa 65820gagctttggc aggtgtgcaa gaggggatgt gggcagagcc tcagcagggc cttttgctgt 65880ttctgctttc ctgtgcagag agttccataa actggtattc aagatcaatg gctgggagtg 65940agcccaggag gacagtgtgg gaagagcaca gggaaggagg agcagccgct atcctacact 66000gtcatctttt gaaagtttgc cctgtgccca caatgctgca tcatgggatg cttaacagct 66060gatgtagaca cagctaaaga gagaatcagt gaaatgcatt tgcagcacag atctgaataa 66120atcctccaga atgtggagca gcacagaagc aagcacacag aaagtgcctg atgccaaggc 66180aaagttcagt gggcaccttc aggcattgct gctgggcaca gacactctga aaagcactgg 66240caggaactgc ctgtgacaaa gcagaaccct caggcaatgc cagccctaga gcccttcctg 66300agaacctcat gggcaaagat gtgcagaaca gctgtttgtc atagccccaa actatggggc 66360tggacaaagc aaacgtccat ctgaaggaga acagacaaat aaacgatggc aggttcatga 66420aatgcaaact aggacagcca gaggacaaca gtagagagct acaggcggct ttgcggttga 66480gttcatgaca atgctgagta attggagtaa cagaggaaag cccaaaaaat acttttaatg 66540tgatttcttc taaataaaat ttacacccgg caaaatgaac tatcttctta agggataaac 66600tttcccctgg aaaaactata aggaaaatca agaaaacgat gatcacataa acacagtggt 66660ggttacttct actggggaag gaagagggta tgagctgaga cacacagagt cggcaagtct 66720cctaacaaga acagaacaaa tacattacag taccttgaaa acagcagtta aacttctaaa 66780tcgcaagaag aggaaaatgc acacacctgt gtttagaaaa ttctcagtcc agcactgttc 66840ataatagcaa agacattaac ccaggttgga taaataagcg atgacacagg caattgcaca 66900atgatacaga catacattca gtatatgaga catcgatgat gtatccccaa agaaatgact 66960ttaaagagaa aaggcctgat gtgtggtggc aatcacctcc ctgggcatcc ccggacaggc 67020tgcaggctca ctgtgtggca gggcaggcag gcacctgctg gcagctcctg gggcctgatg 67080tggagcaggc acagagctgt atatccccaa ggaaggtaca gtcagtgcat tccagagaga 67140agcaactcag ccacactccc tggccagaac ccaagatgca cacccatgca cagggaggca 67200gagcccagca cctccgcagc caccaccacc tgcgcacggg ccaccacctt gcaggcacag 67260agtgggtgct gagaggaggg gcagggacac caggcagggt gagcacccag agaaaactgc 67320agaagcctca cacatccacc tcagcctccc ctgacctgga cctcacctgg cctgggcctc 67380acctgacctg gacctcacct ggcctgggct tcacctggcc tgggcttcac ctgacctgga 67440cctcacctgg cctcgggcct cacctggcct gggcttcacc tggcctgggc ttcacctgac 67500ctggacctca cctggcctgg gcctcacctg acctggacct cacctggcct gggcttcacc 67560tggcctgggc ttcacctggc ctgggcttca cctgacctgg acctcacctg gcctgggctt 67620cacctgacct ggacctcacc tggcctcggg cctcacctgc acctgctcca ggtcttgctg 67680gagcctgagt agcactgagg ctgtagggac tcatccaggg ttggggaatg actctgcaac 67740tctcccacat ctgacctttc tgggtggagg cacctggtgg cccagggaat ataaaaagcc 67800ccagaatgat gcctgtgtga tttgggggca atttatgaac ccgaaaggac atggccatgg 67860ggtgggtagg gacagtaggg acagatgtca gcctgaggtg aagcctcagg acacaggtgg 67920gcatggacag tgtccaccta agcgagggac agacccgagt gtccctgcag tagacctgag 67980agcgctgggc ccacagcctc ccctcggggc cctgctgcct cctcaggtca gccctggaca 68040tcccgggttt ccccaggcct ggcggtaggt ttgaagtgag gtctgtgtca ctgtggtatt 68100actatgatag tagtggttat tactaccaca gtgtcacaga gtccatcaaa aactcatgcc 68160tgggagcctc ccaccacagc cctccctgcg ggggaccgct gcatgccgtg ttaggatttt 68220gatcgaggac acggcgccat gggtatggtg gctaccacag cagtgcagcc catgacccaa 68280acacacgggg cagcagaaac aatggacagg cccacaagtg accatgatgg gctccagccc 68340accagcccca gagaccatga aacagatggc caaggtcacc ctacaggtca tccagatctg 68400gctccaaggg gtctgcatcg ctgctgccct cccaacgcca aaccagatgg agacagggcc 68460ggccccatag caccatctgc tgccgtccac ccagcagtcc cggaagcccc tccctgaacg 68520ctgggccacg tgtgtgaacc ctgcgagccc cccatgtcag agtaggggca gcaggagggc 68580ggggctggcc ctgtgcactg tcactgcccc tgtggtccct ggcctgcctg gccctgacac 68640ctgagcctct cctgggtcat ttccaagaca ttcccaggga cagccggagc tgggagtcgc 68700tcatcctgcc tggctgtcct gagtcctgct catttccaga cctcaccagg gaagccaaca 68760gaggactcac ctcacacagt cagagacaac gaaccttcca gaaatccctg tttctctccc 68820cagtgagaga aaccctcttc cagggtttct cttctctccc accctcttcc aggacagtcc 68880tcagcagcat cacagcggga acgcacatct ggatcaggac ggcccccaga acacgcgatg 68940gcccatgggg acagcccagc ccttcccaga cccctaaaag gtatccccac cttgcacctg 69000ccccagggct caaactccag gaggcctgac tcctgcacac cctcctgcca gatatcacct 69060cagccccctc ctggagggga caggagcccg ggagggtgag tcagacccac ctgccctcaa 69120tggcaggcgg ggaagattca gaaaggcctg agatccccag gacgcagcac cactgtcaat 69180gggggcccca gacgcctgga ccagggcctg tgtgggaaag gcctctggcc acactcaggg 69240gctttttgtg aagggccctc ctgctgtgtg actacggtgg taactcccac agtgatgaaa 69300ccagcagcaa aaactgaccg gactcgcagg gtttatgcac acttctcggc tcggagctct 69360ccaggagcac aagagccagg cccgagggtt tgtgcccaga ccctcggcct ctagggacac 69420ccgggccatc ttagccgatg ggctgatgcc ctgcacaccg tgtgctgcca aacaggggct 69480tcagagggct ctgaggtgac ttcactcatg accacaggtg ccctggtccc ttcactgcca 69540gctgcaccag accctgttcc gagagatgcc ccagttccaa aagccaattc ctggggccgg 69600gaattactgt agacaccagc ctcattccag tacctcctgc caattgcctg gattcccatc 69660ctggctggaa tcaagagggc agcatccgcc aggctcccaa caggcaggac tcccacacac 69720cctcctctga gaggccgctg tgttccgcag ggccaggccg cagacagttc ccctcacctg 69780cccatgtaga aacacctgcc attgtcgtcc ccacctggca aagaccactt gtggagcccc 69840cagccccagg tacagctgta gagagagtcc tcgaggcccc taagaaggag ccatgcccag 69900ttctgccggg accctcggcc aggccgacag gagtggacgc tggagctggg cccacactgg 69960gccacatagg agctcaccag tgagggcagg agagcacatg ccggggagca cccagcctcc 70020tgctgaccag agacccgtcc cagagcccag gaggctgcag aggcctctcc agggggacac 70080agtgcatgtc tggtccctga gcagccccca ggctctctag cactgggggc ccctggcaca 70140gctgtctgga ccctccctgt tccctgggaa gctcctcctg acagccccgc ctccagttcc 70200aggtgtggtt attgtcaggg ggtgccaggc cgtggtagag atggctacaa ttaccacagt 70260ggtgccgccc atagcagcaa ccaggccaag tagacagacc cctgccacgc agccccaggc 70320ctccagctca cctgcttctc ctggggctct caaggctgct gtctgccctc tggccctctg 70380tggggagggt tccctcagtg ggaggtctgt gctccagggc agggatgact gagatagaaa 70440tcaaaggctg gcagggaaag gcagcttccc gccctgagag gtgcaggcag caccacagag 70500ccatggagtc acagagccac ggagccccca gtgtgggcgt gtgagggtgc tgggctcccg 70560gcaggcccag ccctgatggg gaagcctgcc ccgtcccaca gcccaggtcc ccaggggcag 70620caggcacaga agctgccaag ctgtgctcta cgatcctcat ccctccagca gcatccactc 70680cacagtgggg aaactgagcc ttggagaacc acccagcccc ctggaaacaa ggcggggagc 70740ccagacagtg ggcccagagc actgtgtgta tcctggcact aggtgcaggg accacccgga 70800gatccccatc actgagtggc cagcctgcag aaggacccaa ccccaaccag gccgcttgat 70860taagctccat ccccctgtcc tgggaacctc ttcccagcgc caccaacagc tcggcttccc 70920aggccctcat ccctccaagg aaggccaaag gctgggcctg ccaggggcac agtaccctcc 70980cttgccctgg ctaagacagg gtgggcagac ggctgcagat aggacatatt gctggggcat 71040cttgctctgt gactactggg tactggctct caacgcagac cctaccaaaa tccccactgc 71100ctcccctgct aggggctggc ctggtctcct cctgctgtcc taggaggctg ctgacctcca 71160ggatggcttc tgtccccagt tctagggcca gagcagatcc caggcaggct gtaggctggg 71220aggccacccc tgtccttgcc gaggttcagt gcaggcaccc aggacaggaa atggcctgaa 71280cacagggatg actgtgccat gccctaccta agtccgcccc tttctactct gcaaccccca 71340ctccccaggt cagcccatga cgaccaacaa cccaacacca gagtcactgc ctggccctgc 71400cctggggagg acccctcagc ccccaccctg tctagaggag ttggggggac aggacacagg 71460ctctctcctt atggttcccc cacctggctc ctgccgggac ccttggggtg tggacagaaa 71520ggacgcctgc ctaattggcc cccaggaacc cagaacttct ctccagggac cccagcccga 71580gcaccccctt acccaggacc cagccctgcc cctcctcccc tctgctctcc tctcatcact 71640ccatgggaat ccagaatccc caggaagcca tcaggaaggg ctgaaggagg aagcggggcc 71700gctgcaccac cgggcaggag gctccgtctt cgtgaaccca gggaagtgcc agcctcctag 71760agggtatggt ccaccctgcc tggggctccc accgtggcag gctgcgggga aggaccaggg 71820acggtgtggg ggagggctca gggccctgca ggtgctccat cttggatgag cccatccctc 71880tcacccaccg acccgcccac ctcctctcca ccctggccac acgtcgtcca caccatcctg 71940agtcccacct acaccagagc cagcagagcc agtgcagaca gaggctgggg tgcagggggg 72000ccgccagggc agctttgggg agggaggaat ggaggaaggg gaggtcagtg aagaggcccc 72060cctcccctgg gtctaggatc cacctttggg acccccggat cccatcccct ccaggctctg 72120ggaggagaag caggatggga gattctgtgc aggaccctct cacagtggaa tacctccaca 72180gcggctcagg ccagatacaa aagcccctca gtgagccctc cactgcagtg cagggcctgg 72240gggcagcccc tcccacagag gacagaccca gcaccccgaa gaagtcctgc cagggggagc 72300tcagagccat gaaggagcaa gatatgggga ccccaatact ggcacagacc tcagctccat 72360ccaggcccac caggacccac catgggtgga acacctgtct ccggcccctg ctggctgtga 72420ggcagctggc ctctgtctcg gacccccatt ccagacacca gacagaggga caggcccccc 72480agaaccagtg ttgagggaca cccctgtcca gggcagccaa gtccaagagg cgcgctgagc 72540ccagcaaggg aaggccccca aacaaaccag gaggtttctg aagctgtctg tgtcacagtc 72600gggtatagca gcggctacca caatgacact gggcaggaca gaaaccccat cccaagtcag 72660ccgaaggcag agagagcagg caggacacat ttaggatctg aggccacacc tgacactcaa 72720gccaacagat gtctcccctc cagggcgccc tgccctgttc agtgttcctg agaaaacagg 72780ggcagcctga ggggatccag ggccaggaga tgggtcccct ctaccccgag gaggagccag 72840gcgggaatcc cagccccctc cccattgagg ccatcctgcc cagaggggcc cggacccacc 72900ccacacaccc aggcagaatg tgtgcaggcc tcaggctctg tgggtgccgc tagctggggc 72960tgccagtcct caccccacac ctaaggtgag ccacagccgc cagagcctcc acaggagacc 73020ccacccagca gcccagcccc tacccaggag gccccagagc tcagggcgcc tgggtggatt 73080ctgaacagcc ccgagtcacg gtgggtatag tgggagctac taccactgtg agaaaagcta 73140tgtccaaaac tgtctcccgg ccactgctgg aggcccagcc agagaaggga ccagccgccc 73200gaacatacga ccttcccaga cctcatgacc cccagcactt ggagctccac agtgtcccca 73260ttggatggtg aggatggggg ccggggccat ctgcacctcc caacatcacc cccaggcagc 73320acaggcacaa accccaaatc cagagccgac accaggaaca cagacacccc aataccctgg 73380gggaccctgg ccctggtgac ttcccactgg gatccacccc cgtgtccacc tggatcaaag 73440accccaccgc tgtctctgtc cctcactcag ggcctgctga ggggcgggtg ctttggagca 73500gactcaggtt taggggccac cattgtgggg cccaacctcg accaggacac agatttttct 73560ttcctgccct ggggcaacac agactttggg gtctgtgcag ggaggacctt

ctggaaagtc 73620accaagcaca gagccctgac tgaggtggtc tcaggaagac ccccaggagg gggcttgtgc 73680cccttcctct catgtggacc ccatgccccc caagataggg gcatcatgca gggcaggtcc 73740tccatgcagc caccactagg caactccctg gcgccggtcc ccactgcgcc tccatcccgg 73800ctctggggat gcagccacca tggccacacc aggcagcccg ggtccagcaa ccctgcagtg 73860cccaagccct tggcaggatt cccagaggct ggagcccacc cctcctcatc cccccacacc 73920tgcacacaca cacctacccc ctgcccagtc cccctccagg agggttggag ccgcccatag 73980ggtgggggct ccaggtctca ctcactcgct tcccttcctg ggcaaaggag cctcgtgccc 74040cggtcccccc tgacggcgct gggcacaggt gtgggtactg ggccccaggg ctcctccagc 74100cccagctgcc ctgctctccc tgggaggcct gggcaccacc agaccaccag tccagggcac 74160agccccaggg agccgcccac tgccagctca caggaagaag ataagcttca gaccctcagg 74220gccgggagct gccttcctgc caccccttcc tgccccagac ctccatgccc tcccccaacc 74280acttacacac aagccaggga gctgtttcca cacagttcaa ccccaaacca ggacggcctg 74340gcactcgggt cactgccatt tctgtctgca ttcgctccca gcgcccctgt gttccctccc 74400tcctccctcc ttcctttctt cctgcattgg gttcatgccg cagagtgcca ggtgcaggtc 74460agccctgagc ttggggtcac ctcctcactg aaggcagcct cagggtgccc aggggcaggc 74520agggtggggg tgaggcttcc agctccaacc gctccactag ccgagactaa ggaagtgaga 74580ggcagccaga aatccagacc attccatagc aaatggattt cattaaagtt accagacttc 74640agtgtaagta acatgagccc catgcacaac aatcccttat gaaggggaag tcagtgtcgc 74700ctcggatttc ttgaaaaaca caaaaactta tcaatgcctg taaaagtctg ttggaaagaa 74760aatatgattc aagaatgtta tgcccaacaa agctggcata ttttctaccc ggacacactc 74820agggaatgtg gtcccttgag tgcttctctc actgcgtaaa tcctacgtgg tgtttaagca 74880tattcataaa tgtgtatgtc tatttttatg tgtaagatgg ttcattttta ttttatttat 74940tcaatatgta caataaagaa tattgacaaa taggctggac atggtggctc ccacctgtaa 75000tcccagccct ttgggaggcc gaggcgggca gatcacctga ggtctggagt tcgagaccag 75060cctggccaac atgatgaaaa cccatctcta ctaaaaatac aaagattagc caggcatggt 75120ggtgcatgcc tgtaatccca gccactcagg aggctgagac aggagaaatg cgtgaacccg 75180gaaggcggag gttgcagtga gccgagatca caccactgca ctccagcctg gcgacagagc 75240aagattccat ctcaaaaaaa aaaaaagaca aagaaatttg tttttttgaa taaagacaaa 75300tttcatcaca cgaagataaa gatgcaaagc tccagacagg aaggcacgga cagcacagtg 75360aagcccggag cgggcgctgg ggggccaggg gcatggcggg ggtgccagcg tctctcggtt 75420cctaccatgg ccactccagc ctgtgttctc acgaggatgg ctgtgcaatg ctaggagcgt 75480gttcgaagct ctagggcaac cactggaagt gaggctgagg agcagagccc agaggcccgt 75540ggagctgatg aaaagaaagc tggagaaagt gtttgctgcc tcccaacatg gtaagaaaag 75600atagaaagag agagcacacg gcaaagggag cttgctgagg gactctttac aatggcttgc 75660acagagctca gggggtctgg gaggctaggg ccctgcgcag ggcagtcacc ccagcctgct 75720gaccaaggtt tgctgcaggc agctctgggg gtggttgagg cgcggtccct ggagccaccc 75780ctcaagggaa cgaggcagca gagtgggcca aggcccaggt cggctgcaag gctgcccagg 75840acttggggtc cttacatcag cagccactga tgcagctggc ccagagagag gcgccgagca 75900ggttgcctcc aggggacaaa ccaggtcgga gagggtgagg cagtggatgg agccacaaca 75960accccgggca cgggtgacac gcacgttcat gcacatctga cccttcctcc ctcaccaaac 76020aggtccccct gccttcccca tggttgcgaa aaagcaaaat gtagacgttt tttctttttt 76080aattcatgtt ttaattgaca aatgaagccg tatatattta ttgtgtacaa catgatgctt 76140taaaatatgt atacatcgtg gaacagcaac gttgagctaa tttaacacgc attacttcac 76200atacttgtca tcttttgtgg cgagaatgct taaaatccac tctcttagta ttttttaaga 76260atgcaataca ttgttgtcaa ctgtggtcac cgtcatgcat agccaagctc ccgacctcac 76320cctcctgcca gctcaggctg tgcatccttt caccagcatc ccccaccccg gcccctggcc 76380ctggtaacta ccactctata ctctacgtat gagttcagct ttttaagatt ccacagatga 76440atgagatcat acagtatttg ctttctatgc ctggcttatt ttagttaaca cactgtcctc 76500cagatccatc cgttgttgca aatgacaggg tttcattctt tttaaagtct aaagagtatt 76560ccattgtgtc aatggacctc atttgcttta tccatgcatc aactatggac atttaggttg 76620attccatttc ttagctgttg tggatggtgc tgcagtaaac atggggctgc agatgtctct 76680tcaacatact gacatcatgt cctttggata aatacccagt agtgggatcg ctggatcaca 76740atgtacagtt ttttttttaa tggaaacttt cattttttgg tgaaattagg aaaacagata 76800aaacccacag aatccaaaat atatgtgaag atgccaaaaa cagttgacat tgggcagagg 76860tcacatggaa ggaagtgaat acatgacggg gtgtgagggc ccagaggcag ctgaaatacg 76920ctttctaaac acaaggacct cttctgagag ggcagaagtt ttatcctgca catgcaatga 76980ccagcacagc taaaatacac tttctaaaca tgaggacctc ttctgagagg gcagctttat 77040cctgcaaatg caatgaccag cacaggaccc agaataaaga gagttgccag cggacgcctg 77100gtgtccatgt gtccaggtga gttcgagatg cggacggcgc tggccagcca gtcacaccct 77160aagtcaatct gctgcatgca tttgtccttg ccacagcaga aaacgagaaa gcctttgggc 77220tgcaaagctt cacaggctcc tcttctcccg actccatgga aacagctaca aagagcaggc 77280ccagtagagc ttaattcatg aaaatgagta ataaacttga actggaacag tatcgacttt 77340ttagaaacgg cagcaaagtg tataaaaaat attcaccaga acaatatttc caaacgatga 77400gatgagaatt tcagccaagt aatcctccat ggatagaaaa taatgaaggg attggattta 77460tgaaggaaaa tcatggagct caaatacaag aaaagagaat caaaaatgaa caggaggaga 77520taaaatatgg tttggccaaa gttacaaaat aaatttttta aaaacccttc atcatggcaa 77580gtagaaagag cgagaggaaa aacagatccc gtggaagaca caaataggac atggggagaa 77640aaatgaatga gatgaaacag agcagaaata aaattttacg gaactaaaga caagtgatct 77700gaacctgcct ggggcctggg ggacctcgcc accctgaagg gaaagaacat gcctggctgg 77760ctttgccacc tgctcattgc agagccccac agcttgcaac aaacataggc ggtagccagg 77820gagtggttac agcaggcctt gagcaagacc cagtgttgtg ctgacttcag gtctgaccca 77880gcactgtcat agtggtggtg tccatagtgg tagtgggggt gcttgtgtca ctccaccccc 77940atctccagga ggctcagaac agacagagag agactccatt tgtttgggag aaagtaaggg 78000atgagaacaa gagtctctgc ctggtaatcc agagaattat tctagatctt ggccaagatt 78060atcaaagcag tacctctatg agtcttttgg gcttggagtc cccctaaagc agatatagct 78120aagatcacaa cacccaagtc cttttgaata tgtgggaaga cttcccaagg acaggagcaa 78180acaaacaagc ccagactgca aaaaaacaag ccgagactgc aataaacacc tcactcttca 78240atgcccaggc actgaagaac atctcctagc agcaacacca tccaggaaaa catggcctca 78300accagtgaac taaataaggc accagggacc agtctcggag aaatagaggt atgttatctt 78360tcagagaatt caaagtagct ttgttgagga aactcaaaga aattcaagat aacacagtga 78420aggaattcag aatcctatcc gataaattta acagagattg aagcaattaa aaagaattaa 78480gcagaaatta tggagctgaa aaatgcaatt ggcatactga aaaatgcatc agagtatttt 78540catagcctca tatatcaagt agaagaaaga attagtgagc ttgaaaacag gctatttgga 78600aaagcacgat aaaaggagac aaaagagaaa agaataaata acaatgaagc atatctacag 78660gatctagaaa atagcctcaa aaggccaaat ctaagaatta ttagccttaa agaggaggta 78720gagaaagagg gatggagagt ttattcaaag ggataataac agaaaacttc ccaaacctag 78780agaaagatat caatatccaa atgcaagaag gatgtagtac accaaggaga tttaatgcaa 78840agaagactac ctcaaggcat tcaatactca aactcccata tgacaaggac tttaaaaaga 78900tcctaaaagc agcaaaagaa aagaaatgaa taaaatacta tggagctcca atatgtctgg 78960cagcagactt ttcagtgaag actttatatg ccaggagaga gtgtcataat ggatttaaag 79020tgctgaagga aaaaactttt accctcgaac agtatagctg gtgaaattat ccttcaaaca 79080tgaaggagaa ataatttgtt tccagacaaa tgttgaggga tttcatgaac accagacctg 79140tcttttaaga aatgctaaag ggagtacttc aatcagaaag aaacacgtta gtgaacaata 79200agaaatcatc tgaaggcaca aaactcaccg gtaatagtaa gtacacagaa aaacacagaa 79260tattataaca ctgtaactgt ggtgtgtaaa ctccttttgt ttgtttgttt gtttgtttgt 79320ttgtttttgt ttttagacgg agttttgctc cagcccaggc tggagtgcaa tggcacaatc 79380tcagctcact gcaacttcca cctcccgggt tcaagcaatt ctcctgcctc agcctcccaa 79440gtagctggga ttacaggcat gtgctaccat gtccagctaa ttttgtattt tagtagagac 79500ggtgtttcac catgttggtc aggctagcct tatcttgagt agaaaaacta aatgatgaag 79560caatgaaaaa taataactac aacttttcaa gacatagtac aataagatat aaatcataac 79620aaaaagttaa aaggtggagg gatgaagtta aggcatagag tctttattag ttttcttttt 79680acttgtctgt ttatgcaaac agtgttaagt tgtcatcagt ttaaaataat gggtcataag 79740atactatttg caagcctcat ggtaacgtca aaccaaaagc aatacaacag atacacaaaa 79800aacaaaaagc aagaagctaa attacgtcat cagagaaaat caccttcact aaaaggaaga 79860cggagaaaag aatgaagaga gagaagacca aaagcaaata gcaatatggc aggagtaagt 79920ccttacttat caataatacc attgaatgta aatggactaa actctccaat caaaagacat 79980agagtggctg aatcaattaa agaaaaaaca agacccattg atctgttgtc cacaagaaac 80040acactttatc tataaagaca cacatagact gaaaacaaag ggatggaaaa agatactcca 80100cgccaatgga aaccaaagaa agagcaggag tagctacact tatatcaggc aaaatagatt 80160tcaagacaaa aactataaga agagacaagg tcactaatga taaacaggtc aattcagcaa 80220gaggatataa caattgtaaa tatatatgca cccaatgctg gagcacccag atatataaag 80280caagtattta ctagagctaa agagagaaat agactccaat gcaataatag ctggagattt 80340caacatccca ctttcaacat tgaacagatc ctccagatag aaaatcaaca aagaaatatt 80400ggacttaatc tgcactatcg accaaatgga tctaacagat atttacagaa catttcatcc 80460aacagctgca gaacacacat tcttttcctc agcacataga tcattctcaa ggatagacca 80520tatgttgggt cacaaaacaa gttttaaaat attcaaatac attgaaataa tatcaagcat 80580cttctgtgac cacaatggac taaaactaga aatcaataac aagaggaatt ttggaaacta 80640tataaatata tggaaattaa tgaatgctga gtgggtcaat gaagcaatta agaaggaaac 80700tgaaattttt cttggaacga atgatcatgg aaacagaaaa taccaaaacc tatgggatac 80760agcaaaagca gtactaagag ggaagtttac agctacaaat gcttacatta aaaaagaaga 80820aaaacttcaa taaaaaaacc taacaatgca tcttaaagaa ctagaaaagc aagaggaaat 80880caaatccaaa attagtagaa gaaaacagta aaggtcagag cagaaataag taaaattgaa 80940atgaagaaaa caatacaaaa gatcaataaa acaacaggtt gttttcttga aaagttaaac 81000aaaattgaca aacctttagc cagactaaga aaaaaagaca gaagatccaa ataaataaaa 81060tcagagatga aaaaggtgac attacaactt acaccacaga aattcaaagg atcattagtg 81120gctactataa gcaactatat gccaataaat tggaaaatct agaagaaatg cagaaattcc 81180tagacacata caacctccca agattaaacc aagaagaaat tcaaaacctg aacagactga 81240taacaagtaa tgagatcaaa gccgtaataa aaagcctccc agtaaagaga agcccaggac 81300ccgacggctt cactgctgaa ttctaccaaa catttaaagt agaactaata ccaatcctac 81360tcaaactatt ccaaaaaata gaggtggaag gaatacttca aaactcatta tacgaggcca 81420gtattaacct gacaccaaaa ctagacaaag acacatgaaa aaaagaaaac tacaggccaa 81480tatgtctgat gaatattgac acaaaaatcc tcaacaaaat actagcaaac caaattcaac 81540tacacattag aaagttcact catcatgacc aagtggaatt tatctaactt gggatgcaaa 81600gatggttcaa catatgcaaa tcaatcaatg tgatacatca tatcaacaga atgaacaaca 81660aaaaccattt gatcatttaa ttgatactga aaaagcattt gataaaattc aacattcctt 81720cataataaaa attctcttct atactaggta caaaagaaac ttacctcaac ataataaagc 81780catatatgac agtcccacag tatgatacta aatgaggaaa aactgagagc ctttcctcta 81840cgatctggaa catgacaaag atgcccactt tcatcactgt tattcaacat agtactggaa 81900gtcctagctg gagcgatcag acaagagaaa gatataaaag acatccaaat tggaaaggaa 81960taagtcaaat tatcctcatt tgcatatggt atgatcttct atttagagct aactaaagac 82020tccaccaaaa aaagttatta gaactgacga acaaattcag taaagctgca ggatacaaaa 82080tcaacataca aaaatcagta gcatttctat atgccaacaa tgaccaatgt gaaaaagaaa 82140ttaaaaagta accctattta caataaccac aaataaacac ctaggaatta accaaagagg 82200taaaagattt ctgtaatgaa aactataaaa cactgatgaa agaaattgaa gagtacacca 82260aaaaatggaa agcaattgca tgttcatgga ttagaagaat cagtgttgtt ataatgtcca 82320tactatccaa agcaatctac agattcaatg caatccttat caaaatacca atgacatcat 82380tcacagaaat agaaaaaaaa aatcctaaaa tttacgtgga accacaaaga cccagaatag 82440ccaaagctct cctaagcaaa aagaacgaaa ctgtaggaat gacattgcct gtcttcaaat 82500tctactacag agctatagat agtaaccaaa acagcgtggt actggcataa aaacagacac 82560agagacaaac agaacaaaat ttaaaaaccc agaaataaat ccacacacct acagcaaatt 82620catttttgac aaagttgcca agaacatact ctggggaata gataatgata tctcttcaat 82680aaatagtgtg gggaaaactg gatatccata tacataacag tgaaactaga cccctctctc 82740tctcactata tacaaaaatc aaatcaaaat tgtttaagga cttaaatcta agacctcata 82800ctatgaaacc actgcaagac aaccttggcg gaaactctcc aagacatcag tccaggcaaa 82860gatttcttga gtaatatccc acaagcacag acaaccaaag caaaaatgga caaatgggat 82920cacatcaagt taaaaagctt ctgcacagta agggaaacaa ccaacaaaat gaagagacaa 82980cccacagaat gggagaaaat atttgaaaaa tacccatctg gcaagggatt aaaaaccaga 83040atatatgcag aatatataag gagctcaaac agtgctatag aaaaaaaaat ctaataatct 83100gatttaaaaa tgggaaaaat gttagaatag acatttctta aaataagaca tacagatggc 83160aaaccgacat ggaacggtgc tcaacatcat ggattatcac agaaacacaa tcaatcaaaa 83220ctaaaactaa aatgtgctat catctcaccc cagttaaaat ggctgatatc cagaagacag 83280gcaataacaa atgctggcaa ggatgtgggg aaaagggagc ccccatacac tgttgctggg 83340attgtaaatt agtacaacca ctgtggagag cagcatgaaa gttcctcaaa aaactgaaag 83400aaagctacca taggatccag caatcccact gctgtgtata tactacaaaa gaaaggaagt 83460cagtatatga agaggtatct gcactcccat gtttgttgca gccctgttca caacagccaa 83520gatttggaag caacctaagt gtccatcagc agttgaatgt ataaagaaaa tgtggtgcat 83580atacacaatg gagtattatt caataataaa aaggaatgag attgagtcat ttgcaacaac 83640atggatggaa ctggagatca ttatgtgaag tgaaataagc caggcacaga aagacaaaca 83700ttacaatgtt cttacttatt aatgagatct aaaaatcaaa acaattgcac ccatgttcat 83760aaagagtaaa aggatggtta ccagatgctg agaacggtgg tggggggata gggaaaggtg 83820gcagtggtta acgggtacaa aaaaatagaa agaatgaata agacttgcta cttgatagca 83880cagcaaggtg gctatagtca gtaatttagt tgtatatttt taataatgaa aggtgtataa 83940ttggattgtt tctaacacaa aggataatgc ttaagaggat ggatacccca ttttccatga 84000tgtgattatt tcacattgca cgcctagatc aaaacatcca atgtacccca taaatatata 84060catcttctat gtacccataa aaattctgta aaataaaata tataaaaaga ggtgacagat 84120atggaagaca ggcaaagaag agacgacatc cacataatcc gagtacctaa gaaagaatgg 84180agtccagtgc atctcaggag ccaccattct aagccaattt tctctggttc tctcagtcac 84240cctaccaata cgtgggcaat cttgttttat ttcaggatag agtttttgaa attatagatt 84300taagtatgct ttctgttcta ttacttttgg taattaattt tagaaagaac taatttgggc 84360acaaatttga aaaaattcta aatccaaaaa aaaaaagaaa aaaacacaca cacaatcatc 84420tataaggggg atgatgacca gtcctagatt tctcaccagc cacattcaag atcagtaaat 84480ggtaggacaa aacctgtagg gtccttaagg gggaaagaag tagtggatag tccagagtct 84540atatacagcc aactgttctt gaagaaaaaa ggctgctgaa aaggagttcc aaacattcta 84600taatccataa tctcatgatg aaactactag aggaagacca ccagccatca aaaggtgctt 84660ggagaaccca gggccaagaa ccaaaagtaa atattaagtg tccttaactg cgagactaag 84720atagaaatga ctgtggggga ccatgtggcc tcaacagagg tgaaatggtg tctgcctgac 84780aaagtggaca ttttacaatg atcaaaacac agaatatgag atagagagca cttctgaatt 84840actgcctcac tccaaataac tctcagccaa aggacttcag taaaaccaaa ttgggcatat 84900tagacagtac aaacaaattc taagaaaata atattactga ttacaatcac atgatgctag 84960agatggaggg gaaaaggaag aggaaaccag gtaatttcat actcgtatat agtaaagaac 85020taaagtacat tgtccaaaga agaacaaaga atattttgga aagttataaa ggtagccact 85080acacatagaa gatagcaaag aacaagaaaa cttaagatgg aaaacttttt ggaagcataa 85140gaatagaaaa tataaactac taagataaga ttgaagccaa acagatctat gaaaacaaca 85200aacatcaatg gccttaactt gcctattaaa aggaagagac tttcaaattg gaccacaaga 85260taaaacccaa ctctatatag catatgagta ttacacacaa aatgggaaaa gctgaaaaaa 85320cttgggcaaa attcacccca agcaaattcc actgtttcct ttgggacaaa atgccaagct 85380ccatgccagg gaagatgatt ctcctcagac cttctcctca ctctcccagt cctcttaggg 85440aaggaattgg gtgttagagg agggagactc tgtcgattat cagctgaagc agtggtgtgc 85500tcctgcgttg cttctgacct gggaaatgaa gcagcaagac tctttctgct gtgtctttgc 85560ccagaagggc catcccccca gagcagagta cccaggccgg caggagcagt ggtggaagcg 85620tggaaaccac gtctcctaca gcagagacca tcagaagcgg agcctcgggt ataagggaaa 85680caacgcgttc tccctaacct gggagtgaca gacagcgtca ttcctcacag tgataccctg 85740tgttctagcc atctggccca tgacagagcc agcccagagc cagcccagag ccagcccctc 85800accatcctgg agcctggcca gctcgccaag ctgcaccata ggcctggaag gcgtggagac 85860ctgcggcagt gccctgtcct cccgtgaggc ctgccatccc tgccaggggt cgcctctggc 85920ttctccttct ccaggaccgc acggtccaga ggctcagtgc ctggagtagg tgttgcctcc 85980ctgcttctag gcccagaccc tcccttgttc ctgaccccgg gcctttccct ctggcttgga 86040catccagggc cctgtctcag ctggggagct gctcctgctc aaggactgtc ttccgcggga 86100tcgaaaggcc gcgtcctgaa caatgcgtgg gccacgtaag cggagcaggc tctaaaggcc 86160gcgtcctaaa cagtgcgtgg gccacgtgag cggagcaggc tctaaaggcc gcgtcctaaa 86220cagtgcgtgg gccacgtgag cggagcaggc tctaaaggcc gcgtcctaaa cagtgcgtgg 86280gccacgtgag cggagcaggc tctaaaggcc gcgtcctaaa cagtgcgtgg gccacgtgag 86340cggagcaggc tctaaaggcc gcgtcctaaa cagtgcgtgg gccacgtgag cggagcaggc 86400tctaaaggcc gcgtcctaaa cagtgcgtgg gccacgtgag cggagcaggc tctaaaggcc 86460gcgtcctaaa cagtgcgtgg gccacgtgag cggagcaggc tctaaaggcc gcgtcctaaa 86520cagtgcgtgg gccacgtgag cggagcaggc tctaaaggcc gcgtcctaaa cagtgcgtgg 86580gccacgggag cggagcagac tctaaaggcc gcgtcctaaa cagtgtgtgg gccacgtgag 86640cggagcgccc tctccactgc cctcggggcc gcagctccca gctcagctcc cagccctgct 86700cagggcagcc aggccaggag gtaccatcca ggctaagtga ccctcagggg ggacaggtgc 86760cccaggagat gccagctgtt gggagaggct gggggaccaa ctcgacctgg cctgtgggcc 86820ctgccctggc cacccattgt aggatccagc cgccacgcct gtgacactcg tgtgctttcc 86880ctggtgtgtg cttgtggcag gtgggggcag agggtcctca ggccagagag ccactccccc 86940agcgccagac caccctcttc ctcactcccc cacctcaccc cctcacaggt gcctcccagg 87000ccatcagggc ccaaccaccc ctaaacaaat gggttctcgg cccctcgtgg ctggaggtgg 87060gttctctcac cattcccagc ctaagactcc atccccatgc tggcagctgt tcaaccatgt 87120ctagagagat ccactgtccc agacagcacc tcagggtccc ccgtcctgcc tggaaccctg 87180taggaaactc cacaaaccgc cgccattctg tccacacccc tacaggagcc ccaaccctct 87240ccccacatcc aggcttccct cccagacccc tcatccctgc ccgcacggtg cctgaggggg 87300ccttcttggg cagcgcctaa gcaagccccc agcacccttc ggccccttca aggcacacag 87360gccccctttc cacccagcct caggaaacca cctgtgtcct ccaacgacag gtcccagcct 87420cccagccttt gccttgcctg ttcctctccc tggaactctg ccccgacaca gaccctcccc 87480agcaagcccg caggggcacc tcccctgccc ccagacaccc tgtgcccgtc agttcatccc 87540cagcagaggc cctcaccagg cacaccccca tgctcacacc tggccccagg cctcagcctc 87600cctgagggcc ccacccagcc cgcgtctggc cagtggtgcg tgcaaagccc ctcacccaga 87660ctcggcggaa ggcagccagt gcaggcctgg ggaggggctc tccttagacc accttgcacc 87720ttccctggca cccaccatgg gaagagctga gactcactga ggaccagctg aggctcagag 87780aagggaccca gcactggtgg acacgcaggg agcccacgcc agggcgccgt ggtgagtgag 87840gcccagtgcc acccactgag gcctcccgtt cagtgggacg acggtgaaca ggtggaacca 87900accaggcaac ccccgccggg ccccacagac gggatcagag caggaaaggc ttcctgcccc 87960tgcaggccag cgaggagccc tggcgggggc cgtggccctc caggcgagga ggctcccctg 88020gccaccgcca cccgggcctc tctgctgctg ggaaaacaag tcagaaagca agtggatgag 88080aggtggcgtg acagacccag cttcagatct gctctaattt acaaaagaaa aggaaaaaca 88140cacttggcag ccttcagcac tctaatgatt cttaacagca gcaaattatt ggcacaagac 88200tccagagtga ctggcagggt tgagggctgg ggtctcccac gtgttttggg gctaacagcg 88260gaagggagag cactggcaaa ggtgctgggg gcccctggac ccgacccgcc ctggagaccg 88320cagccacatc agcccccagc cccacaggcc ccctaccagc cgcagggttt tggctgagct 88380gagaaccact gtgctaactg gggacacagt gattggcagc tctacaaaaa ccatgctccc 88440ccgggacccc gggctgtggg tttctgtagc ccctggctca gggctgactc accgtggctg 88500aatacttcca gcactggggc cagggcaccc tggtcaccgt ctcctcaggt gagtctgctg 88560tctggggata gcggggagcc aggtgtactg ggccaggcaa gggctttggc ttcagacttg 88620gggacaggtg ctcagcaaag gaggtcggca ggagggcgga gggtgtgttt

ttgtatggga 88680gaagcaggag ggcagaggct gtgctactgg tacttcgatc tctggggccg tggcaccctg 88740gtcactgtct cctcaggtga gtcccactgc agccccctcc cagtcttctc tgtccaggca 88800ccaggccagg tatctggggt ctgcagccgg cctgggtctg gcctgaggcc acaccagctg 88860ccatccctgg ggtctccgcc atgggctgca tgccagagcc ctgctgtcac ttagccctgg 88920ggccagctgg agcccccaag gacaggcagg gaccccgctg ggcttcagcc ccgtcaggga 88980ccctccacag gtagcaagca ggccgagggc agggacggga aggagaagtt gtgggcagag 89040cctgggctgg ggctgggcgc tggctgttca tgtgccgggg accaggcctg cgctttagtg 89100tggctacaag tgcttggagc actggggcca gggcagcccg gccaccgtct ccctgggaac 89160gtcacccctc cctgcctggg tctcagcccg ggggtctgtg tggctgggga cagggacgcc 89220ggctgcctct gctctgtgct tgggccatgt gacccattcg agtgtcctgc acgggcacag 89280gtttgtgtct gggcaggaac agggactgtg tccctgtgtg atgcttttga tatctggggc 89340caagggacaa tggtcaccgt ctcttcaggt aagatggctt tccttctgcc tcctttctct 89400gggcccagcg tcctctgtcc tggagctggg agataatgtc cgggggctcc ttggtctgcg 89460ctgggccatg tggggccctc cggggctcct tctccggctg tttgggacca cgttcagcag 89520aaggcctttc tttgggaact gggactctgc tgctggggca aagggtgggc agagtcatgc 89580ttgtgctggg gacaaaatga ccttgggaca cggggctggc tgccacggcc ggcccgggac 89640agtcggagag tcaggttttt gtgcacccct taatggggcc tcccacaatg tgactacttt 89700gactactggg gccagggaac cctggtcacc gtctcctcag gtgagtcctc acaacctctc 89760tcctgcttta actctgaagg gttttgctgc atttttgggg ggaaataagg gtgctgggtc 89820tcctgccaag agagccccgg agcagcctgg ggggctcagg aggatgccct gaggcaacag 89880cggccacaca gacgaggggc aagggctcca gatgctcctt cctcctgagc ccagcagcac 89940gggtctctct gtggccaggg ccaccctagg cctctggggt ccaatgccca acaacccccg 90000ggccctcccc gggctcagtc tgagagggtc ccagggacgt agcggggcgc cagttcttgc 90060ctggggtcct ggcattgttg tcacaatgtg acaactggtt cgacccctgg ggccagggaa 90120ccctggtcac cgtctcctca ggtgagtcct caccaccccc tctctgagtc cacttaggga 90180gactcagctt gccagggtct cagggtcaga gtcttggagg cattttggag gtcaggaaag 90240aaagccgggg agagggaccc ttcgaatggg aacccagcct gtcctcccca agtccggcca 90300cagatgtcgg cagctggggg gctccttcgg ctggtctggg gtgacctctc tccgcttcac 90360ctggagcatt ctcaggggct gtcgtgatga ttgcgtggtg ggactctgtc ccgctccaag 90420gcacccgctc tctgggacgg gtgccccccg gggtttttgg actcctgggg gtgacttagc 90480agccgtctgc ttgcagttgg acttcccagg ccgacagtgg tctggcttct gaggggtcag 90540gccagaatgt ggggtacgtg ggaggccagc agagggttcc atgagaaggg caggacaggg 90600ccacggacag tcagcttcca tgtgacgccc ggagacagaa ggtctctggg tggctgggtt 90660tttgtggggt gaggatggac attctgccat tgtgattact actactacta cggtatggac 90720gtctggggcc aagggaccac ggtcaccgtc tcctcaggta agaatggcca ctctagggcc 90780tttgttttct gctactgcct gtggggtttc ctgagcattg caggttggtc ctcggggcat 90840gttccgaggg gacctgggcg gactggccag gaggggacgg gcactggggt gccttgagga 90900tctgggagcc tctgtggatt ttccgatgcc tttggaaaat gggactcagg ttgggtgcgt 90960ctgatggagt aactgagcct ctagactgag cattgcagac taatcttgga tatttgtccc 91020tgagggagcc ggctgagaga agttgggaaa taaactgtct agggatctca gagcctttag 91080gacagattat ctccacatct ttgaaaaact aagaatctgt gtgatggtgt tggtggagtc 91140cctggatgat gggataggga ctttggaggc tcatttgagg gagatgctaa aacaatccta 91200tggctggagg gatagttggg gctgtagttg gagattttca gtttttagaa taaaagtatt 91260agctgcggaa tatacttcag gaccacctct gtgacagcat ttatacagta tccgatgcat 91320agggacaaag agtggagtgg ggcactttct ttagatttgt gaggaatgtt ccacactaga 91380ttgtttaaaa cttcatttgt tggaaggaga gctgtcttag tgattgagtc aagggagaaa 91440ggcatctagc ctcggtctca aaagggtagt tgctgtctag agaggtctgg tggagcctgc 91500aaaagtccag ctttcaaagg aacacagaag tatgtgtatg gaatattaga agatgttgct 91560tttactctta agttggttcc taggaaaaat agttaaatac tgtgacttta aaatgtgaga 91620gggttttcaa gtactcattt ttttaaatgt ccaaaattct tgtcaatcag tttgaggtct 91680tgtttgtgta gaactgatat tacttaaagt ttaaccgagg aatgggagtg aggctctctc 91740ataacctatt cagaactgac ttttaacaat aataaattaa gtttcaaata tttttaaatg 91800aattgagcaa tgttgagttg gagtcaagat ggccgatcag aaccagaaca cctgcagcag 91860ctggcaggaa gcaggtcatg tggcaaggct atttggggaa gggaaaataa aaccactagg 91920taaacttgta gctgtggttt gaagaagtgg ttttgaaaca ctctgtccag ccccaccaaa 91980ccgaaagtcc aggctgagca aaacaccacc tgggtaattt gcatttctaa aataagttga 92040ggattcagcc gaaactggag aggtcctctt ttaacttatt gagttcaacc ttttaatttt 92100agcttgagta gttctagttt ccccaaactt aagtttatcg acttctaaaa tgtatttaga 92160attcattttc aaaattaggt tatgtaagaa attgaaggac tttagtgtct ttaatttcta 92220atatatttag aaaacttctt aaaattactc tattattctt ccctctgatt attggtctcc 92280attcaattct tttccaatac ccgaagcatt tacagtgact ttgttcatga tcttttttag 92340ttgtttgttt tgccttacta ttaagacttt gacattctgg tcaaaacggc ttcacaaatc 92400tttttcaaga ccactttctg agtattcatt ttaggagaaa gacttttttt ttaaatgaat 92460gcaattatct agacttattt cagttgaaca tgctggttgg tggttgagag gacactcagt 92520cagtcagtga cgtgaagggc ttctaagcca gtccacatgc tctgtgtgaa ctccctctgg 92580ccctgcttat tgttgaatgg gccaaaggtc tgagaccagg ctgctgctgg gtaggcctgg 92640actttgggtc tcccacccag acctgggaat gtatggttgt ggcttctgcc acccatccac 92700ctggctgctc atggaccagc cagcctcggt ggctttgaag gaacaattcc acacaaagac 92760tctggacctc tccgaaacca ggcaccgcaa atggtaagcc agaggcagcc acagctgtgg 92820ctgctgctct taaagcttgt aaactgtttc tgcttaagag ggactgagtc ttcagtcatt 92880gctttagggg gagaaagaga catttgtgtg tcttttgagt accgttgtct gggtcactca 92940catttaactt tccttgaaaa actagtaaaa gaaaaatgtt gcctgttaac caataatcat 93000agagctcatg gtactttgag gaaatcttag aaagcgtgta tacaattgtc tggaattatt 93060tcagttaagt gtattagttg aggtactgat gctgtctcta cttcagttat acatgtgggt 93120ttgaattttg aatctattct ggctcttctt aagcagaaaa tttagataaa atggatacct 93180cagtggtttt taatggtggg tttaatatag aaggaattta aattggaagc taatttagaa 93240tcagtaagga gggacccagg ctaagaaggc aatcctggga ttctggaaga aaagatgttt 93300ttagttttta tagaaaacac tactacattc ttgatctaca actcaatgtg gtttaatgaa 93360tttgaagttg ccagtaaatg tacttcctgg ttgttaaaga atggtatcaa aggacagtgc 93420ttagatccga ggtgagtgtg agaggacagg ggctggggta tggatacgca gaaggaaggc 93480cacagctgta cagaattgag aaagaataga gacctgcagt tgaggccagc aggtcggctg 93540gactaactct ccagccacag taatgaccca gacagagaaa gccagactca taaagcttgc 93600tgagcaaaat taagggaaca aggttgagag ccctagtaag cgaggctcta aaaagcacag 93660ctgagctgag atgggtgggc ttctctgagt gcttctaaaa tgcgctaaac tgaggtgatt 93720actctgaggt aagcaaagct gggcttgagc caaaatgaag tagactgtaa tgaactggaa 93780tgagctgggc cgctaagcta aactaggctg gcttaaccga gatgagccaa actggaatga 93840acttcattaa tctaggttga atagagctaa actctactgc ctacactgga ctgttctgag 93900ctgagatgag ctggggtgag ctcagctatg ctacgctgtg ttggggtgag ctgatctgaa 93960atgagatact ctggagtagc tgagatgggg tgagatgggg tgagctgagc tgggctgagc 94020tagactgagc tgagctaggg tgagctgagc tgggtgagct gagctaagct ggggtgagct 94080gagctgagct tggctgagct agggtgagct gggctgagct ggggtgagct gagctgagct 94140ggggtaagct gggatgagct ggggtgagct gagctgagct ggagtgagct gagctgggct 94200gagctggggt gagctgggct gagctgggct gagctgggct gagctggggt gagctgagct 94260ggggtgagct gagctgagct ggggtgagct gagctgagct ggggtgagct ggggtgagct 94320gagctggggt gagctgagct gagctggggt gagctgagct ggggtgagct gagctgagct 94380ggggtgagct gagctgagct gagctgagct gagctggggt gagctgagct gagctgagct 94440ggggtgagct ggggtgagct gagctgagct ggagtgagct gagctgggct gagctggggt 94500gagctgggct gagctggggt gagctgagct gagctgagct gagctggggt gagctgagct 94560gagctggggt gagctgagct ggggtgagct gggctgagct gagctgagct gagctgagct 94620gagctgagct gagctgagct gagctgagct gagctgagct gagctgagct gagctgagct 94680ggggtgagct gagctgagct gggctgagct ggggtgagct gggctgagct gggctgagct 94740gggctgagct ggggtgagct gagctggggt gagctgagct gagctgggct gagctgagct 94800gagctggggt gagctgagct gagctggggt gagctgagct gagctgagct ggggtgagct 94860gagctgagct gggctgagca gggctgagct ggggtgagct gagctgagct ggggtgagct 94920gggctgagct gggctgagct gagctgagct gggctgagct gggctgagct gggctgagct 94980gggctgagct gggctgagct ggggtgagct gagctggggt gagctggggt gagctgagct 95040ggggtgagct gagctggggt gagctgagct gagctggggt gagctgagct ggggtgagct 95100gagctgagct ggggtgagct gagctgagct ggggtgagct gagctagggt gaactgggct 95160gggtgagctg gagtgagctg agctgaggtg aactggggtg agccgggatg ttttgagttg 95220agctggggta agatgagctg aactggggta aactgggatg agctgtggtg agcggagctg 95280gattgaactg agctgtgtga gctgagctgg ggtcagctga gcaagagtga gtagagctgg 95340ctggccagaa ccagaatcaa ttaggctaag tgagccagat tgtgctggga tcagctgtac 95400tcagatgagc tgggatgagg taggctggga tgagctgggc tagctgacat ggattatgtg 95460aggctgagct agcatgggct ggcctagctg atgagctaag cttgaatgag cggggctgag 95520ctggactcag atgtgctaga ctgagctgta ctggatgatc tggtgtaggg tgatctggac 95580tcaactgggc tggctgatgg gatgcgccag gttgaactag gctcagataa gttaggctga 95640gtagggcctg gttgagatgg ttcgggatga gctgggaaaa gatggactcg gaccatgaac 95700tgggctgagc tgggttggga gaccatgaat tgagctgaac tgagtgcagc tgggataaac 95760tgggttgagc taagaataga ctacctgaat tgtgccaaac tcggctggga tcaattggaa 95820attatcagga tttagatgag ccggactaaa ctatgctgag ctggactggt tggatgtgtt 95880gaactggcct gctgctgggc tggcatagct gagttgaact taaatgagga aggctgagca 95940aggctagcct gcttgcatag agctgaactt tagcctagcc tgagctggac cagcctgagc 96000tgagtaggtc taaactgagt taaaaatcaa cagggataat ttaacagcta atttaacaag 96060cctgaggtct gagattgaat gagcagagct gggatgaact gaatgagttt caccaggcct 96120ggaccagtta ggctaggacc tcgttctata gaggcagact gtgtgctaca gtggagtttc 96180aagatgattc catgagtcct ccccgccccc aacataaccc accttcctcc taccctacac 96240gcctgtctgg tgtgtaaatc ccagctttgt gtgctgatac agaagcctga gcccctcccc 96300cacctccacc tacctattac tttgggatga gaatagttct cccagccagt gtctcagagg 96360gaagccaagc aggacaggcc caaggctact tgagaagcca ggatctaggc ctctccctga 96420gaacgggtgt tcatgcccct agagttggct gaagggccag atccacctac tctagaggca 96480tctctccctg tctgtgaagg cttccaaagt cacgttcctg tggctagaag gcagctccat 96540agccctgctg cagtttcgtc ctgtatacca ggttcaccta ctaccatatc tagccctgcc 96600tgccttaaga gtagcaacaa ggaaatagca gggtgtagag ggatctcctg tctgacagga 96660ggcaagaaga cagattctta cccctccatt tctcttttat ccctctctgg tcctcagaga 96720gtcagtcctt cccaaatgtc ttccccctcg tctcctgcga gagccccctg tctgataaga 96780atctggtggc catgggctgc ctggcccggg acttcctgcc cagcaccatt tccttcacct 96840ggaactacca gaacaacact gaagtcatcc agggtatcag aaccttccca acactgagga 96900cagggggcaa gtacctagcc acctcgcagg tgttgctgtc tcccaagagc atccttgaag 96960gttcagatga atacctggta tgcaaaatcc actacggagg caaaaacaaa gatctgcatg 97020tgcccattcc aggtaagaac caaaccctcc cagcaggggt gcccaggccc aggcatggcc 97080cagagggagc agcggggtgg ggcttaggcc aagctgagct cacaccttga cctttcattc 97140cagctgtcgc agagatgaac cccaatgtaa atgtgttcgt cccaccacgg gatggcttct 97200ctggccctgc accacgcaag tctaaactca tctgcgaggc cacgaacttc actccaaaac 97260cgatcacagt atcctggcta aaggatggga agctcgtgga atctggcttc accacagatc 97320cggtgaccat cgagaacaaa ggatccacac cccaaaccta caaggtcata agcacactta 97380ccatctctga aatcgactgg ctgaacctga atgtgtacac ctgccgtgtg gatcacaggg 97440gtctcacctt cttgaagaac gtgtcctcca catgtgctgc cagtgagtgg cctgggctaa 97500gcccaatgcc tagccctccc agattaggga agtcctccta caattatggc caatgccacc 97560cagacatggt catttgctcc ttgaactttg gctccccaga gtggccaagg acaagaatga 97620gcaataggca gtagaggggt gagaatcagc tggaaggacc agcatcttcc cttaagtagg 97680tttgggggat ggagactaag cttttttcca acttcacaac tagatatgtc ataacctgac 97740acagtgttct cttgactgca ggtccctcca cagacatcct aaccttcacc atccccccct 97800cctttgccga catcttcctc agcaagtccg ctaacctgac ctgtctggtc tcaaacctgg 97860caacctatga aaccctgaat atctcctggg cttctcaaag tggtgaacca ctggaaacca 97920aaattaaaat catggaaagc cctcccaatg gcaccttcag tgctaagggt gtggctagtg 97980tttgtgtgga agactggaat aacaggaagg aatttgtgcg tactgtgact cacagggatc 98040tgccttcacc acagaagaaa ttcatctcaa aacccaatgg taggtatccc cccttccctt 98100cccctccaat tgcaggaccc ttcctgtacc tcatagggag ggcaggtcct cttccaccct 98160atcctcacta ctgtcttcat ttacagaggt gcacaaacat ccacctgctg tgtacctgct 98220gccaccagct cgtgagcaac tgaacctgag ggagtcagcc acagtcacct gcctggtgaa 98280gggcttctct cctgcagaca tcagtgtgca gtggcttcag agagggcaac tcttgcccca 98340agagaagtat gtgaccagtg ccccgatgcc agagcctggg gccccaggct tctactttac 98400ccacagcatc ctgactgtga cagaggagga atggaactcc ggagagacct atacctgtgt 98460tgtaggccac gaggccctgc cacacctggt gaccgagagg accgtggaca agtccactgg 98520taaacccaca ctgtacaatg tctccctgat catgtctgac acaggcggca cctgctattg 98580accatgctag cgctcaacca ggcaggccct gggtgtccag ttgctctgtg tatgcaaact 98640aaccatgtca gagtgagatg ttgcatttta taaaaattag aaataaaaaa aatccattca 98700aacgtcactg gttttgatta tacaatgctc atgcctgctg agacagttgt gttttgcttg 98760ctctgcacac accctgcata cttgcctcca ccctggccct tcctctacct tgccagtttc 98820ctccttgtgt gtgaactcag tcaggcttac aacagacaga gtatgaacat gcgattcctc 98880cagctacttc tagatatatg gctgaaagct tgcatgcctg caggtcgact ctagaggatc 98940cccgggtacc gagctcgaat tcgccctata gtgagtcgta ttacaattca ctggccgtcg 99000ttttacaacg tcgtgactgg gaaaaccctg gcgttaccca acttaatcgc cttgcagcac 99060atcccccttt cgccagctgg cgtaatagcg aagaggcccg caccgatcgc ccttcccaac 99120agttgcgcag cctgaatggc gaatggcgcc tgatgcggta ttttctcctt acgcatctgt 99180gcggtatttc acaccgcata tggtgcactc tcagtacaat ctgctctgat gccgcatagt 99240taagccagcc ccgacacccg ccaacacccg ctgacgcgaa ccccttgcgg ccgc 99294417DNAArtificial Sequencesynthetic 4tgcggccgat cttagcc 17518DNAArtificial Sequencesynthetic 5ttgaccgatt ccttgcgg 18621DNAArtificial Sequencesynthetic 6acgagcgggt tcggcccatt c 21719DNAArtificial Sequencesynthetic 7ggtggagagg ctattcggc 19817DNAArtificial Sequencesynthetic 8gaacacggcg gcatcag 17923DNAArtificial Sequencesynthetic 9tgggcacaac agacaatcgg ctg 231019DNAArtificial Sequencesynthetic 10tcctccaacg acaggtccc 191120DNAArtificial Sequencesynthetic 11gatgaactga cgggcacagg 201224DNAArtificial Sequencesynthetic 12tccctggaac tctgccccga caca 241325DNAArtificial Sequencesynthetic 13ctctgtggaa aatggtatgg agatt 251426DNAArtificial Sequencesynthetic 14ggtaagcata gaaggtgggt atcttt 261530DNAArtificial Sequencesynthetic 15atagaactgt catttggtcc agcaatccca 301620DNAArtificial Sequencesynthetic 16tggtcacctc caggagcctc 201721DNAArtificial Sequencesynthetic 17gctgcagggt gtatcaggtg c 211830DNAArtificial Sequencesynthetic 18agtctctgct tcccccttgt ggctatgagc 301928DNAArtificial Sequencesynthetic 19gatgggaaga gactggtaac atttgtac 282026DNAArtificial Sequencesynthetic 20ttcctctatt tcactctttg aggctc 262127DNAArtificial Sequencesynthetic 21cctccactgt gttaatggct gccacaa 272223DNAArtificial Sequencesynthetic 22ggtgtgcgat gtaccctctg aac 232325DNAArtificial Sequencesynthetic 23tgtggcagtt taatccagct ttatc 252432DNAArtificial Sequencesynthetic 24ctaaaaatgc tacacctggg gcaaaacacc tg 322517DNAArtificial Sequencesynthetic 25gccatgcaag gccaagc 172624DNAArtificial Sequencesynthetic 26agttcttgag ccttagggtg ctag 242724DNAArtificial Sequencesynthetic 27ccaggaaaat gctgccagag cctg 242822DNAArtificial Sequencesynthetic 28aactacgcac agaagttcca gg 222918DNAArtificial Sequencesynthetic 29gctcgtggat ttgtccgc 183016DNAArtificial Sequencesynthetic 30cagagtcacg attacc 163119DNAArtificial Sequencesynthetic 31tgagcagcac cctcacgtt 193223DNAArtificial Sequencesynthetic 32gtggcctcac aggtatagct gtt 233318DNAArtificial Sequencesynthetic 33accaaggacg agtatgaa 1834296DNAHomo sapiens 34caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaga 2963598PRTHomo sapiens 35Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg36294DNAHomo sapiens 36caggtccagc tggtgcaatc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agctatacta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaga 2943798PRTHomo sapiens 37Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30Thr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr65

70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg38275DNAHomo sapiens 38caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgatgac acggc 2753991PRTHomo sapiens 39Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr 85 9040296DNAHomo sapiens 40caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaga 2964198PRTHomo sapiens 41Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg42294DNAHomo sapiens 42caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180gcacagaagt tccagggcag agtcacgatt accacggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gaga 2944398PRTHomo sapiens 43Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Thr Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg44296DNAHomo sapiens 44caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaga 2964598PRTHomo sapiens 45Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg46233DNAHomo sapiens 46agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggaggcacc ttcagcagct 60atgctatcag ctgggtgcga caggcccctg gacaagggct tgagtggatg ggaaggatca 120tccctatctt tggtacagca aactacgcac agaagttcca gggcagagtc acgattaccg 180cggacgaatc cacgagcaca gcctacatgg agctgagcag cctgagatct gag 2334777PRTHomo sapiens 47Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr1 5 10 15Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly 20 25 30Leu Glu Trp Met Gly Arg Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr 35 40 45Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr 50 55 60Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu65 70 7548296DNAHomo sapiens 48caggtccagc tggtgcaatc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agctatacta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtac agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaga 2964998PRTHomo sapiens 49Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30Thr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Arg Ile Ile Pro Ile Leu Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg50296DNAHomo sapiens 50caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaga 2965198PRTHomo sapiens 51Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg52296DNAHomo sapiens 52caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc agtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tccttggtat agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaga 2965398PRTHomo sapiens 53Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg54296DNAHomo sapiens 54caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtac agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaga 2965598PRTHomo sapiens 55Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Arg Ile Ile Pro Ile Leu Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg56296DNAHomo sapiens 56caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaga 2965798PRTHomo sapiens 57Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg58296DNAHomo sapiens 58caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc agtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaga 2965998PRTHomo sapiens 59Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg60305DNAHomo sapiens 60gagcccactc ccaggtgcag ctggtgcagt ctggggctga ggtgaagaag cctggggcct 60cagtgaaggt ctcctgcaag gcttctggat acaccttcac cggctactat atgcactggg 120tgcgacaggc ccctggacaa gggcttgagt ggatgggacg gatcaaccct aacagtggtg 180gcacaaacta tgcacagaag tttcagggca gggtcaccag taccagggac acgtccatca 240gcacagccta catggagctg agcaggctga gatctgacga cacggtcgtg tattactgtg 300cgaga 3056198PRTHomo sapiens 61Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ser Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Val Val Tyr Tyr Cys 85 90 95Ala Arg62307DNAHomo sapiens 62gagcccactc ccaggtgcag ctggtgcagt ctggggctga ggtgaagaag cctggggcct 60cagtgaaggt ctcctgcaag gcttctggat acaccttcac cggctactat atgcactggg 120tgcgacaggc ccctggacaa gggcttgagt ggatgggatg gatcaaccct aacagtggtg 180gcacaaacta tgcacagaag tttcagggca gggtcaccat gaccagggac acgtccatca 240gcacagccta catggagctg agcaggctga gatctgacga cacggccgtg tattactgtg 300cgagaga 3076398PRTHomo sapiens 63Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg64307DNAHomo sapiensvariation(124)..(124)n=a, g, t, or cmisc_feature(124)..(124)n is a, c, g, or t 64gagcccactc ccaggtgcag ctggtgcagt ctggggctga ggtgaagaag cttggggcct 60cagtgaaggt ctcctgcaag gcttctggat acaccttcac cggctactat atgcactggg 120tgcnacaggc ccctggacaa gggcttgagt ggatgggatg gatcaaccct aacagtggtg 180gcacaaacta tgcacagaag tttcagggca gggtcaccat gaccagggac acgtccatca 240gcacagccta catggagctg agcaggctga gatctgacga cacggccgtg tattactgtg 300cgagaga 3076598PRTHomo sapiensVARIANT(38)..(38)Xaa=any amino acid 65Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Leu Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Xaa Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg66294DNAHomo sapiens 66caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180gcacagaagt ttcagggctg ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gaga 2946798PRTHomo sapiens 67Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Trp Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg68346DNAHomo sapiens 68aggatgtggg ttttcacact gtgtctctcg cacagtaata cacgaccgtg tcgtcagatc 60tcagcctgct cagctccatg taggctgtgc tgatggacgt gtccctggtc atggtgaccc 120tgccctgaaa cttctgtgca tagtttgtgc caccactgtt agggttgatc cgtcccatcc 180actcaagccc ttgtccaggg gcctgtcgca cccagtgcat atagtagccg gtgaaggtgt 240atccagaagc cttgcaggag accttcactg aggccccagg cttcttcacc tcagccccag 300actgcaccag ctgcacctgg gagtggacac ctgtggagac tcgcga 3466998PRTHomo sapiens 69Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg

Leu Arg Ser Asp Asp Thr Val Val Tyr Tyr Cys 85 90 95Ala Arg70150288DNAArtificial Sequencesynthetic 70gcgcgccctg gcatggagga aatgacaaag attattagat tgaagacttt ctcagaaaat 60gatattaagt cattaaggaa aaggaacaat ataaacgtgt atttgagaaa ttttaattat 120ttgagagatt tttcatacaa tatttattct gcaagcaaat ttcagggatt gaattaataa 180aactgataca gaacttcctc tgtaggtatc tgtgtaaaca tcaatttctg aatcagtgtt 240gtaaatattt tggaacacac acacaaatca cattttatct ctacttttat ctctattttt 300aaaaatgcca aaaaaactca ttttgtgcat gtagcatttt gaattcccac catcaatgca 360tgatagttct tggttttcca cattcatatt gccatttatc attatgagaa ttgtgtgttt 420taaccattct aataggtgag taatggtatc taatttttag ttaaatgcac atttccctaa 480taaaaattca catttaacaa ttttcatata atttttgcca agatgcctct tctcatattt 540ggttcatttt taactgcatt gttttctttt gattagttgt aagtttactt gcatattgat 600tataaaatca tttaacaaat taaaagaatt catttaacaa atatgtgact tggaagtatt 660ttctccaagt ctgcggctgt cttttactcc cttatcagta tgtattgcag aaaagtgtgt 720gtgtgtgtgt gtgtgtgtgt ttatacaaat ttagatttaa aaaatgtaaa atgttattca 780tccacagatc atgtctttgg tattatatct gaaatctcat tataaaatac agtaatagca 840attacttttt ccacgtctct aatctcaggc tacaatcaac tcatgagtgt ttaagcttca 900cctacttgat tagaggacta tcaacctaac atatttggaa tacttctgta aaaagatgtg 960ttcctcttcc tattatttct ttatttgatc acttattaat atgtgtattg gtttatggat 1020gtctatttca tactctgaag aagatccatg ctacattatt cattttattt ttcaaaccac 1080cacggcttta ttatgtgctg ggagctcatt gagtttggat cctgcatcct tacagctcac 1140ctcatgcttt tgtttttgaa cacttccctg tttcctgcta ttataataaa ttctaaactc 1200attttctata ttatcttttt catacataga atcagccatt tttctaaaga ttgcttgctt 1260ctgatgttaa agaatagtat ttaaaaaatt gtaatactgg gtatgtgcat tgttaatgtg 1320gtataagtac ttgcaggacc tctcaaccaa ctggcctagt aaactatgta tctaaccttc 1380tgtaatgtga ttacattaaa aatgagaaca cactggtctc tctacccaat tatgctacca 1440catggatctt tctagccttc cttccttgac tgtctataac ctctcactgc aaaatgagga 1500accccatcca accatatgcc attttattac ttagctgcac aatttcagga cacatgcata 1560gcagtatcag aaatgtaaag ctgtaccctt gtaggaaaca tgtttatcta ctagaataga 1620gtgcttatgt tcagtttctt tacactttaa acttacagag tttcctcatt ttcaaagttc 1680cttaggtcag caacttcatt ttccactttc ttcagtgagg tcatttcaat gacactgtat 1740aatttgattt atttgaaatt ctataaaagc caaaactgta gtcaagtgaa caacaacata 1800tagaggatat tcgaggagtt tagagactgg tataaaataa gttaaaaaga cactgtttaa 1860gaagattaaa attattttta gtgatatgca atggttcaga tatgacacaa ttaatttgtc 1920taagcacata gttttgtgat ggaaaatata aacctaaata tatacaatta aaaaaaaatt 1980tagcagttca ttaacccaag gatcaaatgc agattgtata aaattatctc attacttatt 2040ttgtgagggt ggagatttca tgagatgtat gcaacaaaga atgaggtaat tttcctgatt 2100tgcatataag atgttgccat tcactaaaga cctttaattt tttaaattgt ttttttttta 2160aatcaatttt ctatgtgacc caggtttttt tctcttgaca agcaaataac ccacaggatt 2220attttctttc cttggttgag aaatatttcc ccaaacttca gctcagttca ggcatacact 2280gtccctgaat gggcatttac cctcagatgg gtacacacac ctgtcaacat gtggactctt 2340ctgtcagaca aacgcacctt tactcacgtg gattcttctc tcagacaaac acacatgtcc 2400ccacgtggac tctttcctca gactaccaca tatgttctta catttactct ttcctcagaa 2460aacagacatt tcctcatgtg gactcttgtc tcagacaagc aaacatgtct ccatgtgaac 2520tcttcactca cataagtaca catatgtcca cattgactgt ttccttacac aagtacatat 2580atccaatgtc gaattgttct gtggcaaaat gatctcaaga taatgataat cataaacccc 2640ctccctgaca aggcatagat ctgtattttt ttcattgcaa cctaactttg ccttattgtc 2700aagaacagta gtttgcagct ctaaatatac caattagaga caggtgtcca ttttctctgg 2760aaacgtattt ttatgttctt actggacata tttgttgata atgtttgcta ttatgaagat 2820accccaacag tgtccacatt agagaataaa aaatagtaat gggcagatta actctgtgca 2880tccagaccca gaaatccttt gaccttgact tccctgaaat gtagacacag aggatggatg 2940agcaatgctg agcagtgcac ccatgaccac aaaaagaaag acgtggaaat gtgtcccctc 3000cacttctcat gaaaggcagc tcatcccctg ttccctcagg ccctggcgag gagccacccc 3060atgtctgtgc ccttcctcag tgtccacacc gtggggtctg cattgatctg gattctcttc 3120tcatccccgt caatattagt gtccttcgta aatcaggtcc agctgtggct tctcctcacg 3180gggctgttct cagtctgttt gctgtgttca cggaagtcct gtgtgaagtt tactgatgga 3240gtcagagggg gaaaaaattt acagcccagt ggtgagactc tcctgcaaag cctctggttt 3300cacctttact ggttacagca tgagcttggt ccagcacgct tcacaacagg gataggtgtg 3360ggtgccaaca gtgagtgatc aagtatgaat tctcagggtt actttccatg agtacaaata 3420aattaacaat ctcaagcaac acccttttaa gtgcagtctg ccttacaatg accaatctga 3480aagccaagga caaggtcatg tattactgtg agtgacacag tgagggaaac cctgtgtgag 3540cccagacaca aagctcaccg cagggagaca ggaggggact atgtggtaga tgctgctcag 3600aaccaccagg gggcatcagg accatcaggg agggtgcaca gaaccaccag gaggggctca 3660ggacaccagg gggcgctcag aaccaccagg gggccctcag gacaccagag ggtgctcaga 3720accaccagga ggcgctcagg acaccagggg gcgctcagaa cactaggagg tgctatgaat 3780cactaggggg cgctcaggac acaagggagc actcagaacc accagggata gctcaggata 3840ccagggggca ctcggaaccg ccagggggcg ctcaggacac tagggggcgc tcagaaccac 3900cagggggcac tcaggaccat cagggagggt gcacagaacc accaggaggg gctcaggaca 3960ccagggggcg ctcaggacca caagggggcc ctcaggacac cagggggcac tcggaaccac 4020cagggggcac tcagaaccat cagggagggt gcacagaacc accaggaggg gctcaggacc 4080accaggaggt gctcaggaca ccagggggcg ctcagaacac taggaggtgc tatgaatcac 4140tagggggcgc tcaggacaca agggagcact cagaaccacc agggatagct caggacacca 4200gggggcactc ggaaccgcca gggggcgctc aggacactag ggggcgctca gaaccaccag 4260gaggcactca ggaccatcag ggagggtgca cagaaccacc aggaggtgct caggacacca 4320gggggcgctc agaacactag gaggtgctat gaatcactag ggggcgctca ggacacaagg 4380gagcactcag aaccaccagg gatagctcag gataccaggg ggcactcgga accgccaggg 4440ggcgctcagg acactagggg gcgctcagaa ccaccagggg gcactcagga ccatcaggga 4500gggtgcacag aaccaccagg aggggctcag gacaccaggg ggcgctcagg accacaaggg 4560ggccctcagg acaccagggg gcactcggaa ccaccagggg gcactcagaa ccatcaggga 4620gggtgcacag aaccaccagg aggggctcag gaccaccagg aggtgctcag gacaccaggg 4680ggcgctcaga acactaggag gtgctatgaa tcactagggg gcgctcagga cacaagggag 4740cactcagaac caccagggat agctcaggac accagggggc actcggaacc gccagggggc 4800actcaggaca ctagggggca ctcagaaccg ccaaggggcg ctcagaagaa gcagggggtg 4860ctcagaacac cagagggtgc tcagaagcac cagggggcgc tcaggacacc aaagggcact 4920catgagactg tggcaagggg gtgctgagaa ccacaggatg tgaccaagac accaaggggc 4980actcagaact gccagggggt gctcaggaca ccagaggatt ctcagaacca ccaggggatg 5040ctcaggaaac tagcgggtgc tcagaaccac cggaggacac tcagaaaacc aggggatgct 5100caggaaccac cagggggcgc ccacgacacc agagggcagt cagaaccacc ggggcatgct 5160cagaaccacc agggggcgct caggacacca ggggatgctc aggacactag gggcgctcag 5220gaaccaccag gggacgctca ggacactagt agggtctcag aaccaccagg ggatgctcag 5280gacactaggg ggcgctcagg aaccaccagg ggtcacccag gacaccaggg gtcgctcagg 5340aaaccagagg gtgcccagga aaccagggga ggttcaggaa ccaccagggg gcactgagga 5400caccaagggg tgctcagaac caccaggggg cgctcaggaa ccaccagggg gcgctcagga 5460cactagtagg cactgaggaa ccaccagggg gcgctcagga cactagtagg cactgaggaa 5520ccaccagggg gggctcagga cactagtagg cactgaggaa ccaccagggg gcgctcagga 5580cactagtagg cactgaggaa ccaccagggg gggctcagga caccagaggt cgctcagaaa 5640accagggggt gctcagaacc accagggggc actcaggaac caccagtggg tgttcaggac 5700agcaagaatg gctcaggaca ccagggagca ctcaggacct ccaaggggct ctttggaggc 5760agctccatat caggtacctg gggaggatga ggtttccttt tccaccttgg tgattcctga 5820cctggtcaag caaaagtctt ccccaggatc tcttacgatg tcttccttgt aactcatggt 5880ttctttcacc tataaaacat taacttagaa caggggttca attcaacttt taactctgcc 5940tattttcaga gttatactag caatgatata tctcagtata ttttttttaa ttgtgtatat 6000tcaatccaaa gtctggctct atgcacaatt tttttgtttt ctgtgctgtc agacacacta 6060ttgtaaatgc ttttctaaca actcagcata tgcatggggt ccagtttctt ttcctttcat 6120cggctgtttg tgcagatgaa acaccacttt aagggctcct gtcctccact ttggcccctg 6180gtgttctgct tctcaaactt tctccatctt ctctttttct gtcaaaatat tttatcttcc 6240tcagtctcca tgcaggaaac aggaagtcct tttacttcct gtcctccatg tctggtaaat 6300cagttcactt cttttcatga tcactgaagc caaccaagtt taggagagta acagttctcc 6360ttagaataca ctctacctgc agaccctctg ccctcatcac acttttctag ggtcctgcag 6420acataacccc cacccattcc tctttttccc taagtaccac agactaggct ctgcaactta 6480tgctaccctc tgtgtgctca gcccaggggc tcagtagtgc tttcatgaag tccaaatccc 6540taatgtgttt gcccactctc agaccaccct ccagcaagct gccattgtga ttgaatcctg 6600caaagcatgg gctgctttca gtttcctatt gctggatgtt ctttattata aaggcatatt 6660ggcaaataac gactagagtt tgtattgaaa attaacgcca aaaagttttt taaaaagttt 6720ttcaaataga aaagttctat cctgcctagt ttaaaaaaat acaatgttac tttaatcaat 6780gatttaataa aaatttaagt gatgtttgtc ttattagtta ttcaatttat taataactga 6840ctgatattta aaaagtaaat actggctggg cgcagtggct cacgcctgta atctcagcac 6900tttgggaggg tgaggtgggt ggatcacctg aggtcgggaa ttcgagacca gcctgaccaa 6960catggagaaa ccccctctct actaaaaata caaaattagc tgggcgtggc ggggaagctg 7020aggcaggaga atcgcttgaa cctgggaggc ggaggttgcg gtgagccgag aacacgccat 7080tgcactccag cctgggcgac aagaccaaaa ctctgtctca aaaaaaaaaa aaagtaaata 7140ccattgtaca cttaagtaat atatttggca agaatggcat ttacattcat tcaaaaatga 7200aactgcaaat acgagttaca ttcaattaaa taattaaaat aatatagaaa aaaatgggtg 7260tgttgttttg gtgtttaata tacattcatt tttgcatgga cgggtatatg tgtcattgct 7320gggctgttgt gtatgtgtgc gtgtgtgtgt gtgtctgtgt gtacaactat gaagtttaaa 7380atatattatt aaattacgta gttatattaa tccaaattta tcatgttaaa atattaggaa 7440aaaaacacca gtagagaaat tacagagaac atcagcaatg cctacagcat ttacaagagt 7500cacattaata acaaacaaac tagttcaaat gtttagatat gacacatgca gtagaaaacg 7560ttcacatggt attaacacaa aaatggtgca caactgagga aattataata cgttcatgat 7620attggctaca taaatgctta tgatagtaat gcttttcatc catcaaatgc ttatgataat 7680gcttttcatc catcatatta tagatgataa aacaactcta taaacacttc catcactagc 7740gtttaatatg agatgcctca catctttttc tgaaataaat aaacatctgt ccaccacttc 7800gatgatcatt tcaggattat cctctgaaat aattatccat aataatttta gtaacaatat 7860tattttcaga agcctatttt ataaggtctt tgaactatta tttttatgat tgttacttta 7920tattttacac actttttatt tggaataatt ataggttatc agaacaattg taaggaaaat 7980acagtgtgtt cacatccatc tccaagtttt cactaaagtt aatatgtcaa aaaaaacatg 8040ggacatggga ctaatatatt tacattgata agtttctgtt tattcagctc tgggatttat 8100ttgaattttg ccaattttta acagtttcct tttttccttt ttcttttctt tttgagataa 8160ggtgtcactt tcctattgct ttttgtttgt ttctttgttc aacccacgta accacatcaa 8220attcagtcac catgttcctc tcatatcttc tggttaatca cagtttgggt tcctgctgtc 8280ttcccattga atattctata aatgaaacta gtcaaataag ttgattctgg tcacttatat 8340atttacctat tttatcacgt ttgttttgtc aatcacagta agtgtcgaat tcgctatctg 8400ttatagatgt tagcctattt tctatcccag atccattggt taaatctttg gtgatgcctt 8460ttagaaaact gatcccttta ccctatgtaa tatgcccctt gattcctgaa agtcttatgt 8520ctaccttgtc tgaatttaac atagctaagc acgctttctt ttcgttcata ttttcatggt 8580ccatgttttc ctgtatttaa cttttctatg tagagcaaat ttctgtacag agctagtagt 8640tgggtcttgc tttttaaatc aactataata attctatttt aaaactggta ttactatttt 8700tctgttaatt tctgttttaa tttggcattt tatgatcatg tttatttctc tattaactta 8760ttgtttagtt catcttttat gaatattgta ttggccctaa gatatacaat aagaattgtg 8820tataatcaga ttctaattca aataacgtaa aacctcttca taggttgtag agctattata 8880acttattctt ctaaacactc tttctcatcc gttgtcttag tttattctca gtttgcactt 8940atatgtgcta taaaatataa tatgtgcatt tttatcatta catagacata tattagaaca 9000attaaaaata taaaaactac atttcaactt cattttttca ttcttgacca catgttttat 9060ttggatagat tcatgtttcg gatgtatatc atatggctac tcaccctggc agaaaatttg 9120ccaaagcacc tactgaagga tgaatgcact agcaataaat tttctcagaa tcgatttgtc 9180ttacagggta ttcatttgac tttcgcttta aatgaaattt ttaatatata tagaattcca 9240gtttgacttt aatttgtaat ttattttctt gtactcatgt attcattatt ttcttcctga 9300agatggtcac acattccatt ctgctgggcc ttcattatag atatttgtgt gtatctattc 9360agggctatat ttgcaattta tggatgccac aattatcaga gttgaagtca gcttctgctg 9420tccacagaga tttcaagttc ctcccatgat acttgctttt gtgtccctgt ttgatcctgg 9480gtctttatat ttagttttcc ccagggaggc tgtctgtttc agctgtggaa agtgcaccct 9540actgacagtt taaattgatg actgtgtggt gaaggaggtt ggacaaagcg ggacttcctc 9600caaccttctg actgagtctc cttcttatgc aggagtagta agcatagttc tggggagtgg 9660ccttccacat tgtcctgtcc ttaactcttt ccccagggct ggaacgtctt ttcccagaca 9720caactgtttt tcaccagtgt ccccagcttt ttacccacta tccttaccct aaagagtaag 9780gatttctttc ctgaggaagg agatgggagg tgtttctgga tcaagtttcc ttggtgtcgt 9840ctgtttcctt ttgtttctgt tgacttcacc acagctcata tgacacatgc tttggtggat 9900ttcccctgga ggtagtggag gtgcattcag gcattccaca ggagctgctg ttcttttccc 9960cagtcaacac cacaagacac cagatgagga agttgtccgt ggatttttca agttctctag 10020gaaaagcttg caagcactag gccaatctaa caccattagt acatgcatac taaaaaaaaa 10080aaagtcatta agtatttcta ggttagtctg tttctatctc aaatgccatc cagtggcacc 10140tgccctacgt acactagcag gtaggtcctg gttctctctg caggctccta tcttctcaga 10200tttcagtttt cttgtttgct tggtgaaatc aactcagata tgttgaatgt tttttctctc 10260ttttatttgt agctgttcag cttcgttgtt aatgaggtca gaataaaatc acagttttct 10320catttttttc acattcccac actgaatagc tgctttccgt ataaaagcca gaaactgaga 10380gaacacattg aatatccatt acaggtgaat gttaaacaat ttgagatatg tttgtgtact 10440ggaataaaat gctgcattac aatcaagtca tcactcattc acataaaaca tggccacatt 10500ctcaaataat gtagggacct gagtgcccct ccatctactg gcctctcctg gggccctagc 10560ctggccacac cttcttgcag ggcagtcttg gacgccctgg gatcccgcac caaaatttct 10620gccctggcag aacatgcctg actggtggag agctccaatc gggcagccct catgtgcaca 10680caccagctta cacacttcct ccgaatactg taggttcacc caggcccacg taacttccca 10740catcactttg cagtcacatg tctgtatagg tgggttttgc ttttcttgtc ccaccattgc 10800gtggagtgca gtcccctccc cccaccccaa ccaccatggc agaggaagct ttggtgggga 10860aaaagccagg gccgctcctg tcagcgtccc gcacttgcgc taattctgca cagagaatag 10920cagatcatct cacacattca gaaatcactc ctgcttgtgg ggcatgaata cggcacccgg 10980gcctgtgccc acaagtgtcc catccctgag ccaacacctc ctccagtgtg accttgaaca 11040cagtcaccaa cagggcccca cagacgcaat gcctctgcca ctgtggcgaa cacctgcagg 11100gaggcaggca cccagacacc cactagcact ctgccacagc tgccacacct ccaacagccc 11160aggacagtgg attcctaacc ttaaggagcc ggagaaccaa gtcagggact agtataactt 11220cccccagagt cagagcacac agtctaggtg ttgggagctg agcactggcc acctaaattt 11280ttccagaaat gaagccagtt ggctgaatcc accttatacc acaatcaaac cctcaaggtc 11340atccaatagg gtaaaagaaa ataaaaatgt atccaaaggt cagcaacttc aaagattgaa 11400ggtggataag cccacaaaga tgagaaagaa ccagtgcaaa agtcctgaaa acaaaaaggg 11460cgccctcttt cctccaaaca accacagcac ctcttcaaca gcagttctga atggggctga 11520gatggctgaa atgacagaaa cagaactcag aatatggaga gtgaaaatgt agatgaatac 11580agctatttat ggagaatact ataaatgttc ctcaaaaaat aaagaaacaa aatctactgt 11640agaatccagc agtctcactg ctggctatgt atccaaagga aatgaaatca acatgtcaaa 11700gagatatctg cactccatgt tcacgttcat tgcagcatta tttaaaatag taaagatatg 11760gaaacatcct aaattcccat gaatggatga atgaataaag aaaatgcata cagacacaac 11820agagtaatgt tcatccttaa ataagaagga aaccctgcct ctgtgacagc atgcatgaat 11880ctagaggacc ttatgccaag tgaaacaagc caggaacaga ggaagagtca ttcatgattt 11940cactgtatat attaaagcag tagacttgca gaggtagagt agaatgttgg ttaccagggc 12000ctagaggggt ggactgggaa agggagatgt gggttaaagt gcacaacgtt ccagttagac 12060cggaggtata agttatgcct ttctaatgca cagcatgtca actatagctg ataaggtagt 12120atatatttca aaattactaa aaaaataaac attagaattt ccccactaag aaatgataaa 12180tttgtgaggt gatgaatata agcggcttga gttacccagt tcataatgta tacatgtatc 12240ataactaaac aacatatgtc ataaatatat gcaaaaatta tttgtaattt ataataaaat 12300aagtttcata tttaaataat tacattaaga aaatgaacag aaactttcag atttcaagaa 12360tattttatat atatatatat atatcttaaa acaaacttgc aacagaatat agaaataagt 12420tttacgactc aatggaaaag aacagaattc aataaaaact ggctaaaaga aacaacagct 12480gcatcattat agaaaattct ggaataatca gccatataaa gattctcact ctcttagaac 12540tagaattccg taggacttgt aattcctcct gacctgggtg ggaggcaaaa ggaagaacag 12600ctaatggtga ttcagtgagt tttatacctg tgtgtacttc tgtgctcact cagcagaaag 12660aaaagaagaa aagaaagaaa gagagaaaga aagaaacaga aagaaagaaa gaaagaagaa 12720agaaagaaag aaagaaagaa agaaagaaag aaagaaagaa agaaagagaa agaaagaaga 12780aggaagaagg aaggaaagaa aagaaagaaa gaaagagaga gagggagaga gggaaggaag 12840ggacagcaga agtcattgtg gtgtgtgtga aagcacaatc cttgggctcc cccacatcca 12900tctctactcc agtcccatca atgtccagca aatacatttt ctaagatgaa gtattttaaa 12960ctttctaaat cctgctagaa aacccctcag ctctttcagt tttgctctat cacttgaatt 13020attgaattaa atctagtttt tgtgggccta tcaataccat aagccaaaat aacacatgaa 13080gaaattgcac tgagacacat gaaaaccttc tgaaagctcc ataatttcag atctgcattc 13140ttatttcccc gaacctaaat cactgaatag agactcagaa cgagttgatc ttgttcctga 13200acgtgcacag agccaaggac atcctgtctg tctggaacag ctcaggtttg ttcctgtttc 13260tcctagagga tataaaatct tgagttaggg aaaaacagcc agggacaccc tgggctttgt 13320tcttctctcc cctggaggca ggatgtcctt cagagctttg tcccagtggg taacacagct 13380gctgaggtgt acaacccacg tggcctcgtt ttggtcactt ttgcatggtg agcctgcttt 13440gcaccatggc ctacaatatg cgtgtgtaac taatctgtct ccatcttcaa aatgacatta 13500ttccacatca aatctagtgc aggtgcctca cacagaacat tctcaattac ctccatcatt 13560cataaaattg atgccattaa tttcaagtat acatacatca gactcattta acgtattgtt 13620attctcattg tttgaaacat aacttttaga tcaaataatt aacaataata aaaatataaa 13680ttttgaagtc aggtaatgtg atttctctag ttgtgttctc tttgctcaga atggcttggg 13740ctgttctgca tcttttgttt ttccacatat attttaggat tttttaaaaa tttctgtgaa 13800gaatatcatt gttgttttca tagggattgt actgagtctg tagattgctt taagtattat 13860ggacatttta acaatattga atctttgaat tcataaacat ggaatattgt tccatcttgt 13920gtcctcttta tttcctcaat gttttataga tttattgtag ttttttttta ctttgttcat 13980tacacattgt atgcctgtac caaaacatca catataccca acaaatagaa atatatatac 14040tattatgtgc ttataacaat taaaaattat gtatgtatat tgaatctatt caaaatcaga 14100aactatttct ttttactgtt tgtaaggtct tgtctctagg ctataaaaag aatttgtaaa 14160actcaacaga aagcataata taaacagaat tctaaaatga gtgaaaatct gaacaaacac 14220ctcaccaaga aaaaatgtta tctgaaaata agaatatata aaattgttca gtatcaattg 14280tcataaactg atactcatat ttaccaaata caaaagtaaa catgatgtat ttcaacagaa 14340ttgattctca aatatttgta tactcataca gtggaatact atcagtcata aaaactatgg 14400gttattaatt cagaagacaa cattttaaca ttttttctaa gtgaaggaag atggacaaaa 14460gagactaagt attgtacaat tccattcatg agacctgcta aatacagtaa aattaaaagg 14520attttaaaaa caggtttgtg ataggcaggg cttttgggga aagacaagag actgacttgg 14580caaagctcag gggatatttt tagggtaaaa caaactgtgt gccattgtga tatgcctaat 14640ttcttattat atttgttcag agttaatagt gtacgtttca accaactcgg tgattttata 14700ttttctattt gctgatagag acatgttcat ttttgtcaat cactttgcta aatgtggctg 14760agaggctgtt gaaatgaacg ctgagcaaat gtattcacca aatctacaag agcaaattat 14820ttgccaattg ctgattgagt ggggtctata atgtatttga gattgggtgt ggggatgtta 14880ttgtgtgaga tcatgatgtt tagaccatga cactctctgg tgagggatca ctcattcatt

14940gcacatttaa tgaaaggcag gtaggaggag cagaagggga tgagtcacac tcctgaccac 15000agccacaggt tattgaaggc agaactgatg taatccccta aggtagacca ctgcccctcc 15060aaggtgacct tatcctagag ttgacacaca tcctgggaca ccagagacaa ctccttctct 15120cccctttctc tgcacttcag ctggaagcaa ctgtctcacc gagcaccttg tgttaaggaa 15180tgagagttcc tgttccaggt gtgagggccc aggtgcatcc acttgatcca gcacaagagc 15240aagaacagcc ttccagaaaa tgacatcgcc tgaggtataa ccagctctca cctgctgcag 15300cttcctctga ataaaaagga aactgttgaa acttcctcat aagtgtcctg ctgtgccatt 15360ccctttgtcc ccacatgttc agttgtgtct gtccagatgt cacttttgtg tagggagatt 15420agggttctgc ttccagtacc agaacacaca tgacctctta ggggacttca gggttttgct 15480gacatatgtg atgatcttaa aagtcattag ctccatttct acatcaaaaa acatctgaac 15540caaaggagca cataggctca ggcctgtaat cccagcactt tgggaagcca aggcagagga 15600atcacttgag gtcaggaatt tgagaccagc ctggtgaaca tggtgaaacc ccgtctctac 15660taaaaaatat atacaaaaat tagccaggcg tggtggcact agcctgtaat cccagctact 15720tgaaaggctg aggcaggaga attgcttgaa cccaggaggt ggagattgaa gtgagctgag 15780atcgcaccac ttcactccag cctgggcgac agagtgagcc tccatctaaa aaaaaaaaaa 15840atttatatat atatatatat atatatatat ataataaata tatattatat atcatatata 15900tattttatat aatatatatg tatattttta tatattatac atacatatca atatatgata 15960tataatatgt atatataata tataatatgt atattcatat attatataat atgtatattg 16020atatatatta cacatatata ttttgatata tatatatctc caaaccatct aaatatcaag 16080tattttttaa tccatctaag agctgaaatt gctgaaaaaa ctactccctc caaaagctgt 16140agagacaggc acatccacag tcacagcaga gacttgctga cttggaagag aagctcctgg 16200agacacattg gtgagaacat ttacctggtg attatgctga atgtctggag gacaaatgtg 16260gactaggggg agggtgagca ctcctagagg ctgtacaccc cacacttgtg tggacttgcc 16320ctccagggcc ttcaggttct cgtggaagca attaaaatag attccctata gccatgaact 16380ggggaggagt aatcacggag aaaagatgca caaaaagact tttctagaaa gctcatccaa 16440gggaaggtat tctccaaaat cttagtttat gtgggggaag gaaatacttc caaattacag 16500acccctcctc ctcagccttc ctctatcacg caaatgataa aattagccaa gaggagtcag 16560attcaaggcg gtagccctgg gtgcagcatc tgcagaaggg aggaaagaga gaaaatcagc 16620tgtatcactg gagattcctt gtgaaggtca ctgctcagga gaagagggca accaaaccag 16680ggagagtcaa ctgtaagaac ataccatgct cccctgcccc acacattacc tcctcaacag 16740catcattaat atggattaaa gagggcagtg tgattgcttt agatctgttt gagaaagaaa 16800gtcacatact gaggcctagg gtcagggtcg gcggcacttc ccgtgagtaa gatactacga 16860agaaggaaaa attaggggtc cataactgtg aaaatcagcc acagtgtgtg tgagaatgtt 16920tgtgtttgtg tttctgtgtg tttgagtagg agttattgga acagcggacg tggagtgagc 16980tttaatccac atccatctgc agcttcaggt attctcagat gcagtattca tctgcaagag 17040ccgaaatgag aaaagagcca cctccaaccc ccccagagtt ttagcctccc tttgtttcca 17100gtgatccagt gcatctagac ctccaggaag tggactccct ggtgatttta gcgattcttc 17160tcttggagcc accctgaaga ggacattggg tttccaaagg cccattcact atttcaagaa 17220gtggtgccat cagctcatgt tgtcactgaa ggagcattct gagccagggc acagtcactt 17280cctagtgagc tacagaggct gagagaaaaa tgctctgtga gacccaatgg gaagctccct 17340gcagtgcaag gtctgggtgg cagggagcgc tagggcctcg cccagcacag gctgcagccc 17400tggagcaggt gcaagggagg ctggggaggg gttcctccca gggtctgatg tcttcctttt 17460ctcggacaaa catgctttaa taagttaaac aagactttag taaagactat tgatgtgtct 17520ttgtgtcttt cagtatacag ttctatttgt aggatttatc taacctaaca agtcaatgag 17580aatcacatgt aaaaggagaa atttctagga ttttcagata tcttaatagg taggagatgg 17640agaaaaggga tggttttatt aattcagtgc ttgccaatct taacagagac agtagtaaga 17700catgcagaaa gcaaagccca gaaaagtatg aaggtgtcaa agtgccattt aagtatgggt 17760tcacttggag gaccatgttc tgcgggaact tgttttcagc agacaatcta ttttagcaga 17820gttctgggca tacaagggga cacacatcat taaacaagga ttgggacagg gacttcagcg 17880tcccactgtt gcatggccca taaattatgt gtgttctctt tctcatcttg gatcaagtct 17940agagctatga aatagtatcc ctcatgaata tgcaaataac ctgagattta ctgaagtaaa 18000tacagatctg tcctgtgccc tgagagcatc acccagcaac cacatctgtc ctctagagaa 18060tcccctgaga gctccgttcc tcaccatgga ctggacctgg aggatcctct tcttggtggc 18120agcagccaca ggtaagaggc tccctagtcc cagtgatgag aaagagattg agtccagtcc 18180agggagatct catccacttc tgtgttctct ccacaggagc ccactcccag gtgcagctgg 18240tgcagtctgg ggctgaggtg aagaagcctg gggcctcagt gaaggtctcc tgcaaggctt 18300ctggatacac cttcaccggc tactatatgc actgggtgcg acaggcccct ggacaagggc 18360ttgagtggat gggatggatc aaccctaaca gtggtggcac aaactatgca cagaagtttc 18420agggcagggt caccatgacc agggacacgt ccatcagcac agcctacatg gagctgagca 18480ggctgagatc tgacgacacg gccgtgtatt actgtgcgag agacacagtg tgaaaaccca 18540catcctgagg gtgtcagaaa cccaagggag gaggcagctg tgctggggct gagaaatgaa 18600agggattatt atttttaatg ttgtttacag tatgtcatta ataaattgaa aaaaagtaac 18660aatagaagta tatactctaa ttatatggga actttgtttt ttcagttttt tcattttttt 18720tttttttttt ggtttgtttg tgacagagtc tcactctgcc acccaggctg gagtgtaacg 18780gcacaatctc agctcactac aacctccacc tcccaggttc aagcaattct cctgcctcgg 18840cctccagagt agttgggatt acaggcaccc gccaccatgc ccggtgaatt tttgtatttt 18900tagtagagac ggggtttcac catgttagct aggctggtct caaactgctg atctcaggtg 18960atctaccctc ctcagcctcc caaagtcctg ggattacagg cgtgagccac tgcgcctggc 19020ccaattatat gggaattgtt tatataatta tcaccctata agcaaaattc atggaggagg 19080aaaagctcta ctgaagaaag ctgataccgg cattcccatg aaagtatctg tgtagaagta 19140agtattaaaa tcagttgaat aggcaaggca tggtggctca cgcctataat cccagcactt 19200tgggagaccg aggcaggtgg atcacaaggt aaggagttca agatcagcct gcccaagatg 19260gtgaaacccc ttctctacta aaaatacaaa gaattagctg ggcgtggtgg tgggtgcctg 19320taatcgcagc tattcgggag gctgaggcag agaattgctt gaacctggga ggtgaaggtt 19380gcagtgagcc gagatcacgc cactgcactc cagcctgggc gacagagtga aactccatct 19440caaaacaaaa caaaacaaaa caaaacaaaa aaacagttga ataaagtacc ttagagtcat 19500ctgttcaatt aacatgttta actccaaaga aatactgaaa atattttcca aaaaggaagt 19560gccattttac gttcctacca acagtgaata agattttctt ttctggagcc ttgtcagtat 19620tcactaatgc tttgctgtgc agccgttgta atattatagt aaatgagtag cagtatttaa 19680tggttgtttt aaatatacat attcttaata caaagtcttg atgaacactt ttttatacat 19740tgttttatga ggtgtgtgtt cagatctatg tatgccagaa atgcctggca gcgttaattt 19800aagcacactg tgagaatgac cctatagttt atgaagaatg tatgttcaga gctctgagct 19860aagaaatcca ggagctgtca acccagaagt ttattccttg tctgtgaagg acatctgaat 19920ccctggccta tcccttggaa cacaggatgt ccaggtgatt gatgctcttt gttaaatctg 19980gaggttgcta ggtagagggt gctaagtgaa aatcataata taaactacac gtgttttaca 20040aatggtagtg gttttcctgt ccaacacact tttcctgggc cacattgtat gcaagtcctc 20100aatacaccct aggtcttgtt catgggctcc aggtctcctc ttcagccttt tggacatggt 20160gccatgccta ttacagtcaa taggggtcta gcatgacaac tggtaggccc agaacaaggt 20220caaagaaaat cctgcaagct cttagacaac agtgtcaagg aaggggagac ctgtggggaa 20280atcccaggca ggccatgcac atctctgtgg gcccaacagc tgcaatcctt gatggatggg 20340gcccgctgca tgtgtacggg gatgcctcca aaatgccaaa agttctggag gacctgttgc 20400ctgaggtgga tgtgacaatg tgacaaagtg acagtcagat tcctgagctg tggcagctgt 20460tggccactcc tgactgcact ctgagcaacc actgaggcag agctcattgc acaggctagg 20520gtgtgtcagc cacgagaaca gttgtaacta taatgagatg ccgcctgtag ggataggata 20580gcaaattgga gaccattgtt tatttggtag gccatttaaa gtgttgctga ctgccacacc 20640aatgcattag gactactatg actacgtcat cctgggagcc taagtcctgg cgtccgatgt 20700agagctccag tgggaaggag atgaaggtta ggatgagtcc ataaaggttc ttgctctgca 20760gcccctgctt tgctgtctca cttggtgaac agagaatggg aggtcaatgc ggacaaagtc 20820cagggtccag gcttatcagt caaatacttg gtgtcatctg gttacataag actatagtta 20880ttccatattt catcatagat aagataagat gcaggtctac tcatgtccca ccacaccaaa 20940gcagttggaa acctcccaag gcctcctggg acattggcga tcctttattc cccatttcgg 21000caaacccctt gggcccccat ggcacttaga caagaaggtg ccccactgcg actgttccaa 21060aagggaggat gagggctctg aagaagctga agtcacagtg aaatgaatac aaaccttggg 21120agttctagtg cagggacagc cctgtgaatt ggatgtagtc agttaccctg aggggtttag 21180gtggggactg tgttaaaggc aaggacataa gtgtgtgtcc ctaagaccct ggtctcaaag 21240acagaaggaa gctgaagtga gatatactgt ttaggagtag caactgcact acatgtcatg 21300ccttacgagt gtaggatgtg acaaagaggg ccactccaca tccggaacaa cctttagcag 21360gctggctaaa ggatgccttc cagacacaaa agccttggaa tgccaggaca cagtctgtag 21420ccaaatggta cttgtggtgg tcaccaccaa cataaaagtg ggccaactgt gccagcagaa 21480gttagcccca cagaactttc ccccacctaa gagaaggcag tgcaccacaa tgcggaattc 21540caccactgtg gaattggggg agcttagaat tggattcaga cacaagggga gagagtggat 21600cacagggtgg cttctctatg ggataggggg tggagagtat tatactctct ggactcaaga 21660tgagtaaaat gacacccatc acaaaccatc cagccctatg atggcacctt tatggtaagt 21720ggttgcaggc tccaaggggg ccgggtccaa tgaggaagat gcccccacag ctcgttctca 21780atggcagact atagaagagt tgcaggatat cttctgggag tcgagatgag gcatgctaat 21840tatgctgaga attattgaag tcccaacaat gaattgttta ctgcaaaata aaagctacag 21900ttatgtattc agtgcctacc caatggcatg gtgcactgat ttccacgtta agccccctgg 21960gagggcagcc aacatttcat gtgccccagg tagttgctga cttaggagaa aagaagaaac 22020tgagtaagca agggatgcac cctactgtga tgaagaacaa tggcaccaaa ggaagagaga 22080cagccaagga gccagtcagg gtggccagac aacgaatgtg ctctaactgg caacacctac 22140cagttctctg ggcccatagc ggcaataggt ggttatggaa gggccacgga agtcagaccg 22200gttgaactag tgatacgacc tgggggactg ccacccagac cctgtgtagt atacacagct 22260tccatcctag aacacatgag aatggatatc ttcttaggcg tgaccctcca aacaacggcc 22320agggaattcc aacggagagt tagagtggtg atatgtgtga ccaagcagaa ggcaaactgg 22380atgccagtag agctgccaac ccatggggag tcccacagct ggagcaacac cacccgccct 22440gggaggggaa gatgatccaa tcatgaagat tgttaaggag ctagcccagg taggcattag 22500gaggccactg catggttcct acaacagacc tgcatggccc atgcagaggc cagttgagac 22560atggagaatg acagtagatt actgggagtt aaataaggtg gtctcccgag tgaatgcagc 22620tgttcctaat atctcctcca gtctgacgag aataggagag gtgttagcca cgtagcattt 22680ccttatcagt ttagtcaata ccttcttcag catttctgtt gccccagagt caagatcaat 22740ttgcattaac ctaaaaagaa caatggactt ttactgtctt gttccaggga tatttacaca 22800gcccaaatct cacagcctag tgacctccaa cctcagtcga tgggctgacc caaaggggat 22860acatgttttc cactacattg gtgttatcat gataacctct gagtcttttt tcagcttata 22920aattacagcc cctgtcttgc tgtctcactt gctgaataga ggatgggagg ttaatacaga 22980caaaatccag ggtccaggct tatcagtcaa atagttggtg tcatctggtt gggtaaaact 23040aaagtcattc catctgccat catagataag gtgcaggcct acccacgtcc caccacaaca 23100aagcagctgc aaactctcaa ggccttctgg agcatcagtg tccttttatt ccttttattt 23160gacatccctg aaggaggctg ctaggggaga ctgtgtccct cctaaattca tgtgctgaag 23220tcccaaccct tggtccttca gaatgaaatc atacttggat tagtgtcctt taaagaggtg 23280aataagttaa agtgagattc ctggagtggg gccctaatgc aatctgactg ttgttataag 23340aagaggaagc aggagggagg gtgcacaggc cccgagggac ggccatgtta ccacagaaca 23400gtgagaaggc gccatctgca tgccagggag cgagacctca gaggaaaccc acccagctgg 23460cagcttgatc ttaggctttc atcctccata agtgtgagga aattggtttt gtattgtaag 23520ccatccgatc tgtggtattt cgttataaaa gccctataaa atgaatacag taggtaatag 23580gagagcttct atacattgaa aaagtcggat ggccagaaaa acctagacac tcctgttcag 23640acctgagcag ggtgatggac ctgctttggg acaggagagg ggaagagatg aacccagcac 23700ccagacccag ctgagcccat tcctcagcag gccgtccctg ggccggagct tgcacaggtg 23760tgaaagagcc tgtcttggtc ttcaggggct catggagttg gacggagaat ggtgtagact 23820caagaacacg tcatcggtgt gcccgtgttt atctgaatgg gatgtgtttc tagggtgtgc 23880tcatccccaa agaagaatta atcaggtctc ttgggctaaa aagaggttgt ggcatttgtg 23940tgtattaata actgtggtcg gacagtaaat tatgttaaac tgcttatggg aaggcacaat 24000ggaaagaaac actttgttac agaaggaaaa aaaaggtgat tatttaaatg aggtgccttt 24060gaaggtcacc atgccaagag gagcccatca catgatagtg ctggctttca tgttcaggag 24120atcaggaggg tccgtccgct ggcttttatg acaccctaga cagagctgag agtgtaatgt 24180atgaatggag gggaagtgga gagaggggag gccaaatgtt tggtgggaat ggagggtcac 24240tattggagcc attaggaaat acacaagcat gaattatgct ggaggacaga acagtgttcc 24300tggggaatat tgtgttgctt tgggagctgc tgaacataca ggagtttcac tgttcctagt 24360tctcaaattc tctagactct ctggacaacc cagttttaaa tattgggaat ataggtaaga 24420cacattcgtt attaaaaatt attaagagaa gatgtaggaa gaaatttaaa gtaatccatt 24480tggttatgaa aatttagtta cagcgaactg tgatgtccgt ttcttacttg gaataatgga 24540atgtaagtca ttagtcatct caacggttca tttttccata accatcaatt acaaaactgc 24600tgagtaattt cctgaattgc ccaccataga aactgacctc acatttcctc aatgagaaac 24660tgccagtccc gttgatccag cctcgttctt cccatcaggg attttgtatc tctgtggacg 24720tgtggcacag tgctgcatat ccatcggcat atggcctcag gaaaggcgcc agcctatcca 24780tgcatgatga agcttactta ggggatgaag cccgcatgct gggtgagcca gtgccaacag 24840ctgaaagaat caactgcctg gtgtatgatg cttttatgaa aacaagccca gggcctcttg 24900cattcttctg tattagattc tctggtgaag atttttattc atttctgcct gaaattgcca 24960catataatta cctggaagca ttacaataaa ctgatttgga agttaactga cttcctggtg 25020aggttaaaat gagtgtcagg tgcatagtga gacagaccgg agacatggat gcatagcaaa 25080cttgtgctca ccatggtttc tatcttagtt agggaaactt ctgtaccttc cttagatgtt 25140caggcactcc attgaggacc ctggcataac attatttatt gacagaccat agctcaaagt 25200atagaactgg atactaccaa ggaggatata ctattactat tttatcttta tcttaaaata 25260tactcttcca tctgaggtga aaattaatcc agatggtaga acttattgca gttactacag 25320cattttagca aatcaaaagc cgcagaacaa acatatggac agatggcagg tatgttttcg 25380gaatcgtaaa caagttcgtg atgactgtaa aaccaagggg tgtctcacga gggctggaaa 25440cctctcacaa tgaaacaaca caatgaggat ctttgaaaag tactctgacc tcctggtgag 25500ctggctgata tggaggctga gctccatgta gaaagccaaa ggaatttctg caggacgtca 25560tcatgccaag cacagccgta acctgggtcc cagccctttt cacacgctca atggttagat 25620cttgggaggg aatcaaagaa gccatagtaa aatatcaaaa tttaaacccc gattttgaat 25680ttaaaaagtg ttaaaatatg gttgtggcct acactcagaa aatctgtgtc cttcagatgg 25740tttctcagtg gcaccagatg gtttcaagtg gctattcatt aagtttctca gtgaaattac 25800cagacataga ataaataaat tgtcactgtc ttaaatcaac ccatgggaaa ggaaaactgt 25860gtaaatacag cagagaggaa acattgctca agggaaaaac aatctccaga aagtattgtt 25920aaagaaacag aggccctctt tccagccagc gccgagcgat gggcacctct cgggacaact 25980ggcacaaggg ccgcaaagct gggggcaaga gaaggccctg ccacaagaag cggaagtatg 26040agttggggcg cccagctgcc aacagcaaga ctgacccgtg ccgcatccac acagtccgtg 26100tgcgaggagg taacaagaaa tactgtgccc cgaggctgga cgtggggaat ttctcctggg 26160gctcagaatg ctgcgctggt gaaacaaggg tcatcgatgt tgtctacaat gcatccaata 26220acgagctggt tcgtaccaag accgtggtga agaattgcat cgtgcccatc gacagcacgc 26280cctaccgaca gtggtacgag tcccactgtg cactgcccct gggccgcaag aagggagcca 26340agctgactcc tgaggaagaa gagattttaa acaaaaaacg atctaaaaaa attcagaaga 26400aatatgatga aaggaagaag aatgccaaaa tgagcagtct cctgggggag cagttccagc 26460agggcaagct tcttgcgtgc atggcttcaa ggccgggaca gtgtggccga gcagatggct 26520atgtgctaga gggcaaagag ttggagttct atcttaggaa aatcaaggcc cagaaaggca 26580aataaatcct tgttttgtct tcacccatgt aataaaggtg tttattgttt tgttcccaaa 26640aaaaaaaaag aaagaaaaag aaacagaggc atcacactta ctagaaaaac atattctatt 26700tcatatatta tggggatatg acgtgatgtt ttgacatatg cgggcattgt gaaattatta 26760aatcaagtaa ataaacatgt ccatcacctc acatacttat tttttatggt gtaaacgtgt 26820aaaatctact ctcttatcag ttttcaagta tatagtacat tagtatcatg gaagtcacca 26880tgctgtgcaa tagatcttca aacgaattcc ttctatctaa ccaaaactct gtaccctttc 26940accaacgtct cagctttcac atgcccctga cgccagcccc tggtaggcac cattctactc 27000tctactctga gttcaacatt tttagattgc atgtgtaagt gagatcatgg agtaattttt 27060tatacctggc ttatttcact caacataaag agtcaaatgc tcaacatcac taatcatcag 27120ggaaatgcaa attaaaacca cgataagata tcacctcaca catgttacaa tggcttagtc 27180tcagtctgtc tttttgttac tataaccgaa taccagagac tgggcaattt ctaaagaaaa 27240ggaatttatg ctttatggtg cttgagtcag agaagtctaa tatcaaggca ctggcatctc 27300acaagggcct tctcactgcc tcatctcaca gcagaggtgg gtgagcaaga gaccatttgt 27360ccacgagaga aaagagacca tcttttatta gaaattcact cctataataa ctaacccact 27420ccattgatag tgacagtaat ccattcatga ggacagagcc ttcatgactt gatcacataa 27480taaaggtccc acctctcaac actgttgcat taaagattat ttccagatcc taaactttgg 27540gagacacatt taaaccatag cattccattc ctaatatcaa aatttatgtc cttatcacaa 27600tgcaaattac attcattcca tcccaattgt ctccaaagtc ttatccagca tcagtgcaaa 27660agtctgaagt ccaaagtctc atctaaatca gatatgagtg tgactcgagg cacaatttag 27720cctgatataa attgtttcca tctgcgagcc tataaagtca aaacaagtta tctactttca 27780aatacagtga acaatggggc aggtatggga tagaaattcc cattccaaag ctcagagaga 27840ggcaaggaga aagcggtgcc tagttcaaaa cccaacaggg aaaaaaacat taagtcttat 27900agctggaaaa tcatcctctt taacggcatc ttgtgcacac tggggagggg gatgggcccc 27960caaggcctcc ggcagtcttg cctctatata ttttctgggt tcagtccact cagccgctct 28020cacaggtggg actctcaggc ctctagctct cctaggctga ctggaaactc tttgtggtac 28080ctccaaaccc acatttctgc ttggcattgt gctaagggcc cagtgtggtg actctgtctc 28140tgcaacaagt cactgcccga gaccttaggc tgtccttagg ctgcccgaga ccttaggccg 28200tccacagcat tctttgaaat ctaggtggag aaagccatgc cctcgtggtt cttgtattct 28260gcacacctgc agaattaaca acacatggat gccatggaag ttgatgactt gtaccattaa 28320agtgatggct tgagccacac ctaggtcctc ctgagccaca gcatgggcag ccaaggagtg 28380ctgtgcctgg acaccgggaa cagagtccta aagtgcctgc tagaagtcag gccatagatt 28440tccttcaaat ttctcccacc atataacctc gttcatggct ctgaacttcc accttacaga 28500aggacctagg gatgaacaca attcagccac gttctttgcc actttatggc aaggatggcc 28560tttgctccat tttccgatga gctattcttc tttttctcct gagacctcat cagaacggcc 28620tttattgtcc acggttctac tgacattcta atggtcatca cctaaataat ctctaagaag 28680tttcagaatt tcctcacagc tctcttcttc tgagtcctca aaagaatcac ctctagtgtt 28740ctattcaggg caatccagac tttttatagt ctgatcctcc aaattattcc agtctttgtg 28800cattactaca tccacttcta cattttgggg tatttgttat cgcaacagcc ccacctcttg 28860atactgattt ttcgtcttag tccactttgt ggtgcaatga gtgaatacca cacactggct 28920aaagtataag gaaaagaaat ttattttctc gcagctctag aggctgggaa gtcaatatca 28980aggtgttagc atctggcaag agccttcttg ctgtgatgtc catgtggaag gcaggagagc 29040aggtgcgaag gatggaaagg ggtttaaact cattttttaa tgaggaaccc aggcctgtag 29100taactaatct gctaccacaa tgagtaacct actctgacga taatggcatt cattgcttca 29160tgagggcaga gccctcatga cctaatcatt tcttaacatt cccacctctg gacactatgg 29220aatttgggat taagtttcca atacacatcc tttctaaaca gcaggggctt tttaataggt 29280tgaccaccca aggctgcagg aggctctgaa gcagtggcct gaggttggct gtcctttgtg 29340agaatggaga gaagtgaact gactcatgga gacacaagta gatgaggtaa aggcattcat 29400tgcttcatta catggatggt gaggtcgatt gaaggcatta acggattaaa gatggtggca 29460aaaccgtctg aggtggagac cacggggagt ccatcagaaa tggaggacac gtcccaataa 29520atggtgcttc atttccctgc aaagcagaag aaagcaaaga acaaaacaca acatcatagt 29580gtacactgag cagtggattg agagaagagt ttcctaaggc ataactgaca gagtggagaa 29640gacacacaaa tctttgcatg atgctaacat ttggactgtg gcttcattat ttcttattaa 29700tattttactg aaatatcgct agaaggagac tgaaaatgaa gtgtgaaaag ttaaatggga 29760tttctgctct atgtcctttt cagatgagag gaactaggga attccaggga agaaacaata 29820atagctgctg agcaaggctt ttgcagggca ggacaaggaa tccccaaaga gaaaacggaa 29880acctcagctt cactttgcat ctgctcctga gccaggtcct gagcgacccc tgtaggtcct 29940gagtgcccct ccgtaggttc tgagcatccc ttggttgctg ggcgccctct ggtggtgtct

30000gagcccctct ggtggtttct gagccccccg ccttatgtct gatcctccct ggtggtgtcc 30060gagtgcccct gctagtgtct gagccccctg gtggtgtctg agtccccttc ttagtgtctg 30120agccacccta ttagtgtctg aggacccctg atggtgtctg agcccccagt tagtgtctga 30180gccaccctat tagtgtctga gcccccctgg tggtgtctga gcacaggaga gctcctctga 30240aggaagggtc tacatgggga caggcgtgct tgtctcaggg aagggtccat gtggggacag 30300gtgtgcttgt ctgaaggaag gttccacatg gagacaggtg tgcttgtctc agggaagggt 30360ccacatgggg acaggtgagc ctgtctgagg ggacagaagt gcttgtctca aggaagggtc 30420ctcatgtgga caggtgagct cttttgaggg aagggttgac ctggggacag gcatgcttgt 30480ctgaggtaag ggtcctcctg gggacaggtg tgcttctctc agggaagggt ccacgtgggg 30540acagaggtgc ttgtctaagg caagaatcca agtagggaca ggtgagctcg tctcagggaa 30600gggtccaggt ggggacagtt gtgctcatct gagagaagcg ttgaagtggg gacaggtgtg 30660cttgtctcaa ggaagggtcc atgtggggac aggtgtgcta gtatcaagaa agggtccaca 30720tagggacagg tgtgcttctc tcagggaagg gtgcatgtgg ggacaggtgt gcacatcgga 30780gagaatggtc cacctgggga caggtgttct tgcctcaggg aagagtccac cttctcaggg 30840aagaagtgtg ctcctctgag ggaagggtgc acatggggac aggtgtgctt gtctcaggga 30900agggtccatg tgggaacagg tgagctcatc tgagggaaga gtccacgtgg ggacaggtga 30960gctcatctga gggaagggtc cacatgggga caagtgacct cgtctgaggg aagggtccac 31020gtggggacag gtgagctcgt ctgaaggaag ggtccacttg gggaccggtg tgctcctctg 31080agggaagggt ccacgtgggg acaggtgtgc tcctctggag ggaagggtcc acgtggggac 31140aggtgagttc atctgaagga agggtccaca tggggacagt tatgctcctc tgagggaagg 31200gtccatgtgg ggacaggtgt gcttgtctca gggaaaggtc cacgtgggga caggtgtgct 31260caccttgggg aagaggacag atgagctcat ctcagggaag gggccatgtg gggacaggac 31320caagggttgg gacttcagca caagaattta ggaggaacac agtcttccct agcagcctcc 31380ttcagggatg tcaaatattt tccttctgtt ccctgtgaaa gccttaaagg ggtagggaaa 31440gggcgttcaa cctgcacact cgtagagggg aaaccagctt cattagtaat cgttcatctg 31500tggtaaaaag gcaggatttg aagcgatgga agatgggagt acggggcgtt ggaagacaaa 31560gtgccacaca gcgcagcctt cgaaacacac cacggtcacg ttaagtttaa atggagtgac 31620cacattcgcc aggaaaggga aatatttaca cttttgaaga aacagtaatt tgtgtttctg 31680attatgatct ggccttggat tttccctccc ctcataagca atgacagaat tggcagaaat 31740atgtgaaacg ttagttctca gacatgagac acccacagag ggccccctgt gcccttccct 31800gagagctgat cagctcctgc atctgaagaa atgaccaaag accaggagag aaccacacag 31860aagcatcgga gggacagcac ctggggctct gatggggtca ggaatagcat ctgttcccaa 31920tagatggact aagtaaaaag tatcataatt cacaagagtt ttacatagca cagaagaaaa 31980agttacccta tatcaactgt tgatcttgtg aatccaggaa ctctggattc aaggtggtcg 32040ggcacatctt gatttacgca tttcagggac acatgagaca tcagtcaata taagtaagaa 32100ggacattagt tccatccaga aaggctgaga caactcaaag caagtcctcc ccacttaggg 32160cttccaggtc acaggtaggt gagagacaga tggttgcatt cttttgagtt tctgataagt 32220gtttgcaaag gaggccatga ggatatgcac ctgtctctgt gagcagaggg acaactttaa 32280atagactggg aggcagattt gtcctgagtg gtttccagct tgacggggcc caagatattt 32340tcctttcaca atctggtaac ttcaaacaaa acttcaaagc cacaacaaaa caacacaaca 32400acaaaaagaa taagacatgg gtacttatta agagtagaaa aacattcagt ccccaaggaa 32460aatattggca gtgtctacct ccacatgaca aaggagtaag cagtgtgagc cacagaaagg 32520agcactatta acccacagag caaccgagaa taacacgggt gatgcgaggg cattggacgc 32580acatcattgc attttgtaga ttcagaaaga aacggaaaag attgacggtg gtaaaagaga 32640cagccctgct tccctctccc ttttccctcc ccgatgaggc ctcacagcca tgaccctcag 32700cctcatcccg cagtgcagca gctgccgtcc tgtccaggcc caccccctgc cccgccctgg 32760gactgttacc tcattccctc ccggagtcca ggtgcccccc ggggtgtggt gcgggagcct 32820ggggaggccc tttgttctct gtcagggtct ccctgggagg gacgcagcca ccgcagctgg 32880ttggggcctg gcttcgccca ggacagtcct ttcctttccc attgtctttg gatgactatc 32940gctgggctgg gacatgaggc gggcagaggc gcgggtcacc cttaggaccc ccctcttgct 33000gctggggctc tgggcgctcc tggctccggt ccggtgttct caaggccgtc ccttgtggca 33060ctatgcctcc tccgaggtgg tgattcccag gaaggagaca caccatagca aaggccttca 33120gtttcccggc tggctgtcct acagcctgtg ttttggggtc aaagacacgt cattcacatg 33180cggaggaaac accttctttg gcctagacat ctgctggtga caactcagga tgaccaagga 33240gtcttgcaga tgggtgaccc ctacatccct ccagactgct agtacctcgg ctacctggag 33300gaggtgcctc tgtccatggt caccgtcgac acgtgctatg gggacctcag aggcatcatg 33360aggctggacg accttgcgta cgaaatcaaa cccctccagg attcccgcag gtttgaacat 33420gttgtttttc agatagtggc cgagcccaac gcaacagggc ccacatttag agatgatgac 33480aatgagacag accccctgtt ctctgaagca aatgacagca tgaatcccag gatatctaat 33540tcgctgtata gttctcatag aggcaatata aaaggccacg ttcaatgttc caattcatat 33600tatcgcatat atggcaatat tacaacttgt tccaaagagg tggtccagat gttcagtctc 33660attgacagca ttgctcaaaa tattgatctg cggtactata tttatctttt gaccatatat 33720aataatcgtg acccagcccc tgtgaatgaa tatcgaattc agagtgcaat gtttacctat 33780tttaaaacaa ctttttttga tacttttcat gttcattcat ccacactact tattaaatac 33840gtgccacatg aatctaacta tgaacctgaa aggtataact tctgttcccg tatagccctg 33900ttacacattg gtactccagg cagacattat ttattggtag ccgtcataat aacccagaca 33960cagatgagaa gtattggtct ggagtatgat gataactact gcacatgtca gagaagggcc 34020tcctgcatta tgcagcgatt tcctgggatg acagatgcgt tcagtaactg ttcttatgga 34080catgcacaaa attgttttat acattcaggc cggtgtgttt ttgaaacact tgctcctgtg 34140tataacgaaa ccatgacaac ggttcgctgt ggaaacctca tagtggaggg gagggaggaa 34200tgtgactgtg gctccttcaa gcagtgttat gccagttatt gctgccaaag tgactgtcac 34260ttaacaccgg ggagcatctg ccatatagga gagtgctgta caaactgcag cttctcccca 34320ccagggactc tctgcagacc tatccaaaat atatgtgacc ttccagagta ctgtcacggg 34380accaccgtga catgtcccgc aaacgtttat atgcaagatg gaaccccgtg cactgaagaa 34440ggctactgct atcgtgggaa ctgcactgat cgcaatgtgc tctgcaaggc gatctttggt 34500gtcagtgctg aggatgctcc cgaggtctgc tatgacataa atcttgaaag ctaccgattt 34560ggacattgta ttagacaaca aacatatctc agctaccagg cttgtgcagg aatagataag 34620ttttgtggaa gactgcagtg taccaatgtg acccatcttc cccggctgca ggaacgtgtt 34680tcattccatc actcagtgag aggagggttt cagtgttttg gactggatga acaccatgca 34740acagacacga ctgatgttgg gcgtgtgata gatggcactc cttgtgttca tggaaacttc 34800tgtaataaca cccagtgcaa tgtgactatc acttcactgg gctacaactg ccaccctcag 34860aagtgcggtc atagaggagt ctgcaacaac agaaggaact gccattgcca tataggctgg 34920gatcctccac tgtgcctaag aagaggtgct ggtgggagtg tcaacagcgg gccacctcca 34980aaaagaacac gttccgtcaa acaaagccag caatcagtga tgtatctgag agtggtcttt 35040ggtcgtattt acgccttcat aattgcactg ctctttggga cagccaaaaa tgtgcgaact 35100atcaggacca ccaccgttaa ggaagggaca gttactaacc ctgaataaca ctaattcagc 35160ctcccgatcc ctgtaaagat acagagaata taacagcaaa atctatgaaa caggatcagg 35220ggaagggatg gcaaagctca agtccacatt tcttgaagtc cacaggaagc acagggtcct 35280gtttcacatc acagggaaac gggaggcatt ggcttctgtc ccaggttctt gtaggtcgct 35340gatgctcact ctgaaataaa tcttcaaaaa cacacattgg tgccttccac attttcttag 35400actcctctgg gagcccaaac ttggccagaa cctcttgcct ggagagacat gaatgagcat 35460ctggctcttg tcctgaggtc tctggtccca gaattaacgg aagttgccac cagctcctta 35520cagggaacat tcatgacatt tctccagaag agagctccag agcaatgagc ttcctcattc 35580cccaggtaat ctgtccttct ctaaacccga agtcagttta gggtgatcca gggctactcc 35640ctgttccctg tctgttcctc acgggggtgc tgtgggcttt gcagtgagag ggacttgggt 35700tcaaatcccc caccaagcaa atccccctac ctggggccga gcttcccgta tgtgggaaaa 35760tgaatccctg aggtcgattg ctgcatgcaa tgaaattcaa ctagaaaaat aggtagacgt 35820gaggggcaag ctgtctgtca tttagtgtga gctctgtgag tggcagctgc cccctttctt 35880cctgccccca catttccttg aactgaaaca ggaagggaag ctgagtaagt cgtgatgagg 35940aagagaaacc aggcttgtag cagcacaggc tggtccgggt ggaaaacagg gctaggtgta 36000tcactgagtt attgtaaagg aaaatggaag ttaaatgtat aaataactga atgagataac 36060attttatttt aacttaaaat tcacactaat attgactttt aaaatgcagt gtagatatgt 36120cagagagaat ttcaaaggca aagcccaccg acggaagaaa tcacccttcc cataccatcc 36180acagaaaact gttggtattc tagggtagta ctgagatcta gcatttttct gaatacatct 36240gtggttctag atgtcctgct tccatagata ttgtttagaa ttcccacccc tttctccaaa 36300cacagcttga tatcctttct ctgaacctgt tagaaatttc ctccattcag ctgtcataaa 36360gatgcgagca atccattcct gtgcctctgt cagtgtgttc tattattttg tggctgaacg 36420ctaatggaca gttaagtgtg aggtcagtga atacagtgcc ctccctctat gtgtccttcg 36480ggtgtgaggg gttttgctga tagagcagca ggccccatcc caccctttat gcatctccgc 36540cccccacctc acgctccagc tgacctctcc cctgtggcct ggggcgttcc ccagggggaa 36600tgacctctcc tctctccagg gcccacccac tcagtgcccg tgcaagacca ccacgcttgg 36660cacggcccca cctcgtgtca gggcctgtgt cccctgcccc accccctaaa cagatgggaa 36720ccactgggac tctgctcagg gcagggggcg gaggtatgtg tgaaaggaag gcaaatgtgc 36780actctgttgg agaaatatta taggtagttt gagcaaaaaa tctaatgcca tgggaacttt 36840tagaatgata cgtattttaa caaagaacat gaccaataga gtttgtattg aagccaggaa 36900aacactattt agagcaacag caatatcaaa aacacaagcc aacagttcac caagaaaaac 36960caccattaac cccatggaaa tggtcttcca agagcatcgg cacttaaatc ctggaaatct 37020gcctgcctca gcacctgttg tcctgacctg ccctcctgtg tgtcctaatc actcccaaac 37080acggggcctg cactgtggga gattcacact gtgccaggtg gagggagcag gacaactgct 37140aacaggttgt tggtgtggat gccgaggcca cccaagcagg tgtaaactcc cacctgtggg 37200gcagggaaga gtgcacggga gacatgtccc gggcataggg tgagggagag ctgtgggggc 37260tctgggttct gaagtgggtt ctgaagaggg ttctggcctg gcagggataa gaccaaccag 37320catgtgaggc caggctggag tctggacctc tgaagctgca agggtcatgg gctgcttggc 37380cccaggggct gtcctggttc tctatggagt actttcaaac attctttctt cttccaatcc 37440ccctccttct ctcccaaagc ctgcatctcc caaatcctct ttgtcggatc ctcggcttca 37500ctctgcatcc gtcctgagca tcgatcttcc aattccatcc tcttctcttc tgctatgtct 37560aagctgctgt gaagccacct gctgtaattt actgctttat atttaatatt gtaccgtaca 37620tctgttctgt ttccctcatc ataaatgctt catttcatgc tcagcatctg agaacacaag 37680gccttgtcag ctgtcacctc cttccgttct ctgtttcctt cctcctatcc ccatattgct 37740catcatgtcc agtctcctgc catcctgaat gcttctgatg gaaggtctga gatgtctcat 37800gagcactgtg aagattcttt gtaatgtgag cttgttccag gcaggaattc tccttcaccc 37860agccctggaa gccaagtata ggcagatggc catgctcaat caaagactga gctaacttaa 37920cagtggcttt ggttttaagg tttctccaat ccccagggca caggatttca gggaattcag 37980gtgagagtct gggtgttacc cttcaggagg ctgtaaactc catttcacct agtctacacc 38040acagactatg gaaactatat atatatatag ttctgtccct ctagagaaac ctaatatgta 38100tatatacaat atataatacg tattatatat tatatataat acgtattata tattatatat 38160attatatata tattagagtt tattgaggag tattaaactc acaatcacaa ggtcccacag 38220taggccatct gcaagctgag gagcaaggaa gccagtccga gtcccaaagc tgaagaattt 38280gaagtctgat gttcgacggc aggaagcatc cagcacagga gaaagatgta ggctgggagg 38340ctaagccagt ctagtctttt cacgtttttc tgcctgcttt atatcctggc cacactggca 38400gctgattaga tggtgcccac ctagattaag ggtgggtctg cctttcccag tttactggct 38460caaatgttaa tctcctttgg caacaccctc acagacacac ccaggatcaa tactttgcat 38520gcttcaatcc aatcaagttg acactcagta tcaaccatca caagtccacc ccttgtcaac 38580ttgaacccat acaaatctcc tgagatcata cataatcttc aaataaagac aataataagg 38640tcataattac acctaatgta atacaactat cttttgtaca accagaaatg caccaatccc 38700caacccaaat gctattatgt aaagttaaga acacttaaat gctgatatga agtcaataaa 38760ttttatgtca catgataaag gaaaaaagaa atgaaggaat tttcttagta caagtgtgta 38820catgcacaaa catgttttta acaaaagaag aaggaaatac tgatgacaat tacagtcctc 38880atttctgcaa ctgatcacgt ggttgtagct ggtattgatg actaccttct tctactaccc 38940attctgtatt ccctttgcct tcagcaagca tcacagcagg tagagttttt tctcctagtg 39000gagtgatgca aaccttcatt cctgaagggt ctgggccatt tgtagtcctg cctggattgg 39060gctgttgtag tttcccgttg accttaatga cagggcatgg taatgttaag agacgcccta 39120atggatctcc tgtattccat acatattctt ccttacctcc attgtggagt aatagactga 39180ttgcatcttg atagtccagg tcaatcagcc cagccaacac tgtaactccc ctcttagcct 39240gtggacttaa aggtaggagg ggcccaaagt ggccaggtgg aaatctttac ttccagttta 39300atggaattgt tgttgtttct cctgatggca gcattattcc cactggaact aagacctcta 39360ggccaacaga atgtaatgtc atgggaccag gaagcaaaaa ttttgctagt ggatcactag 39420gggtgatggt gaatggtgcc atttccactt ccaccccttg attcctggat ccatgaatta 39480tggctatggg agaaagagta ccatatattg gatgctgatt tggagcatac atggcctttt 39540ggagagcttt gccccagccc tgcaaagtat tggagcctag ttgacattgt aattgtgact 39600ttgaaaggcc attccattct tctatcaatc cagctgcttc aggatgatgg ggaaaatggt 39660aagacaagtg aatcccatga gcatgagccc actgccacac ttctttagcc gtaaagggag 39720tgccttggtc agaggcaatg ctatgtggaa tactgtgaca gtggataagg cattccatga 39780ctccacagat ggtagtcttg gcagaagcat tgcatgcata tctgcagtaa gtgtctattt 39840cagtgaggac aaacctctgc cctttccagg atggaagagg tccaatataa tccaacctgc 39900catcaggtag ctcactgatc accctgagga atggtgtcat ttgggtagag acccagagcc 39960aaaccagatc acgccaccca acccctccca aatctcatgt cctctttgca tttcaaaacc 40020aatcatgcct tcccaacagt cccccaacat cttaactcat ttcagtatta actcaaaagt 40080ccaaatccaa agtcacattg gagacaaggc aagtcccttt catctatgaa cctgtaaaat 40140gaaaaacaag tcagttactt ccaagacaaa atgggggtac aggcattaga tacatgctcc 40200catttcagtt gggagaaatg agccagaata aaggggcttc aggtcacatg caagcccaaa 40260ctccagtggg gcagtcatta aatcttaaag cttcaaaata atctcctttg actccattcc 40320tcacattcag ggcatgctta tgcaaagtgg gggctcctac aaccttggga agctctcacc 40380ctgtggcttt gcagctctga ccccatggct gctctcatgg gctttgcaga gttcagccct 40440cctggctgct ctcattgagt gcatgcagct tttccaggtg cacagtgcaa gccgttaatg 40500gatctaccat tctggggtct gaaagatggt ggccctcttc tcacagcccc attagtcact 40560gtctccagtg gggactctgt gtgggggctc caaccccaca tttcccttct gcactgccct 40620agcagaggct ctccatgaag gctttgcccc tggcgcagac ttctggctgg acatccagtc 40680atttctataa atcctctgag atctgggtgg aggatcacaa agctgaactc ttctcttccg 40740cacatcccta ggcccaacat catgtagaag ccaccaatga ttggggcttt ctgaagcaat 40800ggcctgagct gtacattgga cttttttagc cacagctaga cctggagcag ctgggacaca 40860gggcaccaag tcccaaggct ccaaagagaa gctgggccct ggacccagcc catgaaaaca 40920tttttccctg ataggcctcc aggcctgtga ttggaagggc tgctgcaaag atctccgaca 40980tgccctggaa acattttccc cattgtcttg attattaata ttcatctctt cattacttat 41040gcaaatttct gcagccaact tgaatttctc cctagcaaat gtgtttttct ttactaccac 41100atggccaggc tgcaaatttt ccaaactttt atgctctgtt tcccttttaa aaataagttc 41160ctatttcaga tcatctctct caagggcaaa gttccacaga tttctagggc agggacaaaa 41220ttccatcaag cttggtttta tacattttag agaggcatga gacatcaatc aaatacattt 41280aagagacaca ttggtttggt ccagaaaggt ggaacaactc aaagctaggg cttccaggct 41340ataggtgaat ttaaatattt tctggttgac aattggttga gtttgtctaa agacctggga 41400tagatagaaa ggtaatgttc aggttaagat aaagattgta gagtccaaag ttcttttgaa 41460gtcttatagt ggctgccctt agagataata ggtgacaaat gtttcctatt caaatcttag 41520ttgaactctt taggattggg aggttctaga agaaaaagat ctagctatgt taatagagat 41580tctttacaga tgcaaatttt cccccacaaa gaacagcttt gcagggccct ttctttcttt 41640ctttctttct ttctttcttt ctttctttct ttctttcttt ctttctttct tttttagatg 41700gagttttgct cttgttgccc aggctagagt ataatggcac gatcttgtct caccacaacc 41760tccacctcct gggttcaagt aattctcctg cctcagtctc ccgagtagct atgattacag 41820gcatgcacca ccacacccgg ctaattctgt atttttagta gacacagggt ttctccatgt 41880tggtgaggct ggtctcgaac tcccaacctc aggtgatccg cccacctcag cctcccaaag 41940tgctgggatt acaggcatga gccaccatgc ccggcctgca gggccatctc agagtatggc 42000aaagaaacat gttttggggt aaaatatttt gattttctta tttgtctcat aatgttatgc 42060cagagtcagt ttggaaagta aatcatgata tataggttta aataaaaccc atctgatgag 42120aatttatgat ttgtagagca tgcctcccca gactctttag ataggaattt gggcaagatg 42180aaaaaaaaat cagagtttag tcctcactac ctaagaccag ctcagcttgg acttcactgt 42240tcatgtcact atcagcattt tagtcaaaac cactcaataa gtctctagga agttccaaac 42300tttcccacat cttcccttct cctttcaagt tctccaaact gttccaaccg ctgccaggag 42360gtacccagtt ccaaagttgc ttccagattt tgagttatct ttatagcagt tccccactcc 42420tggtaccaat ttactatatt agtctgtttc cacagtgcta taaagaactg cccgaaagtg 42480gttaatttgt aaagaaaaga ggtttaattg actcacagtg ctgtgtggtt agggtcggag 42540gctcaggaaa cttgcaatca tggtggaagt ggaagcaggc atgtgacaca tggcagcagg 42600tgagagagag aaagagagag agagggaatg aaggaggaac caccatacat ggataaaacc 42660atcagatctc atgagaactc actcactatc aggagaacat gaggacagca tgggggaaac 42720cacccctatg acccagtcac ctcccaccag gtccacccct tgacacataa ggattactat 42780ttgagatgag atttgtttaa tgacacagag ccaaaccaca tcagcatgtg acaaaggtct 42840aatatcaaga atctatgagg gggcagttcc aaaatggctg aataggaaca gctccagtct 42900acagctccca gcatgagcta cacagaagac aggtgatttc tgcatttcca actgaggtac 42960tgggttcatc tcacgggggc ttgttggaca gtgggggcag gacagtgggt gcagcccacc 43020aagagtgagc tgaagcaggg cgaggcattg cctaacccag gaagtgcaag gggtcaggga 43080attcccgttc ctagccaagg gaagcggtga tggacggcac ctggaaaatc cggtcactcc 43140caccctaata ctgcactttt ccaacggtct tagcaaatgg cacaccagga gattatatcc 43200tatgcctggc ttggaggttc ccatgcccac ggaacctcgc ttattgctag cacagcagtc 43260tgagatcaaa ctgcaaggtg gcagtgaggc tgggggaggg gtgcccacaa ttgctgaggc 43320ttgagtaagt aaacaaagtg gctgggaagc tcaaactggg tggagtccac tgcagctcaa 43380ggagacctgt ctgcctctgt agactccacc tctgggggca gggcatagct gaacaaaagg 43440cagcagaaac ctctgcagac ttaaatgtcc ctgtctgaca gctttgaaga gagtagtgtt 43500tctcccacat ggactttgag atctgagaat ggacagactg cctcctcaag tgggtccctg 43560acccccgagt agcctaactg ggaggcaccc tccagtaggg gcagactgac accttacacg 43620gctgggtgcc cctctgagat gaagcttcca gaggaattat caggcagcaa catttgctgt 43680tcagcaatat tcgctgttct gcagcctctg ctgctgatac ccaggaaaat agggtctgca 43740gtagacctcc agcaaactcc aacagacctg cagctgaggg tcctgactgt cagaaggaaa 43800actaacaaac agaaaggaca tccacatgaa aaccccatct gtacatcacc attatcaaag 43860acaaaaggta gataaaacca caaagatggg gaaaaaacag ggcagaaaag ctgaaaattc 43920taaaaatcaa agtgcctctc cccctccaaa ggaatgcagc tcctcgccag caatggaaca 43980aagctggatg gagaatgact ttgatgagtt gagagaaggt ttcagatgat caaacttctc 44040cgagctaaag gaggaagttg gaacccattg caaagaagct aaaaaccttg aaaaaagatc 44100agatgagtag ctaactagaa taatcagtgt agagaagtcc ttaaatgacc tgatggagct 44160gaaaaccatg gtatgagaac tacgtgatga atgcacaagc ttcagtagcc gattcgatca 44220actggaagaa agggtatcag tgattgaaga tcaaatgaaa gaaatgaagg gagaagagaa 44280gtttagagga aaaaaaagta aaaagaaaga aacaaaccct ccaagaaata tcagactatg 44340tgaaaagacc aaatctatgt ctgattggtg cacctgaaag tgacagggag aatggaacca 44400agttggaaaa caccctgcag tatattatcc agcagaactt ccccaaccta gcaagacagg 44460ccaacattca aattcaggaa atacagagaa ccccacaaag atactcctcg agaagagcaa 44520ctccaagaca cataattgtt agattcacca aagttgaaat gaaggaaaaa atattaaggg 44580cagccagaga gaaaggtcgg gttaccctca aagggaagcc catcagacta acagctgatc 44640tctcagcaga aactctacaa gccagaagag agtgggggcc aatattcaac attcttaaag 44700aaaagaaatt tcaacccaga atttcatatc catccaaact aagcttcata agtgaaggag 44760aaataaaatc ctttacagac aaacaaatgc tgatagattt tgtcatcacc aggcctgccc 44820tacaggagct cctgaaggaa gcactaaaca tggaaaggaa caactggtac cagccactgc 44880aaaaacatgc caaatcataa agaccaccaa agcgaggaag aaactgcatc aactaacgag 44940ccaaataacc agctaacatc ataatgacag gatcaaattc acacataaca atattaacct 45000ttaatgtaaa tgggctaaat gctccaatta aaagacacag actggcaaat tggataaaga

45060gtcaagaccc atcagtgtgc tgtattcagg agacccatct cacatgcaga gacacacata 45120ggctcaaaat aaaggcatgg aggaagatct accaagcaac tggaaaacaa aaaaaggcag 45180gagttgcaat cctagtctct gataaaagag actttaaacc aacaaagatc aaaagagacg 45240aagaagacca ttacataatg gtaaagggat caattcaaca agaagagcta actatcctaa 45300atatatatgc atccaataca ggagcaccca gattcataaa gcaagtcctt ggagacctac 45360aaagagactt agattcccac acaataataa tgggagactt taacacccca ctgtcaacat 45420tagacagatc aacgagacag aaagttaata aggatatcca gcaactgaac tcggctctgc 45480accaagcaga cctaatagac atctacagaa ctctccaccc caaatcaaca gaatatacat 45540tcttttcagc accacaccac acctattcca aaattgacca catagatgga agtaaagcac 45600tcctcagcaa atgtaaaaga acagaaatta taacaaactg tctctcagag cacagtgcaa 45660tcaaactaga actcaggatt aagaaactca ctcaaaacca ctcaactaca tggaaactga 45720acaacctgct cctgaatgac tactgggtac ataatgaaac gaaggcagaa ataaagatgt 45780tctttgaaac cagtgagaac aaagacacaa cataccagaa tctctgggac acattcaaag 45840cagagtgtag agggaaattt atagcactaa atgcccacaa gagaaagcag gaaaaatcta 45900aaattgacac cctaacatca caattaaaag agctagagaa gcaagtgcaa acacattcaa 45960aagccagcag aaggcaagac ataactaaga tcagagcaga actgaaggaa acagagacac 46020aaaaaaaccc ttcaaaaaat caatgaatcc aggagctggt tttttgaaaa gatcaacaaa 46080attgatagac cactagcaag actaataaag aagaaaagag agaagaatca aatagatgca 46140ataaaaaatg ataaagggga tatcaccacc gatcccacag aaatacaaac taccatcaga 46200gaatactata aacacctcta cggaaataaa ctagaaaatc tagaagaaat ggataaattt 46260ctcgacacat acaccatccc aagactaaac caggaagaag ttgaatctct gaatagacca 46320ataacaggct ctgaaattga ggcaataatt aatagcttaa caaccaaaaa aagtccagga 46380acagatggat tcacagccga attctaccag agctacaagg aggagctggt accattcctt 46440ctgaaactat tccaatctat agaaaaagag ggaatcctcc ctaactcatt ttatgaggcc 46500agcatcatcc taataccaaa gcctggcaga gacacaacaa aaaaaaagag aattttaggc 46560caataaccct gatgaacatc aatgcaaaaa tcctcaataa aatactggca aaccgaatcc 46620agcagcacat caaaaagctt atccaccatg atcaagtggg cttcatccct gggatgcaag 46680tctggttcaa catacgcaaa tcaataaacg taatccagca tataaacaga accaacgaca 46740aaaaacacat gattatctca atagatgcag aaaaggcctt tgacaaaatt caacaacact 46800tcatgctaaa aactctcaat aaattagata ttgatgggac gtatctcaaa ataataagag 46860ctatctatga caaacccaca gccaatatca tactgaatgg gcaaaaacta caagcattcc 46920ctttgaaagc tggcacaaga cagagacacc ctctctcacc actcctattc aacatagtgt 46980tggaagttct ggccagggca atcaggcagg agaaggaaat aaagggtatt caattaggaa 47040aagaggaagt caaattgtcg ctgtttgcag atgacatgat tgtatatcta gaaaacccca 47100tcgtctcagc ccaaaatctc cttaagctga taagcaactt cagcaaagtc tcaagataca 47160aaatcaatgt gcaaaaatca cacgcatttc tataacccaa taacagacaa acagagagcc 47220aaatcatgag tgaactccca ttcacaattg cttcaaagag aataaaatac cttggaatcc 47280aacttacaag ggacgtgaag gacctcttca aggagaacta caaaccactg ctcaatgaaa 47340taaaagagga tacaaacaaa tggaaaaaca ttccatgctc atgggtagga aggatcaata 47400tcctgaaaat ggccatactg cccaaggtaa tttatagatt caatgacatc cccatcaagc 47460taccaatgac tttcttcaca gaattgggaa aaactgcttt aaagttcata tggaaccaaa 47520aaagagcctg caatgtcaag tcaatcctaa gccaaaagaa caaagctgga ggcatcacgc 47580tacctgactt caaactatac tacgaggtta cagtaaccaa aacagcatgg tactggtacc 47640aaaacagaga tacagaccaa tggaacagaa cagagccctc agaaataatg ccgcatatct 47700acaactatct gatttttggc aaacctgaca aaaacaagaa atgggaaaac gattccctat 47760ttaataaatg gtgctgggaa aactggctag ccatatgtag aaagctgaaa ctggatccct 47820tccttacaca ttatacaaaa attaattcaa gaggattaaa gacttaaatg ttagacctaa 47880aaccataaaa accctagaag aaaacctagg caataccatt caggacatag gcatgggcaa 47940ggacttcatg tctaaaacac caaaagcaat gacaacaaaa gccaaaattg acaaatggga 48000tctaattaaa ctaaagagct tctgcacagc aaaagaaact accatcagag taaacaggca 48060acctacagaa tgggagaaaa tttttgcaat ctacttatct gacaaagggc taatatccag 48120aatctacaat gaactcaaac aaatttacaa gaaaaacaaa caaccccatc aaaaagtggg 48180caaaggatat gaatagacac ttctcaaaag aagacattta tggagccaaa agacacatga 48240aaaaatgctc atcatcacta gccatcagag aaatgcaaat caaaaccaca atgagatacc 48300atctcacacc agttagaacg gcgatcatta aaaagtcagg aaacaacagg tgctggagag 48360gatgtggaga aataggaaca cttttacact gttggtggga ctgtaaacta gttcaaccat 48420tgtggaagtc agtgtggcga ttcctcaggg atctagaact agaaatacca tttgacccag 48480ccatcccatt actgggtata tacccaaagg attataaaac atgctgctat aaagacacat 48540gcacacgtat gtttattgcg gcactattca caatagcaaa gacttggaac caacccatat 48600gtccaacaat gatagactgg attaagaaaa tgtggcacat atacaccatg gaatactctg 48660cagccataaa aaaggatgag ttcatgtcct ttgtagggac atggatgaag ctggaaacca 48720tcattctcag caaactatca caaggacaaa aagacaaaca ctgcatgttc tcattcatag 48780gtgggaattg aacaatgaga acacttggac acaggaaggg gaacatcaca caccagggcc 48840tgttgtgggg tggggggagt ggggagggat agcattagga gatataccta atgttaattg 48900atgagtttat gggtgcagca caccaacatg gcacatatat acatatgtaa caaacctgca 48960cgttgtgcac atgtacccta aaacttaaag tataataaaa aaatttttaa aaaaagaaac 49020acctgctttt ttctgttttc catttgctta gtagattttt ctccatcctt ttactttgag 49080cctggggatg tcattgcatg tgagatgggt ctcttgaaga cagcatacat ttgggtcttg 49140cttctttctc caacttggca attctctgcc ctttaattgg ggcatttagc ccatttacat 49200tcaaggttaa tattgatatg tgcatatttc atcctgttat catgttgtta gctgctcaat 49260atgcagattt gattgtatag ttgatttata gtggcaatcg ttatgtactt aagtgtgttt 49320ttgtggtggc cagtaacgtt cttccattat catatttagc aatcccttaa gggcctcttg 49380taaggcaatc tagtggtgat gaataccctt agcatttgct tgtctgaaaa ggatcttatt 49440tctccttcac ttgtgaagct tcatttggct agatatgaaa ttcttgcttg gaatttcttt 49500tctttaagaa tgctgaatat aggcccccaa tctcttctgg attgtacagt ttctgctgaa 49560acctccattg ttagcctcat tgggttccct ttgtatgtga cctgaacctt ctttctagct 49620gcctctaata ttttttttcc tttcaacctt taagagtctg atgtctgatg gctatatgtc 49680ttagggatgg ttgtcatgta taatatcatg cagaggttat ttgcatttct tgaatttgaa 49740tgttggcctc tctggtgagg ttggagaaat tttcatggag gatagcctga aatgtttttc 49800aagtttcttt ttttctcttt ctcttcttaa gggataccaa tgtgtcatag atctggtctt 49860tttacataat tgcacatttc tctgaggttt tatgccttct tttttattct ttgttcttta 49920tttttgtctg actgagttaa ttcagagaat cagtttttaa gctctgtgat tctttcctca 49980gcttggtcta ttctgctgtt aatacttgta attgtattct gaaattcttg aagtgagttt 50040tttagctcta tcaaatcagt ttggttcttt cttaaaatgg ccatttcatc tttcagcttc 50100tgtatcattt tactttattt cttagctccc ttggattggg tttcaacatt ctcctgaatc 50160tcagtgatct tctttcctgt gcatattctg aattctatgt ctgtcatttc agccatttca 50220gtcaggttaa gaaccattgc tgggaaacca gtgtgattat ttggaggtaa gaagacactc 50280tggattttag agttgcagag tttcttgcat taattctttc tcatctttgt gggctgtttc 50340tttaatcttt gaagtggctg tcctttggat gtttttgtct tttttgttgt tttttggtgt 50400gtgtttttgt ttgtttgttc atttgtttgt tttttgctct tatcttcttt gatactcttg 50460caggtttgat tgtggtataa agtggattca gttagctgtg tttcttgaaa atcttagagg 50520gtccaggctc acctcagcac tcttgtggtg tgttctctgc tctgggactg ggcccctggc 50580tttattctct ggccccttga gtttagaaac ttgctgcatt ggaggggctg aggtgttccc 50640agtccattgg ccacaacact atagtagggg gtgccggcca aagcacttca ttagagtggt 50700ggcagtggga tccattctta ctcatgggtg ccagcagttg tggagtcatg gcagggtgca 50760catgcatctg ctggggtggg ggtactggca ggagcagagt ggcagcatcc ctacataggt 50820tcctgctggc agtcacagcg cagtgaggtg cccgtgtgtt ggcagggaca gggtggtggg 50880gcacacatgc acatgcttgc tggtggtaga gggagttgtg atctgctgtg cactcatgcc 50940agcaaagcag ttgggaggta ctatgggtgg actggtgcac atcagcagag gctggcctgc 51000tggaggtctc caatggttag gcatggtctg ctggcaaagg agctatgatg agggccccca 51060ggaaacaccc tggttgggct tccaaggctg tactgcaagc aggcacagcc agcctggggc 51120cccaggagag gccagaaggc aaggaaattc tcatttcaga tgggccctgt cccatggaca 51180agaccaccct gctttattca ggtcccatag tcactctaag gttaaaatct cctagaggag 51240gttggtgagc cttgggggat gggtgtcccc tggctgtgct ccactacagc cattctcatg 51300tcaaacactc tgggctttac acagactgga gtcctgcccc tggcatctct ctaagcagct 51360gtcccttcca gcacaagtgt ccatgggggt catggggtct cctgctgcta ggattctgga 51420ggcccatggc aacagcaggc cactcctcac ctgttcaact caacctttcc ccaggagttg 51480ctgggagcca ggaatgagtc ctggtgcttg gcatccccat gcagggttcc catcttcctc 51540caccttcagc tcagcatctg tgtcctcccc cgtctactct caatccactc tcaatgcctc 51600cccttcaaag atctgcttgg aaagcacccg tcttcctgat gtctcactcc ctccatggca 51660gatattcctc ctggctgcat ctagtcagcc atcttgactc gcctccaaag tctttttaat 51720taccacttcg gttaaattag taactatcat tttacaatgg cctgtgattc tgttttgatc 51780aaatattttg agccttttag catctataac aaatgttctc aaaaatcaaa atcctaaatc 51840aagtctctgc cttagtctta tttctggggc ttattaaggc tataaaaatt aatcaccata 51900aggttgtaca agctttttac agcttccagt caggctatga actccagtat caccacctcc 51960agcctgataa ttacatatat tggaagaaaa tcagttaaag gactccctct agacccttga 52020aagggtgtga gagacaacat ggtttcgcct gccttcatgt gtcccagtcc atccctgtgg 52080ctgcctctgt ccacctcagc ttgcccactg tctttccttc ccaactgtct gccctgctga 52140cttctggcct cagtgacaga tgcaaagaca aggcgacagc cccacataga ccgtttaacc 52200agtcccacat ttgcataagc taaatggtca tgtcacagtc tgttgcccag gctggtctca 52260aactcctggg ctcaagtgat ccacccacct tgacccccaa ggtgctggga ttacaggctt 52320gagccacagt gcccagccaa gaacccgttt ttgagtgggc accttggcac acacctgtaa 52380acgcaacact ttgggaggcc aaggtgggag tgtggcttga ggccaggagg ttgaggttgc 52440agtgagctat gatggcacca cctcactcca gcgtgggtgg cagagtgaga tcctttagaa 52500aaaaaaaaaa aaaaaacttg ttttctctgc agccgggctc cgtgaccaaa cacaaacaca 52560aacttcccct ccagagggtc caggaggggc tgggctgcag gaggtgctta gggcctctta 52620gggaatggta agtgaccacc caacgcaggc actcagcccc aggggcatat gcagagagag 52680ggtccaggag gagctgggct gcaggaggtg cttagggcct cttagggaat ggtaagtgac 52740cacccaacgc aggcactcag ccccaggggc atatgcagag agagggtcca ggaggagctg 52800ggctgcagga ggtgattagg gcctcttagg gaatggtaag tgaccatcca acgcaggcac 52860tcagccccag gggcatatgc agagagaggc tgggaggaca ctttcagtga ctggggttac 52920aaaccccaac cataagacat tgctggctct gtgagccgcc acctccagaa atctcccact 52980tagttcttag cacttatcca ctcttccctt ttcctactct caattcctgg aggatgccct 53040cctttctcag gctcagacca acctaccagc tccactctag acctgaacac atgactcctc 53100cctctgtctc cacctggaaa tctcatcagt gcctcacatt tacactcctg aaaatcaggt 53160cctgcctacc caccctcttg ctccacctga ttcctgccct gtttcagcca gagaccttgc 53220agtctccttt aactctcaaa cccacccatg tcgtgtgagc atactgactg tgttctatgc 53280aagaaagagc agtttcttgg tggtcctgcg gttttattag tccagaggca aagcgttggc 53340agagctggtt tcttctgaac cctgggaggg agattctgtt ttcatgcctt ttccagattc 53400tagaacccat attccttgct ctgtgtcccc ttcttccatc ttcaaaggcc atcctctcat 53460ctctgtgtcc atcatcacat cacccttccc ctgactctgg ttctcctgct tccacttata 53520agcacccttg tgattacatc atacccaccc agacaatgca gggccatatt ctcccctctc 53580gagattaatt taatcacatc tacaaagttc ctcgtgccat atgaggtcac taaaccacat 53640gttctggggg tttgaatgta aacatttggg ggatgcatta ttcagccacc cacaagcact 53700gctccccact ggccacacac tatgcacagc cgagatcatg caagtgaggc acgttcatca 53760acagcagctt cagcaggaaa ctatatgctc cactttcctg ccatttgtat ctggattttt 53820ttttcgctat cattgtagaa agagtggtat tgtaaaatta aagatggatt attttctttc 53880tagaacactt tggcaatcta tccaacatta tttatcccct tctgagtgtc aagtgtgagg 53940tcattctttc attgagagct caatgcctac aattatgata atgcatattg ggtactttca 54000cacatcagaa agttcttctt tcttaaaatc tgttcttgaa ttattcattc ttctctagct 54060ttttgttgat ctattttata attttagaaa aatcagaaag taacttgaag tatctgtcat 54120ctctacaggt ttacctccct ctttgtggcc ttcagaatgt catgacacgc ttttcccttg 54180ctcatcacat ggtttctatg tatgagacct catcacagga gctgtggtcc cccgggagca 54240ggcatctgtg gatggtgcct tgctcctggc tgctgggacc tgtgtgctgc cagtggcact 54300ccacgacagt gatttcccag ctcagttttg cagctccaga tggtgggtga gacactagga 54360ccactttgtg aacagcgagg gcttggggtt tgcttttcta ccatgtccag ggctgctgtt 54420catgagggaa tgtttctaac ctgacatcat ggctgaagcc aacttagaac ctctctagcc 54480gtatggggag taggtgagtg atacagatgt taattagctc agtggagcca ctcccctatg 54540tagacatgtt acaaaacatt atgctgtaca gaataaatat aggtcatttt tatgtgtcaa 54600tcaaaagaga aactaattat ttaaaaaaaa aaaaaaaacc tctctactca agccgaaacc 54660tcagctccag tcccacaagt cacacaaggc tgctcccgtc ctgtgtatgt taaacctacc 54720tcagaaatgc aagggggcat tcaggtttca ttctcaattc aaatgccctt tttaattttg 54780tctattccta gcacctggca acttccagct ctttttttcg gggctcattc attatttaaa 54840gcacgtataa tttttcaccc acattctaac acatgtagta ctgtagagaa tccttcccta 54900ggaggatcta cagcattaga aaagaattaa gaactccaat atttacaaga aggaaaaagc 54960aaaaagagat caaaaaatgg gcaacttcta gaaatagaaa accctcatga gtatgatgat 55020aaatcgctgg cacacatgtg aatagttact tgatgcttat agtgatgtct gggaaaataa 55080catgaaatac ttataatctg tttctcacac atgtaattca aaagaataga gagaagatga 55140tttgaaatat tcttaagttt gtaggaaaaa agctacttcc atatgcataa ttgcatgtat 55200tttgatactg ccattattaa gaactatcta agagggtcca ttaaaaataa aatttcttgg 55260ctgggcacag tggctcatgc ctgtatccca gcactttgga aggccgaggc aggtggctca 55320cctgaggtca gaagttcaaa accagcctgg ccaacatggt gaaacgctgt atctaccaaa 55380aatacaaaaa ttagctgggc atggtggcat gcacctgtag tctgagctac ttggggggct 55440gaggcaggat aatcgtttga acccaagagg tgtaggttgc agtgagctaa gatcatacca 55500ccgcactcca gcctgacaga caaagcaaga ctctgtctca aaaatattaa aataaaattt 55560ctcattccta ttacagagta atttaattca ttaatgccct gccctgttac aaaactcatt 55620tgtaaaatac taattgtaat tgtgaaaaaa tggcaattga tactaatttt aaattctaaa 55680aacagggcac ccatattaaa gattattctg cagtaagaga attagctata acattttgta 55740ataaggtgga gaaaacattc tccaacttac aatggttggt gagaagaaag tttccagcac 55800ggtagatgga ccctaagagc ccttgttgaa ataataagac aaaaagatat acagagagat 55860gagccagatg aagggagaca gagagagaga gagagagaga gagagaggca cagaaatgag 55920agatacaaag tgaaagaggg caacctgtgg ggtcatcaga tatttgtttt ctgttttgtt 55980tattctaaca taaaggcagt ggtgggtcat cgatgtattt agagtttgca caatcactgt 56040ggaacacaga cagacacagg ggaagaggag aaacacaggg cggtggcttg cccttggact 56100gttcttagtt cctcaaaacg taacagcttt gcccaaccta agggaacttt cagcagctgc 56160tcttctgcca taggcctctt tcctgccttg ttttcatgtg gctgactgtt tctgttcctg 56220caggtcttag ctcatcagac aggcatttat tacctctgtg tcaacagtgg gagcttccat 56280tactctctag catgacactc cccttcctct tttaggaaat ttaacatgga agtgagtttg 56340ccatcggcct tctccccaca gtgttaacag tggtgaggaa gccagcctgt tccaccttgc 56400ccctcccatg attccaacac tgagttcaga cttgtcacat ggaacttatc tttgcatgtt 56460tgtggcacag acagatggac ccaaccatgg attagtggat ggatggatgg atggatggat 56520ggatggatgg atggatggat ggatagatgg atggatggat ggctgagtag gtgtgtggat 56580ggaagagtga aaagatagat ggatgcatgt atgggtggat gggtaggttg atggatgcat 56640ggatgggtgg atggatgggt gagtggatga atgggtgggt aggtgggtgg ctacatgcat 56700ggatgagtac ttggatagat aagtgagtgg atggatggat ggatggatga atgggtatgt 56760gaagggatgg atgtattaga gtgggtagtt aggcaggcat gagctgatag tcaagtgatt 56820gttaaactgc ctctctaaaa taataattgg tctcggctgg acgcggtggc tcatgtctgt 56880aatcccaaca ctttgggagg ctgaggtggg cggatcacaa ggtcaagaga ttgagaccat 56940cctgaccaac atggtgaaac cctgtcttta ctaaaaatac aaaaattagc tgggcgtggt 57000ggcgtgcatc tatagttcca gctactcggg aggctgaggc aggagaattg cttgaacctg 57060ggaggaagag gctgcagtga gctgagattg tgccactgca ctccagcctg gtgacagagc 57120aaagctctgt ctcaaataat aataataata ataaataata attgatctca gccagcgcca 57180agaaaaggca gtctcccaat agatagaaaa cacccgaaac tggtcatcag cagcttcctg 57240ataagatctc aggcattggg tgagtgggct caagcatatg cactaagagg caaagtggca 57300gagtttaact ggcacataat cttcctctag gaacactcta atagtaagag aaggacacct 57360caaatgagca tgtgcacatt tcattaaacc cactgtgtat gcagcccctc ccaagtgctg 57420gcaggccact gtacatgtgg gcagcccact ccaagggaag aatcaaggga gaagaaatac 57480aaatcccaga accatgtcaa tgtataaaac cccaagtcaa gggccggaca gagcacttag 57540atctctcaag tcgcccactt agccctcttc caagtgtact ttacttcctt tagttcccac 57600tttaaaactt taataaacat ttactcctgc tctaaaactt gcttgggtct ctcactcttc 57660tgtatgcccc ttggccaaat tctttcctcc aaggaggcga gaatcaagtt gctgcagacc 57720tgtatggatt cgctcctgct aacagatagc tggatgggtg gacagatgca tgaattagtg 57780gatggacgtt tggatgtgtg ggtgggtggg tggattgtgg gatggctgga tgaatgcatg 57840gctggatggg tggacagatg catgaattag tggatggatg tttggatgtg tgagtgggtg 57900ggtggattgt gggatggctg gatgaatgca tggctggatg ggtggacaga tgcatgaatt 57960cgtggatgga cgtttggatg tgtgggtggg tgggtggatt gtgggatggc tggatgaatg 58020catggctgga tgggtggaca gatgcatgaa ttcgtggatg gacgtttgga tgtgtgggtg 58080ggtgggtgga ttgtgggatg gctggatgaa tgcatggctg gatgggtgga cagatgcatg 58140aattcgtgga tggacgtttg gatgtgtggg tgggtgggtg gattgtggga tggctggatg 58200aatgcatggc tgggtgggtg gatggatgca tggataagtg gtggacggat ggacgggtga 58260gtggatgggt ggatgtgtgt gtggatgggt ggataggaaa gccctctaat tgattacagg 58320gctcagtgtg tgcttcaaca tcatgatggc atcatcacat tggtccctgt atgaagcagt 58380gggggaggag agtgtaccag gggagcagga atgacttttc tccagaatcg acctctccca 58440ccctgcagcc tgggctgtgc aggccacatt ggagaaggtg cggtcgacta ctcctaaatg 58500ttgttgtgtc caatggcttg ttgacgttga tgtaggaatg agcctacatc tccaccatag 58560atggaactgt ttgggtcccc aaagcagaaa gcctcttctg ttgcaggtgc tgaagtttcc 58620atcttcttct gcttatacgg aagctcacgc atcccttgga tggcaggcgt caggttcctg 58680tgcgcactga gttcccccct tacatgcttt ggacagaagt gtgagacaca caagattgct 58740gcaggaagtc cacctgtggg gatgctgcga cttctccagc aagaacacga gtctgctcat 58800tgaccatcac cacacataac aaattaagtg tccctttttt gataacacgt cattgtttca 58860cagagtattc ttttaaagtg tataagttga ctgcagttat tattttttac ttctgttact 58920aatttactca taattaggca caatttacac ttaagaaatt tcttaatagt tttttcctcc 58980ttaaggtgaa ctacagtcag ataacatact tatcaattgt ctctagctct tgtcagaaaa 59040acatatagat gtgtgtgtgc gtgtgtcttg gcctttccaa tgatgaatta agatgtgcat 59100tgagaaggca ttcactttat ttgacgttaa ggaagtacca agaagacgct ctccacagac 59160cctgggaaag ccagcagctg caccccgagg ctgtgccagg cagggaacaa ggaggcagca 59220ccacctgctg ggcagggaaa atgtcctccc agtccctgcc gcttctctgc agaggcacaa 59280agagctgccc cttctcctgg gccttctcct gggctgatga gattgctccc cgatatgcca 59340aatcagggtt gtgcatctga ggctctgtct agactctcag ctccttccta ctcctgcaaa 59400gtgaagaaaa caatgccaag gggtcctgga ggcgtctcta cccctggaga gttttgactc 59460tcttcaatag tctccactac cctgccctca ctccatgtcc tccgtttctc cctaaagcgg 59520tgcccagtct gattgcactg tggcagggat aacgaggggc caggacatca ggggagagaa 59580gtttctacct gagtcacagc agcggctgcc ctgcagactc ctgaagacac aagacacatt 59640tccatcccag agacccagcg aaatgcaacc tcaggctaga gacagccagt tattttttct 59700tgttctgtcc tggagaggcc actgagaaag tcgagcccct tgttgaggaa aacatgagat 59760ctctgtgtgt cgtcctctgc ctgatggctg tacctccatg tgagtgtctc agagatttca 59820gaacgggggc tgtgggctgt ggtgtccgct tgtgactcat ctctttgctt cttgtccctg 59880agtgtcctgc atcagatgca gctactggag tcatgcccag ggctggtgag gtcctcacag 59940acctctgggc ctggacccag cagccctctg ggaaggcgct ggggcacctc agctccaggg 60000gcagcacaca cttcagccca gcctttctgg gccaactctc catctgtaga gacacatcca 60060aggcccagtt atccctgcag ctgagctccg tgatggccaa gggcagggcc gcacattccc

60120gtgggagaca gaatggggac ctcagcgtga gcccagacac aaacctccct gcagggaagc 60180acaagaccac caggcggcgc tccagaccac acagcggccc cagaagcagg ttttaggggg 60240cggggcagac gtgtccgcgt tgagtcaggt cattggtttt actttccctg agcaaacggc 60300ctctgccaag gactcactgc acctctcacc ttcacagttg tttttttttt ttttttaatc 60360accctgtaga gttttgctag ctaatttaga tattgaggag tgcttcatac ttccttgggc 60420ctctgcttgc agaaacatag caattgtaag gaggcacgtg ggaaagcccc ggctcggtga 60480cccgggggat gctgctgtgg ccctggcaag agggcgtcgg gccgcagtaa caaaggtgca 60540gacggctctc agcctgcgcc cgcggagtac aacacataag ggctgtaacc taacgaaaaa 60600agaatcgcag tgcaactgtc ctgcatttga gtttgtgatc agttttgccc tttgtcttta 60660acaggttcta acataaaatt ttgaatgttg gttcaagccc tgtgggtaaa atgcacttac 60720ccacattcct taaacaaata gaacactgag gtggaaatgt tttgaaaaag tagttttcag 60780acatttggaa acaagcatca caggatcata acccctgaga aaagaaaaac aaatgaacga 60840atcctgctat tgcctgaaag cagctgccag gacacacgga aaggcttagt gagctgagcg 60900gacagagagc agagttcaag gcagcagcag cccgagggga ggagcaccgg ggagcaggct 60960gctgtgcagc caggatgggc cggggtgggg cggggggaga acagctggag acttgccgca 61020gggaggggga tccctcaggt ttggggctga gaactgactt atgcctgact tatgcctgca 61080tgaaaagaaa ctactcgata tcagggggaa atcaccagaa acctgtggac ccaaaactac 61140acagagccta cacaaggaaa gcattgtttg tgttctccca gccagggtgg aaagaccttg 61200agatatgtaa agcttcaagc aatcttccga agtaatctcg tgagtagtgg tgccacatta 61260attcaggact aaaggctgct ctgaactgaa cctaagaaat gcttcaagtg tagcctggag 61320cccgggtgca gtggctcaca cctgtaatcc cagcactgtg ggaggccgag gcaggcggat 61380cacttgaggt caggactttg agaccagcct ggccaacatg gcaaaacctg tctctactaa 61440aaacacaaaa attagctggg cgtggtggca gatgcctgta atcacctccc acctggaccc 61500ttccttgata catcagaatt acaactagag atgagattgg ggtggggaca cagagccaaa 61560ccgtatcaca taggaaccta aaaggataat aaagtaggaa aacttcccac atcagtaacc 61620ctttatccga tagtaatccc aatctgcaaa gtaaaactgt gtgattttac taagataacg 61680gaatcttctc tacagaagga ctttccagtg caaaagctcc ccaccctcac catgaaatgc 61740acgtgaccat ttccaatttg tgtaaagtcc tcagttagta ctgagacttc ggaaggttag 61800aaatcccttt gctcatgctg catggtccgg atgagatgta agaatcatta gctaatagac 61860atgcaacagc ttttgtgtga aagatgttat gagacattta aggtatttgc ttgtgattac 61920taagcattca ttgtatcatt ggagcacatg tgcttttata ccctggagaa attccagtaa 61980ttgaattgct gggttgaatg ggattttgat ttggattaaa tttaaactat agattttatt 62040tagggaaaac tggcatctta attatgttat tggggggccc ttgctcccag agctcccaag 62100atggtggcag gccgcttcca aaatgaccgc aggccacttc caagatggtg gcaagcctca 62160tgttctctga cctggggttc ttggcctcac ggattccaag gaatggaagc ttgggccatg 62220cagtgagtgt tatagctcta ttagaagccg tgggtcacgg aagagaaccg tggaacccag 62280tgactagtgt tcagctcgat taggacgaac ccaggcactt agccgtgcag gaacaatggc 62340gagcatttgg cccgatcgag agtggcaatg ggcgcctcgc tggatcagga gcacagcgga 62400taccctgatg gatccggagg gatggaagcc agcggtgggt ctcccacggg ggcaaacagc 62460agtggtggac ggtgagcgaa agcgaagctc gagccgtaac aaacatggac cagaagagtg 62520cagttgcaag atttagtaga gtgaagacag agctcccata caaagggagg ggacccaaag 62580agggtagctg ttaccggctc gaatgcctgg gtttatatcc cgatcattgt ccctcccgct 62640gtgctctcag gtgatagatg attggctatt tctttacctc ctgcttttgc ctaattagca 62700ttttagtgag ctctctttac tatctgattg gtcgggtgtg agctgagttg caagccccgt 62760gtttaaaggt ggaagtggtc accttcccag ctgggcttag ggattcttag tcggcctagg 62820aaatccagct agtcctgtct ctcaattaca ctgagttttc caatccatgc atccaatatg 62880tggtgtatct cttcatatgt tcatagcctc tgagcaatgt tttacaattt tctgtgtaaa 62940gaactccaca tcgttttatg tttcttctaa ggtatatcct gattgctttt tatgtcttca 63000caagtttttt cctttcaaaa ttaattttcc aattgtttgg tgctaatatg ctcaaatgtc 63060cttgattttc ttagtttgaa cagtccgttt ttgttttggg gatttatttt tttttcagat 63120tctttaagat tttctatgtc tataaccata taatctctga acagagacag ttttgctttt 63180tcctttcaac ttgaggtagg ttttctgggt agttcaggac gcgcaggcac tgggtgggtg 63240gtgttagcag ctgcacgatg ccttggagag gacactctcg ggggactgtg gccgctgctc 63300agctgtgacc gttcttatag caccagcagc tgcggccacc attcttatcc aatttccaaa 63360gccacaccac aggccctctc aagaacgagg cgtggaggct atgccctctc ctggacacat 63420catcattccc aagccccacg atgtgggccc catgggacgc acacctttgt ctgtccagac 63480ctcagcccca cctcctcatc ctgcaccaga actcttcaga gcccagtgca tgaaatgggc 63540taccaaggaa atgagggtag gttcctgaga ggaaactggc cctgcatttg ggagctagga 63600gtctgctaat tcgcctggca gccctgtgca gccctccgtg gctacagtcc accccgtgcc 63660catcagtgcc tccttcctgt gcaagcctgg acctcgccct gggctcagga tgggctgtag 63720accgagaatg caggcgggaa agtctttgtc tatcggggcc atagtcaggt tctacagtga 63780gtcagggaaa gacctgtgga ggtgtggatg aggacaatgg gtccaccatc aacaggagga 63840cacgggttcg accccttgca gaggcacagt cccacatcac tgggaggcag ccacactcac 63900tgcctcgccc tctcctcaca cagtgcagtt tccacgttca cagccccagc cagtcaccag 63960gaatgccctg ggggcggcct ttccccagtg cactccgagc cctcccttgg ctgtgcggtg 64020agctccatgc ccaggagata tccacccata gtcctccgga aagcagctga cctgccatgc 64080cctggaacca caaatcccca cagatcagcc agcctgcagt gggccttgga tgtggtgagg 64140agtggtggca cccccgttcc caccccacag atgcaacgcc tgtgggtgac gcatgtgagt 64200actgaggagt agagggtaga actgtaggcc ccgagaacca cagaaactcg ggtgttacac 64260tctggggcca tgtaaggaga aagtgtcact ggacagaaac aggcccctcc tagacactgt 64320gtgcgccata gtcacctgtc attagctctc actcttgcag attcatgatt gaggtggtta 64380aaaaaaaaaa agctcctact cacccatcca accccatcct ggggtgtttc caccaccctt 64440ggggtttggg atgagctgcc cttgcccact gtgctctgtg gacctccctt tagaagctca 64500cagctccctg cactcggctc catcctgccc caccacacag aagcaaaacc cctctccttt 64560ccactgcagg cttttcctgg accagaatgc tgacctgctg cccttcactc ccgaagtggt 64620gggactgcct ggggtggtgt gggtgttgag ccttcttact ctagggacct ggcacctggc 64680cccaggggca cagggatggt gcatctgcct agggatgcct cctcatgcca gggggtgggg 64740gttagtacca tcggccctca ggatttgttg catgaatgag tgaatgggtg aataaatgaa 64800ggggatctga tctatgaata agggtatata gactttggtt gatgtaggac gccaaatgct 64860ggaatttcag agtcatcaca cccaggggcc ctgcctctga gctcctcttt gcatccaatc 64920tgctgaagaa catggctcta gggaaaccca gttgtagacc tgagggcccc ggctcttcaa 64980tgagccatct ccgtcccggg gccttatatc agcaagtgac gcacacaggc aaatgccagg 65040gtgtggtttc ctgtttaaat gtagcctccc ccgctgcaga actgcagagc ctgctgaatt 65100ctggctgacc agggcagtca ccagactcga gtgccatttc attacctctt tctccgcacc 65160cgacatagat tctcactcac ctgtgccatc tccggggaca gtgtctctag caacagtgct 65220gcttggaact ggatcaggca gtccccatcg agaggccttg agtggctggg aaggacatac 65280tacaggtcca agtggtataa tgattatgca gtatctgtga aaagtcgaat aaccatcaac 65340ccagacacat ccaagaacca gttctccctg cagctgaact ctgtgactcc cgaggacacg 65400gctgtgtatt actgtgcaag agacacagtg aggggaagtc agtgtgagcc cagacacaaa 65460cctccctgca gggatgctca ggaccccaga aggcacccag cactaccagc gcagggccca 65520gaccaggagc aggtgtggag ttaagcaaaa atggaacttc ttgctgtgtc ttaaactgtt 65580gttgtttttt tttttttttt ggctcagcaa cagagatcat agaaaaccct ttttcatatt 65640tttgaaatct gttcttagtc taatggagat tctctaatat gtgacaatgt ttttctcttg 65700ctgtttttgg aattctttgt ctttgacttt tgacaacttg acttttgaca gtgtgcctca 65760aagaagttct attttgggtt ctgtgaacct cctggatctg ggaagttttc agctatgatt 65820tcattaaacg tgttttctac accatttccc tactcttttg gaatacccat aatgcaaata 65880tttgttcact taattgtgtc ccataaatgc tggggatttt cttcattcct ttttactctt 65940tttttctttt tattcatctg cctgaattat ttcaaaagat ctgtcttcaa cttcagaaac 66000tcttttgctt ggcctagtct aatcttgaag gtctcaattg tacttttaat ttcattcatt 66060gaattcttca actctggaat ttctgttggt tcttttttat gatacttatc tctttgttga 66120attcctcatt caaatgataa attgttttcc tgatttcact gaattttcta tctgtacact 66180attgtatctc cctgagtttc ttagagatta tccttttgaa ttatttttct gacattctgt 66240atatttcctt atgattgggg tctgctactg gagaatgact gttgtctttt tcaggtgtcg 66300tgtttcctgg ccttttcatg ttttatgtgt tcctacgttg atttctacac atctggcgga 66360ccagtcatcc cttgcaattt aatggagtag gttttgcagg aaaagacttc ctagtacaga 66420cgggtctcag ggtgtcagtg tggcggggcg tgctggcttt agttctaggt tgacgcagta 66480gcgtagtctc catgtcgttt cttcagctgc cgtccacatt ggtgacgttt gcgagtgtct 66540cagtggcctg ggctgagagg tttgtggcag tggaagtgca acgttgctag aggtggactc 66600accaggctgt ttctgaggtc gaggcacatg catgcacatg gtggattgac caacttggtg 66660ccaggctcac tagggttggg gacatggggc tgtttctcag gcccaggatg caaacacaag 66720tctctttggc tggcctgggg gtgtggcttc tgagggcaat ccacagggct gtttctcagg 66780ttcaggacac aagtgcatgg ccgctcaact ggcctgggca tgtgtctccc agggccaccc 66840catgggctct ttctcagacc caggacatgg ccacatggct tcctcagctg gcctgggtgt 66900gtgtctgctg gggggctgca ggggcacagg gttatttctc aggccggggt catgggcgca 66960cagctgcttg ctggcttata ggagtgcctg ccaggggtgg cccatgatgc tgtttctcag 67020gcctaatttc aggtgcagag cctttgggca ggtcaacggc atacctgtgg aaattggagt 67080ggatgccaca gggctatttc tcaggtgcct gagtgtgggc acatatccac tctgccagcc 67140tggagttagt atcaggtgct cggtggctca ggggcctctc ctgctcaggg gagggccctc 67200agcagcttgg ccaaatcaat ggtggattca ccctgggcag gcctggcagg ctcttcctcc 67260agctggatgt gcagcagcag gggttgggtt ttttgctgtg cagggccaga gtcacggcca 67320atcctcagcc taggctctgc acagccaggg ttgtggcatt cagccaccca gatatgggca 67380tcctgaagat ggagccccaa tgctagaaag gggcagtggc taccagcctc agggcaggat 67440gcactccaga ggcggctccg gtctcaaggt ggcgctgggc tgcagcagct aggctcacag 67500tggatgaatg ggggcaggga gtacacacct tgtgctccta atctgggatc attcctggca 67560gctcccaaac ttggctgagg gcttgcaaaa cctgtggaat tctcctgttg caagggctgt 67620agatgtttgc agtggcagtg ggtgctggcg ggaaatctgc ttaccttttc cctacatggg 67680aagtccctcc tgtgtccaga ccaatccgat ctgggtgggg aagacaaggc tgcaaaggcc 67740aggtgcctcc atgctgccct ccgatcacca cgggtgcgtt tccacacctc cactgcactc 67800cgtcagtctc ccttcaacac tccagtcaaa ccttagctgt ttcttctttg ccttattcct 67860tcctcatggg gagggtgtgg gtgaacacca ggcttctcta agttcttcat ccatcttgct 67920gatgtcattc tccatccagg catgggtttt taagaagtag tgaatactga aatttcagca 67980gaggacacct ctataaaaat tctgcaactg gaaaacctcc ttaaattggc tgattgtcat 68040tacaattgga ggaaaactgc caataatttc aaatttagaa ggctgagact ctataaacaa 68100agactaacaa tatgttttct gatatttttc cccaaaataa tacttttcca agacgaaaat 68160ttttccaggg tatataagca catgtgctcc aatgatacaa caaatactta ctaatcataa 68220gcaaatacct taaatgtctt ataacatctt tcacacaaaa gctgttgcat gtctattagc 68280taaaaattct tatgtctcgt ccagatcatg cagcatgagc aaagggattt ttgaccttca 68340aaagtctcag tactaactga ggactttaca caaattggaa atggtcacct gcatttcatg 68400gtggtggtgg ggagcttttg cactggaaaa tccttctgta gagaagattc cattatcttg 68460gtaaaattac atagttttat tttgcagatt gggattacca actgataaag ggttactgat 68520gtggaagttt tcctacttta ttctcctatt aggttcctat gtgatatggt ttggctctgt 68580gtccccaccc caatctcatc tccaattgta attcccatgt gtccagggag ggtccaggtg 68640ggagtgatta gatcaagggt ggtttttccc aggctgtttt catgataggg tgttatcatg 68700agatatgatg gtttaaaagt ggcaggttcc cctgctctct ctctcgcctg ctgccacata 68760agacgtgcct tgctttccct tcaccttctg ccatgattgt aagtttcctg aggcctcccc 68820agccatgcgg aactatgagt caattaaacc tcctctcttt ataaattacc cagtctcagg 68880tagtatcttt atagcggtgt gaaaatggac taatacacta tggctttgaa ttaataattt 68940aaaatttgtc agcttggcaa taaaacatcc tgttgacatt tattttttag gtaatatttt 69000aaattggcag tttcattcat gtttttacaa attcttattt tcagggtgtt taaggccttt 69060gctttgaact tggtggttcc ttacactcca tgctgttagt gaagagggac caggttggga 69120ggcattggtt tgggtggtgg tcaggaaggg cagagtgatt tgagtagggt ctgagtggat 69180aatagctcat cagtttggaa tttataaatg accagggatg atttaaggag attcctgcca 69240gacacctatg ccatggccat gccctatctg gatctccagc cgtgagatga gaacccagcc 69300atgcggggga gtctgttcgt tctgctcaat gttgtaagtg gcacatgcta ttggataatg 69360tagaattgaa tggatatcat tttattatta taatttacaa acttcctaca ataaacttat 69420cacctttata catagaaaca aatataagta cattttccct cccctatgtc attttgagcc 69480ctctctccaa accatcctcc cactctgcga ctcactgtcc tgcatttggc tatgctctgg 69540caagtcctgc ttagacaagc actcaccaga ccacctactc agcctccctt cagcgcccac 69600ctggcccacc tgctcaaata catgttgagt ggtcacacac atggactgaa caccatctat 69660tccatgcact gccccagtga ccgcactgag cagcaagaga gaaatgatcg cattagctat 69720caattatgcc aattcaaatg ctggagtctt tctcagatac ttttcaatgt tcaagaattg 69780ttgattgtga attctatacc caatgaaact atccttcaga aatgagcaga aaatggatac 69840cttctcaaat aaacaaaaac taaaagaatt cttgctacaa gatgtactct taaagactgg 69900ctaaaggaag ttcttcaaac agcaaggaaa ttgaattgat cttatgtcct gcacacttgc 69960taaatttcct ctcaatttta gcagcactgt ttagattcca taggattttc catacaaaca 70020gtcatgtggt ctatatatag agacagattt tcctcttttc cagtggggat aaatttatgt 70080ctttttcttt ctgtgttaca gcaggtagga cctccagtac aatgttaaac agaagtggtg 70140aaaacagaca ttcttgcctg tttcctaacg ttggagtttg gtcttttact atggtgtcag 70200atgttagctg tagggttttt ataaatgccc ttcatcacat tgaggaagtt tgctcctatg 70260cctaattttc tgagagtctt ttaatgtgac actcatgcta gaatttatta aatgctttct 70320gtctactaag atgattatgc agttcttata ttaacatgaa taattacatt tatttattct 70380ttaatatcaa ggcaattttg cattcctgag acaaacccca tttagtcatc atgtgttgtt 70440attgttacat attgttggat tcaatttcct caaaatttgt taagaattgt tacatctatg 70500tttacaagga agattagtct gtagggtatt ttttcttata ataactttgc ctagttttgc 70560aatcagggta atgctggact cacagaatga gttgggaagc tatttcctcc tcttcatttt 70620tctgaaagaa tttgtataaa attggaatta tatcttcctt aaaggtttgc aagatttcat 70680aatgaagtca ttggcctaga gttttctttg tgggaaagtc tttgtttgtt tgttttgtgg 70740tttgggtttt tttttaagag acacagtctc actctgttgc ccaggctgga atgcagtggt 70800gtaatcatag ctcacagcag cctcaacctc ctgggctcaa gcaatcctcc tacctcagcc 70860ttcagagtag ctgggactac gggcatgtac caccacaccc agctgtttgt ttgtttgttt 70920atcgctttgt cttgtttttg aggtcttatt atgttgccca ggctggtctt gaactcctgg 70980cctcaagtaa tcctcatgcc tcagcctccc acagtgctgg aattacaggc atgagccact 71040gcacacagac tgtgggaaag tttttaacta aaaattcaat tttctcttcc ttttccagtg 71100agctttccag tgtctttcaa ttaatgtatc tattttatct aagttgttga atttattgtc 71160aaaatttttt taaacaatat tcctctctta gaggttgaac atctgtagaa tctgtagtga 71220tggcacctct taaatccctg atcttgctca tctgtgtcgt ctctctttct ctaatcagta 71280tgcctaaagt ttaatttcat tgattttctt aaaaaactgg ttttggtttt attgattttt 71340ttccctagtt ttttgtgtta catttcattg acttctgctc tgatatttac tatttccttt 71400ctactgccta cagtaagttt aatttgctat tttcttagtt tcctaaagtg gaagctaagt 71460ttattgactt gaggcctttc ctctgtctgg atgcggatat ttgctgctaa acatttccct 71520ccaacaccat gctgtgagtt ttagttacag cgggcttgga gttggcctga gaaattctac 71580ttaaacagct gcacctatca tgtaagtgat aaatgatgta cctgcctggc cctcacccct 71640ggtcaaagaa tgggatgtac taatgagcaa tgttgctgcg tagctgtgga tttcaaggta 71700ttttctgtgt ggttttatca tcagcattgt ttgttgatga ctgcaagact gatgatttgc 71760acctggcctc ggtgagatcc ccgaaagacc ctgcagatgg gctggttact tagcagaaaa 71820tatgacaacg tggccagcag gaaacaggaa ggtacaatcg gctgcaggtg agctgttgga 71880agtaagttcc aattttccta ttttgtattt gcattttaat agtgagactg cgcttatgtt 71940atttgtgtga aacagcttta ttcatagcac tgtaatttaa agagaaaacc cattcatggg 72000aacaacaaac gacctagaca ccaaggtagc tcatgccatc caaggctata ctgtgcagtg 72060attgggaaaa tgggcactgg tcccagaagt ctgatcgaca ctctgccact ggctagtccc 72120gtgctggggg gcgaggatcc acactctgcc actggttagt cccatgctgg ggacaagtat 72180ccacactctg ccactggcta gtcccgtgct ggggggcgag gatccacact ctgccactgg 72240ttagtcccat gctggggaca agtatccaca ctctgccact ggctagtccc gtgctggggg 72300gcaaggatcc acactctgcc actgattagt gttgtgaaga tttaaataaa gaacccacac 72360catattcttt gacttgtgct ttccgtatac tgagagatag taagagtaca ttattattat 72420ttataaagta aactagaaag cacatgggaa gacaagaaga aaacctgaat aaacatgaat 72480taccccattt tcctcaggag aaaactttca cactctgaag gtacacaaat tagcctacaa 72540atttaatgta aagcaaatag actgttgtag gtaccaattc tcaatgtcac agtgttacat 72600ggaaagtaaa atacacaaga acagcccaaa agatggaaac aatggacgtg gtcaaatgac 72660atcagtacaa catccatatg gtcctaagta gccatcttta aaatgggtta gaaatgcctt 72720caatcattca cacagacaca tgcattgaac aaactctaag aagtgttctt acacgggaaa 72780agcaagttac agatgcatgg gcatgatatg gatgtagatg tgtgtatgtg catcccactc 72840atacacaaaa tacccagcat cgcccacatg cctgctgtgt gcgtaagtgt gagcgagtgc 72900acagacaaca gcgtgcagaa attcaaacca agctgtgggt acttgttacc actgggaagg 72960gagtcggtca cagagggaaa gagaaacagg acatcagcct ttgacttcag aactgttcct 73020gccttttcac atcctgtgct gttttcagca tcatcggagc ccttaacaca catcacggga 73080gtaagagtgt gttagaggga gcattcggtg ggacagatat tgccatggct tgtggataga 73140gttcacagtc cttaataatc cccgagatgg cagccaagag ctacgttctc aatcacgcag 73200cttcacccca gaaactgaca gaaacccaac aaccaaaagg tgtccattct gacagcctca 73260gcctgtgctg gctcagatga gcaaaaatgt acagatatta ataatgatgt tgatttgaag 73320agcacagagg ggggtatgca tgataagggt ccaaattttt accttaaaaa agaatacatt 73380tacttctcaa tcacctacat aacgatcatt ttttaaaaaa ctgatcaaat ttggtgttac 73440aagggcacgt tgcaaattct tctggctact tttctctgac tattctaatt acgttaccgt 73500gttttctcct gtatgtgccc gttcatgtga atgtcatttc tggctacttt tctctgacta 73560ttctaattac gttaccgtgt tttctcctgt atgtgcccgt tcatgtgaat gtcatttctg 73620gctacttttc tctgactatt ctaattacat taccgtgttt tcctgtatgt gcccgttcat 73680gtgaatgtca tttctggcta cttttctctg actattctaa ttacgttacc atggtttctc 73740ctatatgtgc ccgttcatgt gaatgtcatt tctggctact tttctctgac tattctaatt 73800acgttaccgt gttttctcct gtatgtgccc gttcatgtga atgtcatttc tggctacttt 73860tctctgacta ttctaattac attaccgtgt tttcctgtat gtgcccgttc atgtgaatgt 73920catccaggca gatttcccaa atccggcttc ctgtaaccaa gggctgaaag agggaacggt 73980ttcctgggaa tcctttttgc agtttatttt acccggaggc agaagcccac ggttccgtga 74040agagtctatt gctctcccct ctctcctttt gtgtctctat ttttaattga caaaaaagca 74100aatgtgaaga ttcctggggt acaatgcaaa gtgacaatgc ctgtctatat tgtgggatga 74160ttaaaacaag gtaagtggca tatccatcac ctcacacact tatcattttg tggtgagaac 74220atttaaaatc tcatctttta gcaattttga aatagtcatt attgttaact atagtcacca 74280tgctgtgcaa cagatcaaaa gaactgactc ctcccatcag cagaaacttc atgccctttg 74340accagcatct ctcctttccc cgtccacgac taacccccag cccaagagaa cagccaacac 74400ccacctcgct gctgccacac gacatgtcgg gctttgatgg gatggaggtg agggtgggga 74460agacaattcc aaagctggag cactggcctc acagctcaga cactcttcta cttatcctga 74520gagaatgatg tgctgagacc aactaaacct cccctgctct tcccacatgg cagaaaagag 74580gcaacccagg gaagccattg ccaggacatc atggtcaccc aacccttgtg cagaaaggaa 74640gcacctgccc aggatgccat agcacccaac cctcatcccc aaggaaacac agcccagggc 74700accatggaca cccaaccgtc atccccaggg gaggacacag cccagggcac catggacacc 74760caaccctcat ccccagggga ggacacagcc cagggtatct tggacaccca gccctcattc 74820ctaggggagt acacagccca gggcatcttg gacatccaac cctcatcccc agggaaggac 74880acagcccagg gcatcttgga cacccaaccc tcattcccat aagagcacac agcccagggc 74940atcgtggagg cccgaccctc atccctaggg gaggacacag cccagggcac catggacacc 75000caaccctcat ccccagggga agacacaacc caggccacca ttaacaccca atcatgtgca 75060gggagggtgt ccttggagcc tgggactctt gccagtgaag cggtggacaa gaaactgagg 75120atgcgatcag cacacagaaa tctcaggcag cctaggatac atgaggcctc tcacccctgg

75180gaacactgag cagccaccag gagcccacac cttgaggtac agcaggagcc atgcgctctt 75240gctcttgctc actcacactc ctgcacacag ccactgacac acgccctcgt gcacgttgca 75300gattaactcc actggccttg cacttgcaac gctggaggct gagaggtatc cccaggttct 75360tttctcgtga gaggggcagg ctgactttca ctctcctcca tgtgctagag gcagctccac 75420caacactggc tgccctgagt ggatgcacct ggctctggaa ttcctgtcat ttgctttgga 75480tccaggagcc cctgcctcat gtagctactt aacagaaagg aggaatccac ccaggacatg 75540cccagacggg agcctcacag gatggacagt ggtgtctggg gtcacgggca gccctgaccc 75600agcagcgcca gcaccagcac acccagtggg gaaggcgggg aggcccaaac gccacccaca 75660gtttgttact ccactgggtg ggacccggca cccctgcctt cctgacaccc tggagtccct 75720gcctcctcct agagccccca agcccatctg cctcagagca tccagagaca gacctgggga 75780gccatttcct caggccctgg acaaggaaac agggaattcc aggttatggg tgcctggggc 75840aggtctcagg caggtgctgg gaaccagaga gaggggtcac cgcgaggcct caggcctggc 75900accagcactt tgagcctcag tttaccagcc cacgaggtgc tgagtctgga ctggatgacc 75960ttcccacccc cagtgacctc tgccctttcc cgagcatgtc agctctgctc cagcatcctg 76020gtgtgagcgc aatgccactt tttttctcaa caaatacgaa aggaggaagg tgcccccagg 76080gccctgtgcc ctgaggatgc ctgtgtggag gggtccattt catcactggt gtcactcaca 76140ggaagggacg aagccacctg ccttgacgga gcttactcca cctccgccga aggccgggga 76200ggtccctcac agagaacctg aggcccagca ggctgcagag gtgctggcat ggaatgactg 76260ctcagacgcc cggggccggc agagaggacg gatgtggggg aggtgcacac tgaggagcct 76320ctccttggag gtggagacac gtgcaccaca tggaccagga cacagtccac gaagcctcgc 76380atccccctga gctgcagctc aagggcctct ctctgagccc agagtcccac ccctgggagg 76440cagctgcccc agctctgagg gaggagggca tccaccaggc cctccatctc ctgggggcac 76500cagcccagcc cagaggctct gcaggactct gcacctccaa ttcatggcca ggactttctg 76560gatgtatctt aaggactgag gactccacat cagggaccac acaagaccgg ggtcccggac 76620acgggggttg ggggtgagca tgtcaccggg atgggctgtg gcgtcactct ggtacttcat 76680ccggacagcc agggaccaaa gccacgccct cagccccacc ccacccctgc ctcacatggc 76740aacgcagggt ctgcagatgc aggagagtga gaagcatggt agccaggcag actagaggac 76800ccgagctggg gttgagcacc tccctgtcta cccagggcat ggcctgtgag actgcaggtg 76860gcctagtgtg tgctgcaggc tcaaggtcct gccccaggga gcatgacatt caggcccaga 76920aattgcatcg tgctgcacac agtccaaggg gataaccctg tgaagttcag gtcaccagca 76980ggcttggggt caagaccgag ctgcagagga caggtttctg gaaggcacag catcatgggt 77040ggagggactt ggagcaaggt ccttagcccc gggaccagtg aatgtgtgcc cttataggga 77100aagggggtct gtgcagaagc aagttagctg aaaatcatga agtggagagg ctcccctgga 77160ttaaaggggt gagccctaat gtaatcacaa gtgtccttct aggaggttgg cagagggaga 77220ctgacataga cagaagccag gtgaggtggg aagcggaggc agaggccgag agagcagacg 77280ctacgccctg gccctgaaga cggaggagga gccgagagct cagggatgga gagactggag 77340gaggcaggga agttctcccc gcaagcctgg agggagcatg gcctccagca cccccagacc 77400ttggccctgc aggattcatc tggacctgtg gtataaatgg tgtttaagcc actgggctgt 77460gcaaattgtc atagcagcca tggcgcattc ctagagggag ccctggtggg gacccagcag 77520gcagcgacgg ggccctcaca agcctgtgag ccactcagag ccgcgagagt ggctaggctt 77580ggtgaggtgc aggccacgcg cacctccact aaggcagcct tagggcccac acttcctctc 77640tctctctctc tctctctatc tctctccctc cctccttccc tccctcccgc tctcttggtt 77700ggacagctct ccatcatccc cctggacatg accacctccc aaggccgagc tggggcgctt 77760tgctcgaggt gagcactgac atcctggggg tgtgaggggc acctgcccag cggccccgtg 77820tgcaggatgg gcggtgggcc ctagctggca ctgggcatat ggcccggctg gtgcctgcag 77880gctgcagctt ttctggggtg gctgggatca gtgaaggcct ccagagtctg ggcctgggat 77940ccctgcagtg ctggctgagg acaggcgggg ctgggcagtg agggcactgg gtcactatca 78000ccacccacgg tttattactt cactaggtgg gacctggcac ccctgccttc ctgacaccct 78060ggaatccctg cctcctccta cagcccccaa gcccatctcc ctcagagcct ccagagacag 78120acctggggag gcatttcttc tgcccccagc agaagcccgg gaggccggga aggcacagtg 78180ggtctaaagg agaggatccc aggactgcct gaggggtgac tccgacgagg caagcataga 78240gcccactgag aagcggggtg ggagccccac cagggatggg ctagttcctc atgaaggacc 78300aggacccagg aaggacaagg gggcctgctg gggcagggtc tgctatgccg gagtccctgt 78360gagcctggcc cagacctgcc tctctctttc ctcattggtc cccacaggtc cgtggtggtt 78420gccgtatcgg gaggccccat ggtggcaggg gtgggacacc tggtatacgt cgccaggtgt 78480gtccaatagg ctcatgctca caccttctcc tggcacctgg gcaaagcctg agcacccagg 78540cactgaagtg agggcaaggc ctcggggccc cacaggatgg ccgaggagac agctgcaggg 78600cgcctgggac ccctgggctc aggaggtaga aggatacagc ctgaaaaccc acaccacaag 78660ctcaccggcc agtgcaggcc cacagagctc gaggaggcag ccctgagcct cccagggaga 78720gatgctctgt gcacgccggc acaggccctg ggttacaaac cctaggcaca gcccaggaga 78780ggcccaggcc ccagtccagc aaggggttgc aggaagcaag aggtccccgg ccacagcatg 78840agataagccc atcaagccag ggccaggtgg gcaatgggag gcaggcaggg cttgggggtg 78900agtccctgct gcagcgccgt ccactgtcga ccggaggagt ttcttccctg tgcggagtcc 78960acgggcctcc tgtgagtgtg tgcatgggca caagtgtgtg tgtggctctg ctgtgtgtct 79020gtacacacat atgttttggg tttttttgtg tctcagacca cagagtctgc ccctcccacc 79080aaagcccagg cagaaggatg aacccacgcc cctggggccc aggcctcagc agcctctgcg 79140ggatcattgt tcccagttgt cacttgcctt tgccacagcc ctatttctcc acaattcctt 79200aaagtcctca acatgcattt aaggcacaaa ggtgaaactg cccagaaaca tctgactccg 79260ccgtggaacc caggagcaag ctgggttagc taaggagcgg ggccgttggc agaggctggg 79320gatccaggct gaactttgga ggaggcatgt cccagcatgg gctcctgact atgtcctcct 79380gggacaaacc caaacccgct ctttgaatat gggagggact ttgctggccc cggccctgac 79440cgcagcactt ggaaactgag gagtggtcgc ctcctccgtg tcacagctgc ccgttcacca 79500tcatagaagc aactctgtca cctccatggg cccctctgtg gctgctgcct gggtccaagc 79560tgagcccagc tgcccaggcc cagaaggaaa gcccaggcca ggtgcccagc acagaggcag 79620tcacataccc cggggagagc cacagcaagc agccaatatt gcccaggaga ggagtagctg 79680acaaggcaga acgtgagctg ccatcggctc gagaggcttt gctggtcctc ctggggctct 79740ggacatgacc aggaggagcg agggaagaag tcgcatggtg gtcccatcct gggtggggcc 79800tgatggcagc tggccacccg tcccagagtg gcagccagat gccagcgcca ttcccacagt 79860cacatcattg gtcacagaat gcaggacata gagtgtcttc tttccatcac agtgctgtcc 79920agacccatag cctagggtag acctggaaga ttcaatgtcc acacccgggg ctggagcgta 79980gccatgagcc acgccccctg cccgtgcatg gaaagccagc ccaagctctg ctccatccct 80040agccaaagtc agtgtccttt ccccttctcc caagtgagct ctagccacct gcctaccctg 80100ccatctgagg atgacagcct tcattccatt ggaacctggc tctgccacca gcaggcttgc 80160agtcctgggc agactccgtc acctctctat gcctcagcct ttccatctgc acaggaggaa 80220gatgatgatg gtggtgatga tgatggcgat ggtttccttt tgcatctgag gcaaggacta 80280attgagatga tacacatcag gcactgggta tggtgctggt ccttcctgag cactcaatct 80340atgtgagctg tccttgtgaa atgggtgtca ccacatttcc ccacgcagaa catcctttgt 80400ctgccatact tgaaacgtct gccccaatac taacagctcc tcatggaaga tgtgcacacc 80460cacccaccct catactccca aaggtgcccg tgctttatca agccaaagtc cagccaggaa 80520ctttacagca gcatcccttt ccctctccaa gcaccaagga gcaaggcaaa gcactacatc 80580ttccatctgg aggcaatgcc accctcttct cccattttca ctgccatccc taagaggcag 80640tgcttcccca aaaggttcca tagcagcctg cctacagcaa ctctgttcac acgagtttca 80700gcatccttgc agtggctccc ctgccatgct gtggctcttc attcaccctc ttctcctgct 80760ccccgtgaca ggcatagatt ctgagtgatc tggatacatt gctttgttta ataacattac 80820agcttctgtg ctgaaaaaga tacagcagat agagaaggca attgttgaac acaaaatagt 80880gacagcagag atgacggcaa gttggcattt ttcttttcta gcaataaaac ttaaagctga 80940ctcaaggaga aatggaaatc ataattggaa cagtaatcct caagaaagca ttaagattat 81000taaataattg ccctcacaga tgacttcagg ccaagatggc tttatgggtg aagtttagac 81060tttcacaaaa ctaatcagtt cccataagaa ctgctccagg atttggagga acatgggaaa 81120gtctattaaa gggatcacaa ttcacagtcc ccagagtaaa acatgggcta acttgcattt 81180tggcaaagag ccaaatgtta taaatgacat cctagaaggc caaattctgt ccatctcgtt 81240gaacaaggac ttacaccagg aatttagaac tatttatagc tcatcccacc actcaggcca 81300atgatgaccc atgatcatct caccagaaat ggaaagactc agatgattaa tagagtctca 81360atttctctga gacatctaag agcccagccc aagcccagac ccaggagggc acccaggcct 81420ggacagagaa cactgatatc acaccagccc tccagaggga agcagagact ccttcaagct 81480ctggaaacac aggcccagac agctgcccaa agttgggcag gcttcactgc aaacccaaat 81540catgaagcta ggtaacacct ttacagattc tttacattta aaaatcatca aaacaagagt 81600aaataataaa ctcaaataat attaatctaa tatgtaaagg tcttgtacca ttattatgca 81660aacaacatac ataagctaat aagaaaaaga acaaatccct taagaaatcg gcaaaaagga 81720tataacacaa tttctaaaag aaaacaaatg gctagcacac ataaggaaaa cactttgtga 81780acagacattc ttcagaacat tatttataat tataaaatag ttgaaagcaa gatagtgcct 81840gaagaaatta tggtgcatac attagtggga ctattctgca aacattccca attatacttg 81900tcacatatct gtgataacgt gacagccagc attcatgggg tgacctcatt tggtaaaagg 81960gtgcaaagct caacacgcat tgtgagatga ctgtggtgta aaattagtgg gattattccg 82020caaacattcc caattatact taccgcatat ctgtgataac atgacagcat tcatggggtg 82080acctcatttg gtaaaagggt gcaaagctca acacgcattg tgagatgact ggtgtaaata 82140caaagaccaa actgtgaaaa ggagtccatc aattaatcga tgcttacctt cagttttggg 82200ctaattttta aagtatgcta taagcatatg ctcctgttat aacagaatgg agggattatg 82260agagatgatg caggtgtgtc ctgggcctcc cctggcccac tgggccctag agatgccttc 82320ccaggcatcg ctgtcagggc ttccctcaga gggagtcctg tattgacctc accaccaagg 82380tctggagcag gggatcctta gatattggtt ggggttatct caccttaggt ctgaatatgg 82440ggttgtctta gactgttttg tgctgttaga atagaatacc caagactggg aaatttatac 82500tgaacggaaa tttatttctc acagttctag aggctgtgaa gtccaagagc acaggtgcca 82560gagcaagtcc aagagcaagg gaaagtccaa agcaagtcca ggagcatctg gcgaggacct 82620tcttgctgtg tcatcacatg gcggaaggca agaaagagag caagaggggg ccgaactcac 82680ccttttataa cagcaccaat cccacccatg aggtggggac cttatgacct aatcactctt 82740catactgtta caatggcaat gaaatttcaa catgagtttt ggaggagaga agcattcaaa 82800ccacagcaag ggtgctccta cctcctctct cagggcatct gcagaaagag ctgcaactgc 82860acgtccttcc tccgtccatc ctccatccct tcccaatgtc cgtgcatatc ctgtgaccca 82920ggaggtctgg catagggggt gctcctgcct taggtctgag gccctgtctg aagaggggta 82980ggtgaggagg ccatctgatg gtctgggcca agacagtcac aggacgcatc atttatcatc 83040aaggaggctg agggttgagt ctccaggtcc agggaactcc ccacaaagtg ggaaccctgc 83100ccagctccac acagcctctg ctgggggacc ctgctctggt gcagagcctg gggacaggtc 83160ttgagctcag ccagagtctg cctccctgtc atttaggaac taaaccaagc ggcaggatgc 83220tggagcccag cccccatctg accttacagg gccaaggctg gggccctggg ttcccctcaa 83280ggcgcagcag gactggagcc ccaggcagtg caggagtggc caaagctggg gcttcctcca 83340gagcccccaa gcatcacggc accaagaagg gtaggaccct ggcctgagga attggcacca 83400aagccccaga aactaccctg gacaccatgg agagaggcct ggaggggaag caccaggcac 83460tgcctcccct tctgatccca cctgaggtgg ctgccaagcc cagagagccg ctctgatgtc 83520ccccagccct gcagcccagg gatacctgta ctgtgcccct gggggacccc tggccagtct 83580gtgcaaagaa gtcaccaccc tacactcaga gacagtgggg gtcctcgtcc cacatcctca 83640gagcatggcc cggctgctgc agggatggtc tcctggtcct cagagcatgg cccggctgct 83700gcagggatgg tctcctggtc ctcagagcat ggcccagctg ctgcagggat ggtctcctgg 83760aggcccccca gtgctctatt gtcagggctc cctccacccc cccgcaccaa gagagagcca 83820gaccccagca aggcttccag tggcttcagg tcacacccct aggctgaccc cagccccatt 83880aacacctgcc tgagaaagct ccacgcacca gaactgaccg tctgctccaa ctcttgacct 83940cccgttctca gggcgtctgc tgaaaaggct gcaactgcac atccttcctc cgtccgttcc 84000cgatgtccgt gtgtctcctg tggccaggaa ggtctttctc gggacctgag agccgctccc 84060tgaagtgtcc ccattgggaa ggatggggcc tgtgtctcca ggctctggga ggacagaatc 84120ctgacctcaa cagtggccgg cacggacaca actggcccca tcccggggac gctgaccagc 84180gctgggcaac ttttcccttc cccgacgact gagccccgag caccctccct gctcccctac 84240cacctccctt tacaaggctg tggcctctgc acagatgata atggagcttg gctcattccc 84300ctagagtcgg tagggagtta aggacaaaac tcagtttcct ccacctgaac tcaagtctgc 84360ctatgtttac ctaatcacac ctggtggaca gtttggacaa acttgcacac tcagagacac 84420agacacttct agaaatcatt atctccctgc cccggggacc ccactccagc agaagtctgc 84480taggcactgg cctgggccct cctgctgtcc taggaggctg ctgacctcct gcctggctcc 84540tgtccccagg tccagagtca gagcagactc cagggacgct gcaggctagg aagccgcccc 84600ctccaggcca gggtctagtg caggtgccca ggacaagaaa gattgtgaat gcaggaatga 84660ctgggccaca cccctcccgt gcacgccccc tcttgccctg caccccacag cccagccccc 84720cgtgctggat gcccccccac agcagaggtg ctgttctgtg atcccctggg aaagacgccc 84780tcaacctcca ccctgtccca cggcccaagg aagacaagac acaggccctc tcctcacagt 84840ctccccacct ggctcctgct gggaccctca aggtgtgaac agggaggatg gttgtctggg 84900tggcccctag gagcccagat cttcactcta cagaccccaa cccaagcacc cccttctgca 84960gggcccagct catccccctc ctcctccctc tgctctcctc tcgtcgcctc tacgggaaat 85020ccgggactca gcagtaaccc tcaggaagca gggcccaggc gccgtttaat aggaggcttc 85080ctcacaatga aacttttaga aagccttgac tacaatgatg accttggtgt ggctgtgaac 85140actgtcagct cccacagctg ctgcagcaaa aaatgtccat agacagggtg ggggcccggg 85200gtcgtctgct gtcctgctca gcccacagca cgcatggagg atctgaggtg ccacacctga 85260cgcccaggcc agaacatgcc tccctccagg gtgacctgcc atgtcctgca ttgctggagg 85320gacaggggca gcctatgagg atctggggcc aggagatgaa tcctattaac ccagaggaaa 85380actaacagga cccaagcacc ctccccgttg aagctgacct gcccagaggg gcctgggccc 85440accccacaca ccggggcgga atgtgtacag gccccggtct ctgtgggtgt tccgctaact 85500ggggctccca gtgctcaccc cacaactaaa gcgagcccca gcctccagag cccccgaagg 85560agatgccgcc cacaagccca gcccccatcc aggaggcccc agagctcagg gcgccggggc 85620agattctgaa cagccccgag tcacggtggg tacaactgga acgaccaccg tgagaaaaac 85680tgtgtccaaa actgtctcct ggcccctgct ggaggccgcg ccagagaggg gagcagccgc 85740cccgaaccta ggtcctgctc agctcacacg acccccagca cccagagcac aacggagtcc 85800ccattgaatg gtgaggacgg ggaccagggc tccagggggt catggaaggg gctggacccc 85860atcctactgc tatggtccca gtgctcctgg ccagaactga ccctaccacc gacaagagtc 85920cctcagggaa acgggggtca ctggcacctc ccagcatcaa ccccaggcag cacaggcata 85980aaccccacat ccagagccga ctccaggagc agagacaccc cagtaccctg ggggacaccg 86040accctgatga ctccccactg gaatccaccc cagagtccac caggaccaaa gaccccgccc 86100ctgtctctgt ccctcactca ggacctgctg cggggcgggc catgagacca gactcgggct 86160tagggaacac cactgtggcc ccaacctcga ccaggccaca ggcccttcct tcctgccctg 86220cggcagcaca gactttgggg tctgtgcaga gaggaatcac agaggcccca ggctgaggtg 86280gtgggggtgg aagaccccca ggaggtggcc cacttccctt cctcccagct ggaacccacc 86340atgaccttct taagataggg gtgtcatccg aggcaggtcc tccatggagc tcccttcagg 86400ctcctccccg gtcctcacta ggcctcagtc ccggctgcgg gaatgcagcc accacaggca 86460caccaggcag cccagaccca gccagcctgc agtgcccaag cccacattct ggagcagagc 86520aggctgtgtc tgggagagtc tgggctcccc accgcccccc cgcacacccc acccacccct 86580gtccaggccc tatgcaggag ggtcagagcc ccccatgggg tatggactta gggtctcact 86640cacgtggctc ccctcctggg tgaaggggtc tcatgcccag atccccacag cagagctggt 86700caaaggtgga ggcagtggcc ccagggccac cctgacctgg accctcaggc tcctctagcc 86760ctggctgccc tgctgtccct gggaggcctg gactccacca gaccacaggt ccagggcacc 86820gcccataggt gctgcccaca ctcagttcac aggaagaaga taagctccag acccccaaga 86880ctgggacctg ccttcctgcc accgcttgta gctccagacc tccgtgcctc ccccgaccac 86940ttacacacgg gccagggagc tgttccacaa agatcaaccc caaaccggga ccgcctggca 87000ctcgggccgc tgccacttcc ctctccattt gttcccagca cctctgtgct ccctccctcc 87060tccctccttc aggggaacag cctgtgcagc ccctccctgc accccacacc ctggggaggc 87120ccaaccctgc ctccagccct ttctcccccg ctgctcttcc tgcccatcca gacaaccctg 87180gggtcccatc cctgcagcct acaccctggt ctccacccag acccctgtct ctccctccag 87240acacccctcc caggccaacc ctgcacatgc aggccctccc cttttctgct gccagagcct 87300cagtttctac cctctgtgcc taccccctgc ctcctcctgc ccacaactcg agctcttcct 87360ctcctggggc ccctgagcca tggcactgac cgtgcactcc cacccccaca ctgcccatgc 87420cctcaccttc ctcctggaca ctctgacccc gctcccctct tggacccagc cctggtattt 87480ccaggacaaa ggctcaccca agtcttcccc atgcaggccc ttgccctcac tgcccggtta 87540cacggcagcc tcctgtgcac agaagcaggg agctcagccc ttccacaggc agaaggcact 87600gaaagaaatc ggcctccagc accctgatgc acgtccgcct gtgtctctca ctgcccgcac 87660ctgcagggag gctcggcact ccctgtaaag acgagggatc caggcagcaa catcatggga 87720gaatgcaggg ctcccagaca gcccagccct ctcgcaggcc tctcctggga agagacctgc 87780agccaccact gaacagccac ggagcccgct ggatagtaac tgagtcagtg accgacctgg 87840agggcagggg agcagtgaac cggagcccag accataggga cagagaccag ccgctgacat 87900cccgagcccc tcactggcgg ccccagaaca ccgcgtggaa acagaacaga cccacattcc 87960cacctggaac agggcagaca ctgctgagcc cccagcacca gccctgagaa acaccaggca 88020acggcatcag agggggctcc tgagaaagaa aggaggggag gtctccttca ccagcaagta 88080cttcccttga ccaaaaacag ggtccacgca actcccccag gacaaaggag gagccccctg 88140tacagcactg ggctcagagt cctctcccac acaccctgag tttcagacaa aaaccccctg 88200gaaatcatag tatcagcagg agaactagcc agagacagca agaggggact cagtgactcc 88260cgcggggaca ggaggatttt gtgggggctc gtgtcactgt gaggatattg tagtagtacc 88320agctgctata cccacagtga cacagcccca ttcccaaagc cctgctgtaa acgcttccac 88380ttctggagct gaggggctgg ggggagcgtc tgggaagtag ggcctagggg tggccatcaa 88440tgcccaaaac gcaccagact cccccccaga catcacccca ctggccagtg agcagagtaa 88500acagaaaatg agaagcagct gggaagcttg cacaggcccc aaggaaagag ctttggcggg 88560tgtgcaagag gggatgcggg cagagcctga gcagggcctt ttgctgtttc tgctttcctg 88620tgcagatagt tccataaact ggtgttcaag atcgatggct gggagtgagc ccaggaggac 88680agtgtgggaa gggcacaggg aaggagaagc agccgctatc ctacactgtc atctttcaag 88740agtttgccct gtgcccacaa tgctgcatca tgggatgctt aacagctgat gtagacacag 88800ctaaagagag aatcagtgaa atggatttgc agcacagatc tgaataaatt ctccagaatg 88860tggagccaca cagaagcaag cacaaggaaa gtgcctgatg caagggcaaa gtacagtgtg 88920taccttcagg ctgggcacag acactctgaa aagccttggc aggaactccc tgcaacaaag 88980cagagccctg caggcaatgc cagctccaga gccctccctg agagcctcat gggcaaagat 89040gtgcacaaca ggtgtttctc atagccccaa actgagaatg aagcaaacag ccatctgaag 89100gaaaacaggc aaataaacga tggcaggttc atgaaatgca aacccagaca gccagaagga 89160caacagtgag ggttacaggt gactctgtgg ttgagttcat gacaatgctg agtaattgga 89220gtaacaaagg aaagtccaaa aaatactttc aatgtgattt cttctaaata aaatttacag 89280ccggcaaaat gaactatctt cttaagggat aaactttcca ctaggaaaac tataaggaaa 89340atcaagaaaa ggatgatcac ataaacacag tggtcgttac ttctactggg gaaggaagag 89400ggtatgaact gagacacaca gggttggcaa gtctcctaac aagaacagaa caaatacatt 89460acagtacctt gaaaacagca gttaaaattc taaattgcaa gaagaggaaa atgcacacag 89520ctgtgtttag aaaattctca gtccagcact gttcataata gcaaagacat taacccaggt 89580tggataaata aacgatgaca caggcaattg cacaatgata cagacataca ttcagtatat 89640gagacattga tgatgtatcc ccaaagaaat gactttaaag agaaaaggcc tgatatgtgg 89700tggcactcac ctccctgggc atccccggac aggctgcagg cacactgtgt ggcagggcag 89760gctggtacct gctggcagct cctggggcct gatgtggagc aggcacagag ccgtatcccc 89820ccgaggacat atacccccaa ggacggcaca gttggtacat tccggagaca agcaactcag 89880ccacactccc aggccagagc ccgagaggga cgcccatgca cagggaggca gagcccagct 89940cctccacagc cagcagcacc cgtgcagggg ccgccatctg gcaggcacag agcatgggct 90000gggaggaggg gcagggacac caggcagggt tggcaccaac tgaaaattac agaagtctca 90060tacatctacc tcagccttgc ctgacctggg cctcacctga cctggacctc acctggcctg 90120gacctcacct ggcctagacc tcacctctgg gcttcacctg agctcggcct cacctgactt 90180ggaccttgcc tgtcctgagc tcacatgatc tgggcctcac ctgacctggg tttcacctga

90240cctgggcttc acctgacctg ggcctcatct gacctgggcc tcactggcct ggacctcacc 90300tggcctgggc ttcacctggc ctcaggcctc atctgcacct gctccaggtc ttgctggaac 90360ctcagtagca ctgaggctgc aggggctcat ccagggttgc agaatgactc tagaacctcc 90420cacatctcag ctttctgggt ggaggcacct ggtggcccag ggaatataaa aagcctgaat 90480gatgcctgcg tgatttgggg gcaatttata aacccaaaag gacatggcca tgcagcgggt 90540agggacaata cagacagata tcagcctgaa atggagcctc agggcacagg tgggcacgga 90600cactgtccac ctaagccagg ggcagacccg agtgtccccg cagtagacct gagagcgctg 90660ggcccacagc ctcccctcgg tgccctgcta cctcctcagg tcagccctgg acatcccggg 90720tttccccagg cctggcggta ggtttggggt gaggtctgtg tcactgtggt attacgattt 90780ttggagtggt tattataccc acagtgtcac agagtccatc aaaaacccat ccctgggaac 90840cttctgccac agccctccct gtggggcacc gccgcgtgcc atgttaggat tttgactgag 90900gacacagcac catgggtatg gtggctaccg cagcagtgca gcccgtgacc caaacacaca 90960gggcagcagg cacaacagac aagcccacaa gtgaccaccc tgagctcctg cctgccagcc 91020ctggagacca tgaaacagat ggccaggatt atcccatagg tcagccagac ctcagtccaa 91080caggtctgca tcgctgctgc cctccaatac cagtccggat ggggacaggg ctggcccaca 91140ttaccatttg ctgccatccg gccaacagtc ccagaagccc ctccctcaag gctgggccac 91200atgtgtggac cctgagagcc ccccatgtct gagtaggggc accaggaagg tggggctggc 91260cctgtgcact gtccctgccc ctgtggtccc tggcctgcct ggccctgaca cctgggcctc 91320tcctgggtca tttccaagac agaagacatt cccaggacag ctggagctgg gagtccatca 91380tcctgcctgg ccgtcctgag tcctgcgcct ttccaaacct cacccgggaa gccaacagag 91440gaatcacctc ccacaggcag agacaaagac cttccagaaa tctctgtctc tctccccagt 91500gggcaccctc ttccagggca gtcctcagtg atatcacagt gggaacccac atctggatcg 91560ggactgcccc cagaacacaa gatggcccac agggacagcc ccacagccca gcccttccca 91620gacccctaaa aggcgtccca ccccctgcat ctgccccagg gctcaaactc caggaggact 91680gactcctgca caccctcctg ccagacatca cctcagcccc tcctggaagg gacaggagcg 91740cgcaagggtg agtcagaccc tcctgccctc gatggcaggc ggagaagatt cagaaaggtc 91800tgagatcccc aggacgcagc accactgtca atgggggccc cagacgcctg gaccagggcc 91860tgcgtgggaa aggcctctgg gcacactcag gggctttttg tgaagggtcc tcctactgtg 91920tgactacagt aactaccaca gtgatgaacc cagcagcaaa aactgaccgg actcccaagg 91980tttatgcaca cttctccgct cagagctctc caggatcaga agagccgggc ccaagggttt 92040ctgcccagac cctcggcctc tagggacatc ttggccatga cagcccatgg gctggtgccc 92100cacacatcgt ctgccttcaa acaagggctt cagagggctc tgaggtgacc tcactgatga 92160ccacaggtgc cctggcccct tccccaccag ctgcaccaga ccccgtcatg acagatgccc 92220cgattccaac agccaattcc tggggccagg aatcgctgta gacaccagcc tccttccaac 92280acctcctgcc aattgcctgg attcccatcc cggttggaat caagaggaca gcatccccca 92340ggctcccaac aggcaggact cccacaccct cctctgagag gccgctgtgt tccgtagggc 92400caggctgcag acagtccccc tcacctgcca ctagacaaat gcctgctgta gatgtcccca 92460cctggaaaat accactcatg gagcccccag ccccaggtac agctgtagag agagtctctg 92520aggcccctaa gaagtagcca tgcccagttc tgccgggacc ctcggccagg ctgacaggag 92580tggacgctgg agctgggccc atactgggcc acataggagc tcaccagtga gggcaggaga 92640gcacatgccg gggagcaccc agcctcctgc tgaccagagg cccgtcccag agcccaggag 92700gctgcagagg cctctccagg gggacactgt gcatgtctgg tccctgagca gccccccacg 92760tccccagtcc tgggggcccc tggcacagct gtctggaccc tctctattcc ctgggaagct 92820cctcctgaca gccccgcctc cagttccagg tgtggttatt gtcagggggt gtcagactgt 92880ggtggataca gctatggtta ccacagtggt gctgcccata gcagcaacca ggccaagtag 92940acaggcccct gctgtgcagc cccaggcctc cagctcacct gcttctcctg gggctctcaa 93000ggctgctgtt ttctgcactc tcccctctgt ggggagggtt ccctcagtgg gagatctgtt 93060ctcaacatcc cacggcctca ttcctgcaag gaaggccaat ggatgggcaa cctcacatgc 93120cgcggctaag atagggtggg cagcctggcg gggacaggac atcctgctgg ggtatctgtc 93180actgtgccta gtggggcact ggctcccaaa caacgcagtc cttgccaaaa tccccacggc 93240ctcccccgct aggggctggc ctgatctcct gcagtcctag gaggctgctg acctccagaa 93300tggctccgtc cccagttcca gggcgagagc agatcccagg ccggctgcag actgggaggc 93360caccccctcc ttcccagggt tcactgcagg tgaccagggc aggaaatggc ctgaacacag 93420ggataaccgg gccatccccc aacagagtcc accccctcct gctctgtacc ccgcaccccc 93480caggccagcc catgacatcc gacaacccca caccagagtc actgcccggt gctgccctag 93540ggaggacccc tcagccccca ccctgtctag aggactgggg aggacaggac acgccctctc 93600cttatggttc ccccacctgg ctctggctgg gacccttggg gtgtggacag aaaggacgct 93660tgcctgattg gcccccagga gcccagaact tctctccagg gaccccagcc cgagcacccc 93720cttacccagg acccagccct gcccctcctc ccctctgctc tcctctcatc accccatggg 93780aatccagaat ccccaggaag ccatcaggaa gggctgaggg aggaagtggg gccactgcac 93840caccaggcag gaggctctgt ctttgtgaac ccagggaggt gccagcctcc tagagggtat 93900ggtccaccct gcctatggct cccacagtgg caggctgcag ggaaggacca gggacggtgt 93960gggggagggc tcagggcccc gcgggtgctc catcttggat gagcctatct ctctcaccca 94020cggactcgcc cacctcctct tcaccctggc cacacgtcgt ccacaccatc ctaagtccca 94080cctacaccag agccggcaca gccagtgcag acagaggctg gggtgcaggg gggccgactg 94140ggcagcttcg gggagggagg aatggaggaa ggggagttca gtgaagaggc ccccctcccc 94200tgggtccagg atcctcctct gggacccccg gatcccatcc cctccaggct ctgggaggag 94260aagcaggatg ggagaatctg tgcgggaccc tctcacagtg gaatacctcc acagcggctc 94320aggccagata caaaagcccc tcagtgagcc ctccactgca gtgctgggcc tgggggcagc 94380cgctcccaca caggatgaac ccagcacccc gaggatgtcc tgccaggggg agctcagagc 94440catgaaggag caggatatgg gacccccgat acaggcacag acctcagctc cattcaggac 94500tgccacgtcc tgccctggga ggaacccctt tctctagtcc ctgcaggcca ggaggcagct 94560gactcctgac ttggacgcct attccagaca ccagacagag gggcaggccc cccagaacca 94620gggatgagga cgccccgtca aggccagaaa agaccaagtt gcgctgagcc cagcaaggga 94680aggtccccaa acaaaccagg aagtttctga aggtgtctgt gtcacagtgg agtatagcag 94740ctcgtcccac agtgacactc gccaggccag aaaccccatc ccaagtcagc ggaatgcaga 94800gagagcaggg aggacatgtt taggatctga ggccgcacct gacacccagg ccagcagacg 94860tctcctgtcc acggcaccct gccatgtcct gcatttctgg aagaacaagg gcaggctgaa 94920gggggtccag gaccaggaga tgggtccgct ctacccagag aaggagccag gcaggacaca 94980agccccctcc ccattgaggc tgacctgccc agagggtcct gggcccaccc aacacaccgg 95040ggcggaatgt gtgcaggcct cggtctctgt gggtgttccg ctagctgggg ctcacagtgc 95100tcaccccaca cctaaaacga gccacagcct ccggagcccc tgaaggagac cccgcccaca 95160agcccagccc ccacccagga ggccccagag cacagggcgc cccgtcggat tctgaacagc 95220cccgagtcac agtgggtata actggaacta ccactgtgag aaaagcttcg tccaaaacgg 95280tctcctggcc acagtcggag gccccgccag agaggggagc agccacccca aacccatgtt 95340ctgccggctc ccatgacccc gtgcacctgg agccccacgg tgtccccact ggatgggagg 95400acaagggccg ggggctccgg cgggtcgggg caggggcttg atggcttcct tctgccgtgg 95460ccccattgcc cctggctgga gttgaccctt ctgacaagtg tcctcagaga gtcagggatc 95520agtggcacct cccaacatca accccacgca gcccaggcac aaaccccaca tccagggcca 95580actccaggaa cagagacacc ccaataccct gggggacccc gaccctgatg actcccgtcc 95640catctctgtc cctcacttgg ggcctgctgc ggggcgagca cttgggagca aactcaggct 95700taggggacac cactgtgggc ctgacctcga gcaggccaca gacccttccc tcctgccctg 95760gtgcagcaca gactttgggg tctgggcagg gaggaacttc tggcaggtca ccaagcacag 95820agcccccagg ctgaggtggc cccaggggga accccagcag gtggcccact acccttcctc 95880ccagctggac cccatgtctt ccccaagata ggggtgccat ccaaggcagg tcctccatgg 95940agcccccttc aggctcctct ccagacccca ctgggcctca gtccccactc taggaatgca 96000gccaccacgg gcacaccagg cagcccaggc ccagccaccc tgcagtgccc aagcccacac 96060cctggaggag agcagggtgc gtctgggagg ggctgggctc cccaccccca cccccacctg 96120cacaccccac ccacccttgc ccgggccccc tgcaggaggg tcagagcccc catgggatat 96180ggacttaggg tctcactcac gcacctcccc tcctgggaga aggggtctca tgcccagatc 96240cccccagcag cgctggtcac aggtagaggc agtggcccca gggccaccct gacctggccc 96300ctcaggctcc tctagccctg gctgccctgc tgtccctggg aggcctgggc tccaccagac 96360cacaggtcta gggcaccgcc cacactgggg ccgcccacac acagctcaca ggaagaagat 96420aagctccaga cccccaggcc cgggacctgc cttgctgcta cgacttcctg ccccagacct 96480cgttgccctc ccccgtccac ttacacacag gccaggaagc tgttcccaca cagaccaacc 96540ccagacgggg accacctggc actcaggtca ctgccatttc cttctccatt cacttccaat 96600gcctctgtgc ttcctccctc ctccttcctt cgggggagca ccctgtgcag ctcctccctg 96660cagtccacac cctggggaga cccgaccctg cagcccacac cctggggaga cctgaccctc 96720ctccagccct ttctcccccg ctgctcttgc cacccaccaa gacagccctg gggtcctgtc 96780cctacagccc ccacccagtt ctctacctag acccgtcttc ctccctctaa acacctctcc 96840caggccaacc ctacacctgc aggccctccc ctccactgcc aaagaccctc agtttctcct 96900gcctgtgccc acccccgtgc tcctcctgcc cacagctcga gctcttcctc tcctagggcc 96960cctgagggat ggcattgacc gtgccctcgc acccacacac tgcccatgcc ctcacattcc 97020tcctggccac tccagcccca ctcccctctc aggcctggct ctggtatttc tgggacaaag 97080ccttacccaa gtctttccca tgcaggcctg ggcccttacc ctcactgccc ggttacaggg 97140cagcctcctg tgcacagaag cagggagctc agcccttcca caggcagaag gcactgaaag 97200aaatcggcct ccagcgcctt gacacacgtc tgcctgtgtc tctcactgcc cgcacctgca 97260gggaggctcg gcactccctc taaagacgag ggatccaggc agcagcatca caggagaatg 97320cagggctacc agacatccca gtcctctcac aggcctctcc tgggaagaga cctgaagacg 97380cccagtcaac ggagtctaac accaaacctc cctggaggcc gatgggtagt aacggagtca 97440ttgccagacc tggaggcagg ggagcagtga gcccgagccc acaccatagg gccagaggac 97500agccactgac atcccaagcc actcactggt ggtcccacaa caccccatgg aaagaggaca 97560gacccacagt cccacctgga ccagggcaga gactgctgag acccagcacc agaaccaacc 97620aagaaacacc aggcaacagc atcagagggg gctctggcag aacagaggag gggaggtctc 97680cttcaccagc aggcgcttcc cttgaccgaa gacaggatcc atgcaactcc cccaggacaa 97740aggaggagcc ccttgttcag cactgggctc agagtcctct ccaagacacc cagagtttca 97800gacaaaaacc ccctggaatg cacagtctca gcaggagagc cagccagagc cagcaagatg 97860gggctcagtg acacccgcag ggacaggagg attttgtggg ggctcgtgtc actgtgagga 97920tattgtacta atggtgtatg ctatacccac agtgacacag ccccattccc aaagccctac 97980tgcaaacgca ttccacttct ggggctgagg ggctggggga gcgtctggga aatagggctc 98040aggggtgtcc atcaatgccc aaaacgcacc agactcccct ccatacatca cacccaccag 98100ccagcgagca gagtaaacag aaaatgagaa gcaagctggg gaagcttgca caggccccaa 98160ggaaagagct ttggcgggtg tgtaagaggg gatgcgggca gagcctgagc agggcctttt 98220gctgtttctg ctttcctgtg cagagagttc cataaactgg tgttcgagat caatggctgg 98280gagtgagccc aggaggacag cgtgggaaga gcacagggaa ggaggagcag ccgctatcct 98340acactgtcat ctttcgaaag tttgccttgt gcccacactg ctgcatcatg ggatgcttaa 98400cagctgatgt agacacagct aaagagagaa tcagtgagat ggatttgcag cacagatctg 98460aataaattct ccagaatgtg gagcagcaca gaagcaagca cacagaaagt gcctgatgca 98520aggacaaagt tcagtgggca ccttcaggca ttgctgctgg gcacagacac tctgaaaagc 98580cctggcagga actccctgtg acaaagcaga accctcaggc aatgccagcc ccagagccct 98640ccctgagagc ctcatgggca aagatgtgca caacaggtgt ttctcatagc cccaaactga 98700gagcaaagca aacgtccatc tgaaggagaa caggcaaata aacgatggca ggttcatgaa 98760atgcaaaccc agacagccac aagcacaaaa gtacagggtt ataagcgact ctggttgagt 98820tcatgacaat gctgagtaat tggagtaaca aagtaaactc caaaaaatac tttcaatgtg 98880atttcttcta aataaaattt acaccctgca aaatgaactg tcttcttaag ggatacattt 98940cccagttaga aaaccataaa gaaaaccaag aaaaggatga tcacataaac acagtggtgg 99000ttacttctgc tggggaagga agagggtatg aactgagata cacagggtgg gcaagtctcc 99060taacaagaac agaacgaata cattacagta ccttgaaaac agcagttaaa cttctaaatt 99120gcaagaagag gaaaatgcac acagttgtgt ttagaaaatt ctcagtccag cactgttcat 99180aatagcaaag acattaaccc aggtcggata aataagcgat gacacaggca attgcacaat 99240gatacagaca tatatttagt atatgagaca tcgatgatgt atccccaaat aaacgacttt 99300aaagagataa agggctgatg tgtggtggca ttcacctccc tgggatcccc ggacaggttg 99360caggctcact gtgcagcagg gcaggcgggt acctgctggc agttcctggg gcctgatgtg 99420gagcaagcgc agggccatat atcccggagg acggcacagt cagtgaattc cagagagaag 99480caactcagcc acactcccca ggcagagccc gagagggacg cccacgcaca gggaggcaga 99540gcccagcacc tccgcagcca gcaccacctg cgcacgggcc accaccttgc aggcacagag 99600tgggtgctga gaggaggggc agggacacca ggcagggtga gcacccagag aaaactgcag 99660acgcctcaca catccacctc agcctcccct gacctggacc tcactggcct gggcctcact 99720taacctgggc ttcacctgac cttggcctca cctgacttgg acctcgcctg tcccaagctt 99780tacctgacct gggcctcaac tcacctgaac gtctcctgac ctgggtttaa cctgtcctgg 99840aactcacctg gccttggctt cccctgacct ggacctcatc tggcctgggc ttcacctggc 99900ctgggcctca cctgacctgg acctcatctg gcctggacct cacctggcct ggacttcacc 99960tggcctgggc ttcacctgac ctggacctca cctggcctcg ggcctcacct gcacctgctc 100020caggtcttgc tggagcctga gtagcactga gggtgcagaa gctcatccag ggttggggaa 100080tgactctaga agtctcccac atctgacctt tctgggtgga ggcagctggt ggccctggga 100140atataaaaat ctccagaatg atgactctgt gatttgtggg caacttatga acccgaaagg 100200acatggccat ggggtgggta gggacatagg gacagatgcc agcctgaggt ggagcctcag 100260gacacaggtg ggcacggaca ctatccacat aagcgaggga tagacccgag tgtccccaca 100320gcagacctga gagcgctggg cccacagcct cccctcagag ccctgctgcc tcctccggtc 100380agccctggac atcccaggtt tccccaggcc tggcggtagg tttagaatga ggtctgtgtc 100440actgtggtat tacgatattt tgactggtta ttataaccac agtgtcacag agtccatcaa 100500aaacccatgc ctggaagctt cccgccacag ccctccccat ggggccctgc tgcctcctca 100560ggtcagcccc ggacatcccg ggtttcccca ggctgggcgg taggtttggg gtgaggtctg 100620tgtcactgtg gtattactat ggttcgggga gttattataa ccacagtgtc acagagtcca 100680tcaaaaaccc atccctggga gcctcccgcc acagccctcc ctgcagggga ccggtacgtg 100740ccatgttagg attttgatcg aggagacagc accatgggta tggtggctac cacagcagtg 100800cagcctgtga cccaaacccg cagggcagca ggcacgatgg acaggcccgt gactgaccac 100860gctgggctcc agcctgccag ccctggagat catgaaacag atggccaagg tcaccctaca 100920ggtcatccag atctggctcc gaggggtctg catcgctgct gccctcccaa cgccagtcca 100980aatgggacag ggacggcctc acagcaccat ctgctgccat caggccagcg atcccagaag 101040cccctccctc aaggctgggc acatgtgtgg acactgagag ccctcatatc tgagtagggg 101100caccaggagg gaggggctgg ccctgtgcac tgtccctgcc cctgtggtcc ctggcctgcc 101160tggccctgac acctgagcct ctcctgggtc atttccaaga cagaagacat tcctggggac 101220agccggagct gggcgtcgct catcctgccc ggccgtcctg agtcctgctc atttccagac 101280ctcaccgggg aagccaacag aggactcgcc tcccacattc agagacaaag aaccttccag 101340aaatccctgc ctctctcccc agtggacacc ctcttccagg acagtcctca gtggcatcac 101400agcggcctga gatccccagg acgcagcacc gctgtcaata ggggccccaa atgcctggac 101460cagggcctgc gtgggaaagg cctctggcca cactcgggct ttttgtgaag ggccctcctg 101520ctgtgtgact acagtaacta ccatagtgat gaacccagtg gcaaaaactg gctggaaacc 101580caggggctgt gtgcacgcct cagcttggag ctctccagga gcacaagagc cgggcccaag 101640gatttgtgcc cagaccctca gcctctaggg acacctgggt catctcagcc tgggctggtg 101700ccctgcacac catcttcctc caaatagggg cttcagaggg ctctgaggtg acctcactca 101760tgaccacagg tgacctggcc cttccctgcc agctatacca gaccctgtct tgacagatgc 101820cccgattcca acagccaatt cctgggaccc tgaatagctg tagacaccag cctcattcca 101880gtacctcctg ccaattgcct ggattcccat cctggctgga atcaagaagg cagcatccgc 101940caggctccca acaggcagga ctcccgcaca ccctcctctg agaggccgct gtgttccgca 102000gggccaggcc ctggacagtt cccctcacct gccactagag aaacacctgc cattgtcgtc 102060cccacctgga aaagaccact cgtggagccc ccagccccag gtacagctgt agagacagtc 102120ctcgaggccc ctaagaagga gccatgccca gttctgccgg gaccctcggc caggccgaca 102180ggagtggacg ctggagctgg gcccacactg ggccacatag gagctcacca gtgagggcag 102240gagagcacat gccggggagc acccagcctc ctgctgacca gaggcccgtc ccagagccca 102300ggaggctgca gaggcctctc cagggagaca ctgtgcatgt ctggtaccta agcagccccc 102360cacgtcccca gtcctggggg cccctggctc agctgtctgg gccctccctg ctccctggga 102420agctcctcct gacagccccg cctccagttc caggtgtggt tattgtcagg cgatgtcaga 102480ctgtggtgga tatagtggct acgattacca cagtggtgcc gcccatagca gcaaccaggc 102540caagtagaca ggcccctgct gcgcagcccc aggcatccac ttcacctgct tctcctgggg 102600ctctcaaggc tgctgtctgt cctctggccc tctgtgggga gggttccctc agtgggaggt 102660ctgtgctcca gggcagggat gattgagata gaaatcaaag gctggcaggg aaaggcagct 102720tcccgccctg agaggtgcag gcagcaccac ggagccacgg agtcacagag ccacggagcc 102780cccattgtgg gcatttgaga gtgctgtgcc cccggcaggc ccagccctga tggggaagcc 102840tgtcccatcc cacagcccgg gtcccacggg cagcgggcac agaagctgcc aggttgtcct 102900ctatgatcct catccctcca gcagcatccc ctccacagtg gggaaactga ggcttggagc 102960accacccggc cccctggaaa tgaggctgtg agcccagaca gtgggcccag agcactgtga 103020gtaccccggc agtacctggc tgcagggatc agccagagat gccaaaccct gagtgaccag 103080cctacaggag gatccggccc cacccaggcc actcgattaa tgctcaaccc cctgccctgg 103140agacctcttc cagtaccacc agcagctcag cttctcaggg cctcatccct gcaaggaagg 103200tcaagggctg ggcctgccag aaacacagca ccctccctag ccctggctaa gacagggtgg 103260gcagacggct gtggacggga catattgctg gggcatttct cactgtcact tctgggtggt 103320agctctgaca aaaacgcaga ccctgccaaa atccccactg cctcccgcta ggggctggcc 103380tggaatcctg ctgtcctagg aggctgctga cctccaggat ggctccgtcc ccagttccag 103440ggcgagagca gatcccaggc aggctgtagg ctgggaggcc acccctgccc ttgccggggt 103500tgaatgcagg tgcccaaggc aggaaatggc atgagcacag ggatgaccgg gacatgcccc 103560accagagtgc gccccttcct gctctgcacc ctgcaccccc caggccagcc cacgacgtcc 103620aacaactggg cctgggtggc agccccaccc agacaggaca gacccagcac cctgaggagg 103680tcctgccagg gggagctaag agccatgaag gagcaagata tggggccccc gatacaggca 103740cagatgtcag ctccatccag gaccacccag cccacaccct gagaggaacg tctgtctcca 103800gcctctgcag gtcgggaggc agctgacccc tgacttggac ccctattcca gacaccagac 103860agaggcgcag gccccccaga accagggttg agggacgccc cgtcaaagcc agacaaaacc 103920aaggggtgtt gagcccagca agggaaggcc cccaaacaga ccaggaggtt tctgaaggtg 103980tctgtgtcac agtggggtat agcagcagct ggtaccacag tgacactcac ccagccagaa 104040accccattcc aagtcagcgg aagcagagag agcagggagg acacgtttag gatctgagac 104100tgcacctgac acccaggcca gcagacgtct cccctccagg gcaccccacc ctgtcctgca 104160tttctgcaag atcaggggcg gcctgagggg gggtctaggg tgaggagatg ggtcccctgt 104220acaccaagga ggagttaggc aggtcccgag cactctcccc attgaggctg acctgcccag 104280agagtcctgg gcccacccca cacaccgggg cggaatgtgt gcaggcctcg gtctctgtgg 104340gtgttccgct agctggggct cacagtgctc accccacacc taaaatgagc cacagcctcc 104400ggagcccccg caggagaccc cgcccacaag cccagccccc acccaggagg ccccagagct 104460cagggcgccc cgtcggattc cgaacagccc cgagtcacag cgggtataac cggaaccacc 104520actgtcagaa tagctacgtc aaaaactgtc cagtggccac tgccggaggc cccgccagag 104580agggcagcag ccactctgat cccatgtcct gccggctccc atgaccccca gcacgcggag 104640ccccacagtg tccccactgg atgggaggac aagagctggg gattccggcg ggtcggggca 104700ggggcttgat cgcatccttc tgccgtggct ccagtgcccc tggctggagt tgacccttct 104760gacaagtgtc ctcagagaga caggcatcac cggcgcctcc caacatcaac cccaggcagc 104820acaggcacaa accccacatc cagagccaac tccaggagca gagacacccc aataccctgg 104880gggaccccga ccctgatgac ttcccactgg aattcgccgt agagtccacc aggaccaaag 104940accctgcctc tgcctctgtc cctcactcag gacctgctgc cgggcgaggc cttgggagca 105000gacttgggct taggggacac cagtgtgacc ccgaccttga ccaggacgca gacctttcct 105060tcctttcctg gggcagcaca gactttgggg tctgggccag gaggaacttc tggcaggtcg 105120ccaagcacag aggccacagg ctgaggtggc cctggaaaga cctccaggag gtggccactc 105180cccttcctcc cagctggacc ccatgtcctc cccaagataa gggtgccatc caaggcaggt 105240gctccttgga gccccattca gactcctccc tggaccccac tgggcctcag tcccagctct

105300ggggatgaag ccaccacaag cacaccaggc agcccaggcc cagccaccct gcagtgccca 105360agcacacact ctggagcaga gcagggtgcc tctgggaggg gctgagctcc ccaccccacc 105420cccacctgca caccccaccc acccctgccc agcggctctg caggagggtc agagccccac 105480atggggtatg gacttagggt ctcactcacg tggctcccat catgagtgaa ggggcctcaa 105540gcccaggttc ccacagcagc gcctgtcgca agtggaggca gaggcccgag ggccaccctg 105600acctggtccc tgaggttcct gcagcccagg ctgccctgct gtccctggga ggcctgggct 105660ccaccagacc acaggtccag ggcaccgggt gcaggagcca cccacacaca gctcacagga 105720agaagataag ctccagaccc ccagggccag aacctgcctt cctgctactg cttcctgccc 105780cagacctggg cgccctcccc cgtccactta cacacaggcc aggaagctgt tcccacacag 105840aacaacccca aaccaggacc gcctggcact caggtggctg ccatttcctt ctccatttgc 105900tcccagcgcc tctgtcctcc ctggttcctc cttcggggga acagcctgtg cagccagtcc 105960ctgcagccca caccctgggg agacccaacc ctgcctgggg cccttccaac cctgctgctc 106020ttactgccca cccagaaaac tctggggtcc tgtccctgca gtccctaccc tggtctccac 106080ccagacccct gtgtatcact ccagacaccc ctcccaggca aaccctgcac ctgcaggccc 106140tgtcctcttc tgtcgctaga gcctcagttt ctcccccctg tgcccacacc ctacctcctc 106200ctgcccacaa ctctaactct tcttctcctg gagcccctga gccatggcat tgaccctgcc 106260ctcccaccac ccacagccca tgccctcacc ttcctcctgg ccactccgac cccgccccct 106320ctcaggccaa gccctggtat ttccaggaca aaggctcacc caagtctttc ccaggcaggc 106380ctgggctctt gccctcactt cccggttaca cgggagcctc ctgtgcacag aagcagggag 106440ctcagccctt ccacaggcag aaggcactga aagaaatcgg cctccagcac cttgacacac 106500gtccgcccgt gtctctcact gcccgcacct gcagggaggc tccgcactcc ctctaaagac 106560aagggatcca ggcagcagca tcacgggaga atgcagggct cccagacatc ccagtcctct 106620cacaggcctc tcctgggaag agacctgcag ccaccaccaa acagccacag aggctgctgg 106680atagtaactg agtcaatgac cgacctggag ggcaggggag cagtgagccg gagcccatac 106740catagggaca gagaccagcc gctgacatcc cgagctcctc aatggtggcc ccataacaca 106800cctaggaaac ataacacacc cacagcccca cctggaacag ggcagagact gctgagcccc 106860cagcaccagc cccaagaaac accaggcaac agtatcagag ggggctcccg agaaagagag 106920gaggggagat ctccttcacc atcaaatgct tcccttgacc aaaaacaggg tccacgcaac 106980tcccccagga caaaggagga gccccctata cagcactggg ctcagagtcc tctctgagac 107040accctgagtt tcagacaaca acccgctgga atgcacagtc tcagcaggag aacagaccaa 107100agccagcaaa agggacctcg gtgacaccag tagggacagg aggattttgt gggggctcgt 107160gtcactgtga ggatattgta gtggtggtag ctgctactcc cacagtgaca cagacccatt 107220cccaaagccc tactgcaaac acacccactc ctggggctga ggggctgggg gagcgtctgg 107280gaagtagggt ccaggggtgt ctatcaatgt ccaaaatgca ccagactccc cgccaaacac 107340caccccacca gccagcgagc agggtaaaca gaaaatgaga ggctctggga agcttgcaca 107400ggccccaagg aaagagcttt ggcgggtgtg caagagggga tgcaggcaga gcctgagcag 107460ggccttttgc tgtttctgct ttcctgtgca gagagttcca taaactggtg ttcaagatca 107520gtggctggga atgagcccag gagggcagtc tgtgggaaga gcacagggaa ggaggagcag 107580ccgctatcct acactgtcat ctttcaaaag tttgccttgt gaccacacta ttgcatcatg 107640ggatgcttaa gagctgatgt agacacagct aaagagagaa tcagtgagat gaatttgcag 107700catagatctg aataaactct ccagaatgtg gagcagtaca gaagcaaaca cacagaaagt 107760gcctgatgca aggacaaagt tcagtgggca ccttcaggca ttgctgctgg gcacagacac 107820tctgaaaagc cttggcagga tctccctgcg acaaagcaga accctcaggc aatgccagcc 107880ccagagccct ccctgagagc gtcatgggga aagatgtgca gaacagctga ttatcataga 107940ctcaaactga gaacagagca aacgtccatc tgaagaacag tcaaataagc aatggtaggt 108000tcatgcaatg caaacccaga cagccagggg acaacagtag agggctacag gcggctttgc 108060ggttgagttc atgacaatgc tgagtaattg gagtaacaga ggaaagccca aaaaatactt 108120ttaatgtgat ttcttctaaa taaaatttac accaggcaaa atgaactgtc ttcttaaggg 108180ataaactttc ccctggaaaa actacaagga aaattaagaa aacgatgatc acataaacac 108240agttgtggtt acttctactg gggaaggaag agggtatgag ctgagacaca cagagtcggc 108300aagtctccaa gcaagcacag aacgaataca ttacagtacc ttgaatacag cagttaaact 108360tctaaatcgc aagaacagga aaatgcacac agctgtgttt agaaaattct cagtccagca 108420ctattcataa tagcaaagac attaacccag gttggataaa taaatgatga cacaggcaat 108480tgcacaatga tacagacata catttagtac atgagacatc gatgatgtat ccccaaagaa 108540atgactttaa agagaaaagg cctgatgtgt ggtggcactc acctccctgg gatccccgga 108600caggttgcag gcacactgtg tggcagggca ggctggtaca tgctggcagc tcctggggcc 108660tgatgtggag caagcgcagg gctgtatacc cccaaggatg gcacagtcag tgaattccag 108720agagaagcag ctcagccaca ctgcccaggc agagcccgag agggacgccc acgtacaggg 108780aggcagagcc cagctcctcc acagccacca ccacctgtgc acgggccacc accttgcagg 108840cacagagtgg gtgctgagag gaggggcagg gacaccaggc agggtgagca cccagagaaa 108900actgcagaag cctcacacat ccacctcagc ctcccctgac ctggacctca cctggtctgg 108960acctcacctg gcctgggcct cacctgacct ggacctcacc tggcctgggc ttcacctgac 109020ctggacctca cctggcctcc ggcctcacct gcacctgctc caggtcttgc tggaacctga 109080gtagcactga ggctgcagaa gctcatccag ggttggggaa tgactctgga actctcccac 109140atctgacctt tctgggtgga ggcatctggt ggccctggga atataaaaag ccccagaatg 109200gtgcctgcgt gatttggggg caatttatga acccgaaagg acatggccat ggggtgggta 109260gggacatagg gacagatgcc agcctgaggt ggagcctcag gacacagttg gacgcggaca 109320ctatccacat aagcgaggga cagacccgag tgttcctgca gtagacctga gagcgctggg 109380cccacagcct cccctcggtg ccctgctgcc tcctcaggtc agccctggac atcccgggtt 109440tccccaggcc agatggtagg tttgaagtga ggtctgtgtc actgtggtat tatgattacg 109500tttgggggag ttatcgttat acccacagca tcacacggtc catcagaaac ccatgccaca 109560gccctccccg caggggaccg ccgcgtgcca tgttacgatt ttgatcgagg acacagcgcc 109620atgggtatgg tggctaccac agcagtgcag cccatgaccc aaacacacag ggcagcaggc 109680acaatggaca ggcctgtgag tgaccatgct gggctccagc ccgccagccc cggagaccat 109740gaaacagatg gccaaggtca ccccacagtt cagccagaca tggctccgtg gggtctgcat 109800cgctgctgcc ctctaacacc agcccagatg gggacaaggc caaccccaca ttaccatctc 109860ctgctgtcca cccagtggtc ccagaagccc ctccctcatg gctgagccac atgtgtgaac 109920cctgagagca ccccatgtca gagtaggggc agcagaaggg cggggctggc cctgtgcact 109980gtccctgcac ccatggtccc tcgcctgcct ggccctgaca cctgagcctc ttctgagtca 110040tttctaagat agaagacatt cccggggaca gccggagctg ggcgtcgctc atcccgcccg 110100gccgtcctga gtcctgcttg tttccagacc tcaccaggga agccaacaga ggactcacct 110160cacacagtca gagacaaaga accttccaga aatccctgtc tcactcccca gtgggcacct 110220tcttccagga cattcctcgg tcgcatcaca gcaggcaccc acatctggat caggacggcc 110280cccagaacac aagatggccc atggggacag ccccacaacc caggccttcc cagaccccta 110340aaaggcgtcc caccccctgc acctgcccca gggctaaaaa tccaggaggc ttgactcccg 110400cataccctcc agccagacat cacctcagcc ccctcctgga ggggacagga gcccgggagg 110460gtgagtcaga cccacctgcc ctcgatggca ggcggggaag attcagaaag gcctgagatc 110520cccaggacgc agcaccactg tcaatggggg ccccagacgc ctggaccagg gcctgcgtgg 110580gaaaggccgc tgggcacact caggggcttt ttgtgaaggc ccctcctact gtgtgactac 110640ggtgactacc acagtgatga aactagcagc aaaaactggc cggacaccca gggaccatgc 110700acacttctca gcttggagct ctccaggacc agaagagtca ggtctgaggg tttgtagcca 110760gaccctcggc ctctagggac accctggcca tcacagcgga tgggctggtg ccccacatgc 110820catctgctcc aaacaggggc ttcagagggc tctgaggtga cttcactcat gaccacaggt 110880gccctggccc cttccccgcc agctacaccg aaccctgtcc caacagctgc cccagttcca 110940acagccaatt cctggggccc agaattgctg tagacaccag cctcgttcca gcacctcctg 111000ccaattgcct ggattcacat cctggctgga atcaagaggg cagcatccgc caggctccca 111060acaggcagga ctcccgcaca ccctcctctg agaggccgct gtgttccgca gggccaggcc 111120ctggacagtt cccctcacct gccactagag aaacacctgc cattgtcgtc cccacctgga 111180aaagaccact cgtggagccc ccagccccag gtacagctgt agagagactc cccgagggat 111240ctaagaagga gccatgcgca gttctgccgg gaccctcggc caggccgaca ggagtggaca 111300ctggagctgg gcccacactg ggccacatag gagctcacca gtgagggcag gagagcacat 111360gccggggagc acccagcctc ctgctgacca gaggcccgtc ccagagccca ggaggctgca 111420gaggcctctc cagggggaca ctgtgcatgt ctggtccctg agcagccccc cacgtcccca 111480gtcctggggg cccctggcac agctgtctgg accctccctg ttccctggga agctcctcct 111540gacagccccg cctccagttc caggtgtggt tattgtcagg gggtgtcaga ctgtggtgga 111600tacagctatg gttaccacag tggtgctgcc catagcagca accaggccaa gtagacaggc 111660ccctgctgtg cagccccagg cctccacttc acctgcttct cctggggctc tcaaggtcac 111720tgttgtctgt actctgccct ctgtggggag ggttccctca gtgggaggtc tgttctcaac 111780atcccagggc ctcatgtctg cacggaaggc caatggatgg gcaacctcac atgccgcggc 111840taagataggg tgggcagcct ggcgggggac agtacatact gctggggtgt ctgtcactgt 111900gcctagtggg gcactggctc ccaaacaacg cagtcctcgc caaaatcccc acagcctccc 111960ctgctagggg ctggcctgat ctcctgcagt cctaggaggc tgctgacctc cagaatgtct 112020ccgtccccag ttccagggcg agagcagatc ccaggccggc tgcagactgg gaggccaccc 112080cctccttccc agggttcact ggaggtgacc aaggtaggaa atggccttaa cacagggatg 112140actgcgccat cccccaacag agtcagcccc ctcctgctct gtaccccgca ccccccaggc 112200cagtccacga aaaccagggc cccacatcag agtcactgcc tggcccggcc ctggggcgga 112260cccctcagcc cccaccctgt ctagaggact tggggggaca ggacacaggc cctctcctta 112320tggttccccc acctgcctcc ggccgggacc cttggggtgt ggacagaaag gacacctgcc 112380taattggccc ccaggaaccc agaacttctc tccagggacc ccagcccgag caccccctta 112440cccaggaccc agccctgccc ctcctcccct ctgctctcct ctcatcaccc catgggaatc 112500cggtatcccc aggaagccat caggaagggc tgaaggagga agcggggccg tgcaccaccg 112560ggcaggaggc tccgtcttcg tgaacccagg gaagtgccag cctcctagag ggtatggtcc 112620accctgcctg gggctcccac cgtggcaggc tgcggggaag gaccagggac ggtgtggggg 112680agggctcagg gccctgcggg tgctcctcca tcttcggtga gcctccccct tcacccaccg 112740tcccgcccac ctcctctcca ccctggctgc acgtcttcca caccatcctg agtcctacct 112800acaccagagc cagcaaagcc agtgcagaca aaggctgggg tgcagggggg ctgccagggc 112860agcttcgggg agggaaggat ggagggaggg gaggtcagtg aagaggcccc cttcccctgg 112920gtccaggatc ctcctctggg acccccggat cccatcccct cctggctctg ggaggagaag 112980caggatggga gaatctgtgc gggaccctct cacagtggaa tatccccaca gcggctcagg 113040ccagacccaa aagcccctca gtgagccctc cactgcagtc ctgggcctgg gtagcagccc 113100ctcccacaga ggacagaccc agcaccccga agaagtcctg ccagggggag ctcagagcca 113160tgaaagagca ggatatgggg tccccgatac aggcacagac ctcagctcca tccaggccca 113220ccgggaccca ccatgggagg aacacctgtc tccgggttgt gaggtagctg gcctctgtct 113280cggaccccac tccagacacc agacagaggg gcaggccccc caaaaccagg gttgagggat 113340gatccgtcaa ggcagacaag accaaggggc actgacccca gcaagggaag gctcccaaac 113400agacgaggag gtttctgaag ctgtctgtat cacagtgggg tatagcagtg gctggtacca 113460cagtgacact cgccaggcca gaaaccccgt cccaagtcag cggaagcaga gagagcaggg 113520aggacacgtt taggatctga ggccgcacct gacacccagg gcagcagacg tctcccctcc 113580agggcaccct ccaccgtcct gcgtttcttc aagaataggg gcggcctgag ggggtccagg 113640gccaggcgat aggtcccctc taccccaagg aggagccagg caggacccga gcaccgtccc 113700cattgaggct gacctgccca gacgggcctg ggcccacccc acacaccggg gcggaatgtg 113760tgcaggcccc agtctctgtg ggtgttccgc tagctggggc ccccagtgct caccccacac 113820ctaaagcgag ccccagcctc cagagccccc taagcattcc ccgcccagca gcccagcccc 113880tgcccccacc caggaggccc cagagctcag ggcgcctggt cggattctga acagccccga 113940gtcacagtgg gtataactgg aacgaccacc gtgagaaaaa ctgtgtccaa aactgactcc 114000tggcagcagt cggaggcccc gccagagagg ggagcagccg gcctgaaccc atgtcctgcc 114060ggttcccatg acccccagca cccagagccc cacggtgtcc ccgttggata atgaggacaa 114120gggctggggg ctccggtggt ttgcggcagg gacttgatca catccttctg ctgtggcccc 114180attgcctctg gctggagttg acccttctga caagtgtcct cagaaagaca gggatcaccg 114240gcacctccca atatcaaccc caggcagcac agacacaaac cccacatcca gagccaactc 114300caggagcaga gacaccccaa cactctgggg gaccccaacc gtgataactc cccactggaa 114360tccgccccag agtctaccag gaccaaaggc cctgccctgt ctctgtccct cactcagggc 114420ctcctgcagg gcgagcgctt gggagcagac tcggtcttag gggacaccac tgtgggcccc 114480aactttgatg aggccactga cccttccttc ctttcctggg gcagcacaga ctttggggtc 114540tgggcaggga agaactactg gctggtggcc aatcacagag cccccaggcc gaggtggccc 114600caagaaggcc ctcaggaggt ggccactcca cttcctccca gctggacccc aggtcctccc 114660caagataggg gtgccatcca aggcaggtcc tccatggagc ccccttcaga ctcctcccgg 114720gaccccactg gacctcagtc cctgctctgg gaatgcagcc accacaagca caccaggaag 114780cccaggccca gccaccctgc agtgggcaag cccacactct ggagcagagc agggtgcgtc 114840tgggaggggc taacctcccc accccccacc ccccatctgc acacagccac ctaccactgc 114900ccagaccctc tgcaggaggg ccaagccacc atggggtatg gacttagggt ctcactcacg 114960tgcctcccct cctgggagaa ggggcctcat gcccagatcc ctgcagcact agacacagct 115020ggaggcagtg gccccagggc caccctgacc tggcatctaa ggctgctcca gcccagacag 115080cactgccgtt cctgggaagc ctgggctcca ccagaccaca ggtccagggc acagcccaca 115140ggagccaccc acacacagct cacaggaaga agataagctc cagaccccag ggcgggacct 115200gccttcctgc caccacttac acacaggcca gggagctgtt cccacacaga tcaaccccaa 115260accgggactg cctggcacta gggtcactgc catttccctc tccattccct cccagtgcct 115320ctgtgctccc tccttctggg gaacaccctg tgcagcccct ccctgcagcc cacacgctgg 115380ggagacccca ccctgcctcg ggccttttct acctgctgca cttgccgccc acccaaacaa 115440ccctgggtac gtgaccctgc agtcctcacc ctgatctgca accagacccc tgtccctccc 115500tctaaacacc cctcccaggc caactctgca cctgcaggcc ctccgctctt ctgccacaag 115560agcctcaggt tttcctacct gtgcccaccc cctaacccct cctgcccaca acttgagttc 115620ttcctctcct ggagcccttg agccatggca ctgaccctac actcccaccc acacactgcc 115680catgccatca ccttcctcct ggacactctg accccgctcc cctccctctc agacccggcc 115740ctggtatttc caggacaaag gctcacccaa gtcttcccca tgcaggccct tgccctcact 115800gcctggttac acgggagcct cctgtgcgca gaagcaggga gctcagctct tccacaggca 115860gaaggcactg aaagaaatca gcctccagtg ccttgacaca cgtccgcctg tgtctctcac 115920tgcctgcacc tgcagggagg ctccgcactc cctctaaaga tgagggatcc aggcagcaac 115980atcacgggag aatgcagggc tcccagacag cccagccctc tcgcaggcct ctcctgggaa 116040gagacctgca gccaccactg aacagccacg gaggtcgctg gatagtaacc gagtcagtga 116100ccgacctgga gggcagggga gcagtgaacc ggagcccata ccatagggac agagaccagc 116160cgctaacatc ccgagcccct cactggcggc cccagaacac cccgtggaaa gagaacagac 116220ccacagtccc acctggaaca gggcagacac tgctgagccc ccagcaccag ccccaagaaa 116280cactaggcaa cagcatcaga gggggctcct gagaaagaga ggaggggagg tctccttcac 116340catcaaatgc ttcccttgac caaaaacagg gtccacgcaa ctcccccagg acaaaggagg 116400agccccctgt acagcactgg gctcagagtc ctctctgaga caggctcagt ttcagacaac 116460aacccgctgg aatgcacagt ctcagcagga gagccaggcc agagccagca agaggagact 116520cggtgacacc agtctcctgt agggacagga ggattttgtg ggggttcgtg tcactgtgag 116580catattgtgg tggtgactgc tattcccaca gtgacacaac cccattccta aagccctact 116640gcaaacgcac ccactcctgg gactgagggg ctgggggagc gtctgggaag tatggcctag 116700gggtgtccat caatgcccaa aatgcaccag actctcccca agacatcacc ccaccagcca 116760gtgagcagag taaacagaaa atgagaagca gctgggaagc ttgcacaggc cccaaggaaa 116820gagctttggc aggtgtgcaa gaggggatgt gggcagagcc tcagcagggc cttttgctgt 116880ttctgctttc ctgtgcagag agttccataa actggtattc aagatcaatg gctgggagtg 116940agcccaggag gacagtgtgg gaagagcaca gggaaggagg agcagccgct atcctacact 117000gtcatctttt gaaagtttgc cctgtgccca caatgctgca tcatgggatg cttaacagct 117060gatgtagaca cagctaaaga gagaatcagt gaaatgcatt tgcagcacag atctgaataa 117120atcctccaga atgtggagca gcacagaagc aagcacacag aaagtgcctg atgccaaggc 117180aaagttcagt gggcaccttc aggcattgct gctgggcaca gacactctga aaagcactgg 117240caggaactgc ctgtgacaaa gcagaaccct caggcaatgc cagccctaga gcccttcctg 117300agaacctcat gggcaaagat gtgcagaaca gctgtttgtc atagccccaa actatggggc 117360tggacaaagc aaacgtccat ctgaaggaga acagacaaat aaacgatggc aggttcatga 117420aatgcaaact aggacagcca gaggacaaca gtagagagct acaggcggct ttgcggttga 117480gttcatgaca atgctgagta attggagtaa cagaggaaag cccaaaaaat acttttaatg 117540tgatttcttc taaataaaat ttacacccgg caaaatgaac tatcttctta agggataaac 117600tttcccctgg aaaaactata aggaaaatca agaaaacgat gatcacataa acacagtggt 117660ggttacttct actggggaag gaagagggta tgagctgaga cacacagagt cggcaagtct 117720cctaacaaga acagaacaaa tacattacag taccttgaaa acagcagtta aacttctaaa 117780tcgcaagaag aggaaaatgc acacacctgt gtttagaaaa ttctcagtcc agcactgttc 117840ataatagcaa agacattaac ccaggttgga taaataagcg atgacacagg caattgcaca 117900atgatacaga catacattca gtatatgaga catcgatgat gtatccccaa agaaatgact 117960ttaaagagaa aaggcctgat gtgtggtggc aatcacctcc ctgggcatcc ccggacaggc 118020tgcaggctca ctgtgtggca gggcaggcag gcacctgctg gcagctcctg gggcctgatg 118080tggagcaggc acagagctgt atatccccaa ggaaggtaca gtcagtgcat tccagagaga 118140agcaactcag ccacactccc tggccagaac ccaagatgca cacccatgca cagggaggca 118200gagcccagca cctccgcagc caccaccacc tgcgcacggg ccaccacctt gcaggcacag 118260agtgggtgct gagaggaggg gcagggacac caggcagggt gagcacccag agaaaactgc 118320agaagcctca cacatccacc tcagcctccc ctgacctgga cctcacctgg cctgggcctc 118380acctgacctg gacctcacct ggcctgggct tcacctggcc tgggcttcac ctgacctgga 118440cctcacctgg cctcgggcct cacctggcct gggcttcacc tggcctgggc ttcacctgac 118500ctggacctca cctggcctgg gcctcacctg acctggacct cacctggcct gggcttcacc 118560tggcctgggc ttcacctggc ctgggcttca cctgacctgg acctcacctg gcctgggctt 118620cacctgacct ggacctcacc tggcctcggg cctcacctgc acctgctcca ggtcttgctg 118680gagcctgagt agcactgagg ctgtagggac tcatccaggg ttggggaatg actctgcaac 118740tctcccacat ctgacctttc tgggtggagg cacctggtgg cccagggaat ataaaaagcc 118800ccagaatgat gcctgtgtga tttgggggca atttatgaac ccgaaaggac atggccatgg 118860ggtgggtagg gacagtaggg acagatgtca gcctgaggtg aagcctcagg acacaggtgg 118920gcatggacag tgtccaccta agcgagggac agacccgagt gtccctgcag tagacctgag 118980agcgctgggc ccacagcctc ccctcggggc cctgctgcct cctcaggtca gccctggaca 119040tcccgggttt ccccaggcct ggcggtaggt ttgaagtgag gtctgtgtca ctgtggtatt 119100actatgatag tagtggttat tactaccaca gtgtcacaga gtccatcaaa aactcatgcc 119160tgggagcctc ccaccacagc cctccctgcg ggggaccgct gcatgccgtg ttaggatttt 119220gatcgaggac acggcgccat gggtatggtg gctaccacag cagtgcagcc catgacccaa 119280acacacgggg cagcagaaac aatggacagg cccacaagtg accatgatgg gctccagccc 119340accagcccca gagaccatga aacagatggc caaggtcacc ctacaggtca tccagatctg 119400gctccaaggg gtctgcatcg ctgctgccct cccaacgcca aaccagatgg agacagggcc 119460ggccccatag caccatctgc tgccgtccac ccagcagtcc cggaagcccc tccctgaacg 119520ctgggccacg tgtgtgaacc ctgcgagccc cccatgtcag agtaggggca gcaggagggc 119580ggggctggcc ctgtgcactg tcactgcccc tgtggtccct ggcctgcctg gccctgacac 119640ctgagcctct cctgggtcat ttccaagaca ttcccaggga cagccggagc tgggagtcgc 119700tcatcctgcc tggctgtcct gagtcctgct catttccaga cctcaccagg gaagccaaca 119760gaggactcac ctcacacagt cagagacaac gaaccttcca gaaatccctg tttctctccc 119820cagtgagaga aaccctcttc cagggtttct cttctctccc accctcttcc aggacagtcc 119880tcagcagcat cacagcggga acgcacatct ggatcaggac ggcccccaga acacgcgatg 119940gcccatgggg acagcccagc ccttcccaga cccctaaaag gtatccccac cttgcacctg 120000ccccagggct caaactccag gaggcctgac tcctgcacac cctcctgcca gatatcacct 120060cagccccctc ctggagggga caggagcccg ggagggtgag tcagacccac ctgccctcaa 120120tggcaggcgg ggaagattca gaaaggcctg agatccccag gacgcagcac cactgtcaat 120180gggggcccca gacgcctgga ccagggcctg tgtgggaaag gcctctggcc acactcaggg 120240gctttttgtg aagggccctc ctgctgtgtg actacggtgg taactcccac agtgatgaaa 120300ccagcagcaa aaactgaccg gactcgcagg gtttatgcac acttctcggc tcggagctct

120360ccaggagcac aagagccagg cccgagggtt tgtgcccaga ccctcggcct ctagggacac 120420ccgggccatc ttagccgatg ggctgatgcc ctgcacaccg tgtgctgcca aacaggggct 120480tcagagggct ctgaggtgac ttcactcatg accacaggtg ccctggtccc ttcactgcca 120540gctgcaccag accctgttcc gagagatgcc ccagttccaa aagccaattc ctggggccgg 120600gaattactgt agacaccagc ctcattccag tacctcctgc caattgcctg gattcccatc 120660ctggctggaa tcaagagggc agcatccgcc aggctcccaa caggcaggac tcccacacac 120720cctcctctga gaggccgctg tgttccgcag ggccaggccg cagacagttc ccctcacctg 120780cccatgtaga aacacctgcc attgtcgtcc ccacctggca aagaccactt gtggagcccc 120840cagccccagg tacagctgta gagagagtcc tcgaggcccc taagaaggag ccatgcccag 120900ttctgccggg accctcggcc aggccgacag gagtggacgc tggagctggg cccacactgg 120960gccacatagg agctcaccag tgagggcagg agagcacatg ccggggagca cccagcctcc 121020tgctgaccag agacccgtcc cagagcccag gaggctgcag aggcctctcc agggggacac 121080agtgcatgtc tggtccctga gcagccccca ggctctctag cactgggggc ccctggcaca 121140gctgtctgga ccctccctgt tccctgggaa gctcctcctg acagccccgc ctccagttcc 121200aggtgtggtt attgtcaggg ggtgccaggc cgtggtagag atggctacaa ttaccacagt 121260ggtgccgccc atagcagcaa ccaggccaag tagacagacc cctgccacgc agccccaggc 121320ctccagctca cctgcttctc ctggggctct caaggctgct gtctgccctc tggccctctg 121380tggggagggt tccctcagtg ggaggtctgt gctccagggc agggatgact gagatagaaa 121440tcaaaggctg gcagggaaag gcagcttccc gccctgagag gtgcaggcag caccacagag 121500ccatggagtc acagagccac ggagccccca gtgtgggcgt gtgagggtgc tgggctcccg 121560gcaggcccag ccctgatggg gaagcctgcc ccgtcccaca gcccaggtcc ccaggggcag 121620caggcacaga agctgccaag ctgtgctcta cgatcctcat ccctccagca gcatccactc 121680cacagtgggg aaactgagcc ttggagaacc acccagcccc ctggaaacaa ggcggggagc 121740ccagacagtg ggcccagagc actgtgtgta tcctggcact aggtgcaggg accacccgga 121800gatccccatc actgagtggc cagcctgcag aaggacccaa ccccaaccag gccgcttgat 121860taagctccat ccccctgtcc tgggaacctc ttcccagcgc caccaacagc tcggcttccc 121920aggccctcat ccctccaagg aaggccaaag gctgggcctg ccaggggcac agtaccctcc 121980cttgccctgg ctaagacagg gtgggcagac ggctgcagat aggacatatt gctggggcat 122040cttgctctgt gactactggg tactggctct caacgcagac cctaccaaaa tccccactgc 122100ctcccctgct aggggctggc ctggtctcct cctgctgtcc taggaggctg ctgacctcca 122160ggatggcttc tgtccccagt tctagggcca gagcagatcc caggcaggct gtaggctggg 122220aggccacccc tgtccttgcc gaggttcagt gcaggcaccc aggacaggaa atggcctgaa 122280cacagggatg actgtgccat gccctaccta agtccgcccc tttctactct gcaaccccca 122340ctccccaggt cagcccatga cgaccaacaa cccaacacca gagtcactgc ctggccctgc 122400cctggggagg acccctcagc ccccaccctg tctagaggag ttggggggac aggacacagg 122460ctctctcctt atggttcccc cacctggctc ctgccgggac ccttggggtg tggacagaaa 122520ggacgcctgc ctaattggcc cccaggaacc cagaacttct ctccagggac cccagcccga 122580gcaccccctt acccaggacc cagccctgcc cctcctcccc tctgctctcc tctcatcact 122640ccatgggaat ccagaatccc caggaagcca tcaggaaggg ctgaaggagg aagcggggcc 122700gctgcaccac cgggcaggag gctccgtctt cgtgaaccca gggaagtgcc agcctcctag 122760agggtatggt ccaccctgcc tggggctccc accgtggcag gctgcgggga aggaccaggg 122820acggtgtggg ggagggctca gggccctgca ggtgctccat cttggatgag cccatccctc 122880tcacccaccg acccgcccac ctcctctcca ccctggccac acgtcgtcca caccatcctg 122940agtcccacct acaccagagc cagcagagcc agtgcagaca gaggctgggg tgcagggggg 123000ccgccagggc agctttgggg agggaggaat ggaggaaggg gaggtcagtg aagaggcccc 123060cctcccctgg gtctaggatc cacctttggg acccccggat cccatcccct ccaggctctg 123120ggaggagaag caggatggga gattctgtgc aggaccctct cacagtggaa tacctccaca 123180gcggctcagg ccagatacaa aagcccctca gtgagccctc cactgcagtg cagggcctgg 123240gggcagcccc tcccacagag gacagaccca gcaccccgaa gaagtcctgc cagggggagc 123300tcagagccat gaaggagcaa gatatgggga ccccaatact ggcacagacc tcagctccat 123360ccaggcccac caggacccac catgggtgga acacctgtct ccggcccctg ctggctgtga 123420ggcagctggc ctctgtctcg gacccccatt ccagacacca gacagaggga caggcccccc 123480agaaccagtg ttgagggaca cccctgtcca gggcagccaa gtccaagagg cgcgctgagc 123540ccagcaaggg aaggccccca aacaaaccag gaggtttctg aagctgtctg tgtcacagtc 123600gggtatagca gcggctacca caatgacact gggcaggaca gaaaccccat cccaagtcag 123660ccgaaggcag agagagcagg caggacacat ttaggatctg aggccacacc tgacactcaa 123720gccaacagat gtctcccctc cagggcgccc tgccctgttc agtgttcctg agaaaacagg 123780ggcagcctga ggggatccag ggccaggaga tgggtcccct ctaccccgag gaggagccag 123840gcgggaatcc cagccccctc cccattgagg ccatcctgcc cagaggggcc cggacccacc 123900ccacacaccc aggcagaatg tgtgcaggcc tcaggctctg tgggtgccgc tagctggggc 123960tgccagtcct caccccacac ctaaggtgag ccacagccgc cagagcctcc acaggagacc 124020ccacccagca gcccagcccc tacccaggag gccccagagc tcagggcgcc tgggtggatt 124080ctgaacagcc ccgagtcacg gtgggtatag tgggagctac taccactgtg agaaaagcta 124140tgtccaaaac tgtctcccgg ccactgctgg aggcccagcc agagaaggga ccagccgccc 124200gaacatacga ccttcccaga cctcatgacc cccagcactt ggagctccac agtgtcccca 124260ttggatggtg aggatggggg ccggggccat ctgcacctcc caacatcacc cccaggcagc 124320acaggcacaa accccaaatc cagagccgac accaggaaca cagacacccc aataccctgg 124380gggaccctgg ccctggtgac ttcccactgg gatccacccc cgtgtccacc tggatcaaag 124440accccaccgc tgtctctgtc cctcactcag ggcctgctga ggggcgggtg ctttggagca 124500gactcaggtt taggggccac cattgtgggg cccaacctcg accaggacac agatttttct 124560ttcctgccct ggggcaacac agactttggg gtctgtgcag ggaggacctt ctggaaagtc 124620accaagcaca gagccctgac tgaggtggtc tcaggaagac ccccaggagg gggcttgtgc 124680cccttcctct catgtggacc ccatgccccc caagataggg gcatcatgca gggcaggtcc 124740tccatgcagc caccactagg caactccctg gcgccggtcc ccactgcgcc tccatcccgg 124800ctctggggat gcagccacca tggccacacc aggcagcccg ggtccagcaa ccctgcagtg 124860cccaagccct tggcaggatt cccagaggct ggagcccacc cctcctcatc cccccacacc 124920tgcacacaca cacctacccc ctgcccagtc cccctccagg agggttggag ccgcccatag 124980ggtgggggct ccaggtctca ctcactcgct tcccttcctg ggcaaaggag cctcgtgccc 125040cggtcccccc tgacggcgct gggcacaggt gtgggtactg ggccccaggg ctcctccagc 125100cccagctgcc ctgctctccc tgggaggcct gggcaccacc agaccaccag tccagggcac 125160agccccaggg agccgcccac tgccagctca caggaagaag ataagcttca gaccctcagg 125220gccgggagct gccttcctgc caccccttcc tgccccagac ctccatgccc tcccccaacc 125280acttacacac aagccaggga gctgtttcca cacagttcaa ccccaaacca ggacggcctg 125340gcactcgggt cactgccatt tctgtctgca ttcgctccca gcgcccctgt gttccctccc 125400tcctccctcc ttcctttctt cctgcattgg gttcatgccg cagagtgcca ggtgcaggtc 125460agccctgagc ttggggtcac ctcctcactg aaggcagcct cagggtgccc aggggcaggc 125520agggtggggg tgaggcttcc agctccaacc gctccactag ccgagactaa ggaagtgaga 125580ggcagccaga aatccagacc attccatagc aaatggattt cattaaagtt accagacttc 125640agtgtaagta acatgagccc catgcacaac aatcccttat gaaggggaag tcagtgtcgc 125700ctcggatttc ttgaaaaaca caaaaactta tcaatgcctg taaaagtctg ttggaaagaa 125760aatatgattc aagaatgtta tgcccaacaa agctggcata ttttctaccc ggacacactc 125820agggaatgtg gtcccttgag tgcttctctc actgcgtaaa tcctacgtgg tgtttaagca 125880tattcataaa tgtgtatgtc tatttttatg tgtaagatgg ttcattttta ttttatttat 125940tcaatatgta caataaagaa tattgacaaa taggctggac atggtggctc ccacctgtaa 126000tcccagccct ttgggaggcc gaggcgggca gatcacctga ggtctggagt tcgagaccag 126060cctggccaac atgatgaaaa cccatctcta ctaaaaatac aaagattagc caggcatggt 126120ggtgcatgcc tgtaatccca gccactcagg aggctgagac aggagaaatg cgtgaacccg 126180gaaggcggag gttgcagtga gccgagatca caccactgca ctccagcctg gcgacagagc 126240aagattccat ctcaaaaaaa aaaaaagaca aagaaatttg tttttttgaa taaagacaaa 126300tttcatcaca cgaagataaa gatgcaaagc tccagacagg aaggcacgga cagcacagtg 126360aagcccggag cgggcgctgg ggggccaggg gcatggcggg ggtgccagcg tctctcggtt 126420cctaccatgg ccactccagc ctgtgttctc acgaggatgg ctgtgcaatg ctaggagcgt 126480gttcgaagct ctagggcaac cactggaagt gaggctgagg agcagagccc agaggcccgt 126540ggagctgatg aaaagaaagc tggagaaagt gtttgctgcc tcccaacatg gtaagaaaag 126600atagaaagag agagcacacg gcaaagggag cttgctgagg gactctttac aatggcttgc 126660acagagctca gggggtctgg gaggctaggg ccctgcgcag ggcagtcacc ccagcctgct 126720gaccaaggtt tgctgcaggc agctctgggg gtggttgagg cgcggtccct ggagccaccc 126780ctcaagggaa cgaggcagca gagtgggcca aggcccaggt cggctgcaag gctgcccagg 126840acttggggtc cttacatcag cagccactga tgcagctggc ccagagagag gcgccgagca 126900ggttgcctcc aggggacaaa ccaggtcgga gagggtgagg cagtggatgg agccacaaca 126960accccgggca cgggtgacac gcacgttcat gcacatctga cccttcctcc ctcaccaaac 127020aggtccccct gccttcccca tggttgcgaa aaagcaaaat gtagacgttt tttctttttt 127080aattcatgtt ttaattgaca aatgaagccg tatatattta ttgtgtacaa catgatgctt 127140taaaatatgt atacatcgtg gaacagcaac gttgagctaa tttaacacgc attacttcac 127200atacttgtca tcttttgtgg cgagaatgct taaaatccac tctcttagta ttttttaaga 127260atgcaataca ttgttgtcaa ctgtggtcac cgtcatgcat agccaagctc ccgacctcac 127320cctcctgcca gctcaggctg tgcatccttt caccagcatc ccccaccccg gcccctggcc 127380ctggtaacta ccactctata ctctacgtat gagttcagct ttttaagatt ccacagatga 127440atgagatcat acagtatttg ctttctatgc ctggcttatt ttagttaaca cactgtcctc 127500cagatccatc cgttgttgca aatgacaggg tttcattctt tttaaagtct aaagagtatt 127560ccattgtgtc aatggacctc atttgcttta tccatgcatc aactatggac atttaggttg 127620attccatttc ttagctgttg tggatggtgc tgcagtaaac atggggctgc agatgtctct 127680tcaacatact gacatcatgt cctttggata aatacccagt agtgggatcg ctggatcaca 127740atgtacagtt ttttttttaa tggaaacttt cattttttgg tgaaattagg aaaacagata 127800aaacccacag aatccaaaat atatgtgaag atgccaaaaa cagttgacat tgggcagagg 127860tcacatggaa ggaagtgaat acatgacggg gtgtgagggc ccagaggcag ctgaaatacg 127920ctttctaaac acaaggacct cttctgagag ggcagaagtt ttatcctgca catgcaatga 127980ccagcacagc taaaatacac tttctaaaca tgaggacctc ttctgagagg gcagctttat 128040cctgcaaatg caatgaccag cacaggaccc agaataaaga gagttgccag cggacgcctg 128100gtgtccatgt gtccaggtga gttcgagatg cggacggcgc tggccagcca gtcacaccct 128160aagtcaatct gctgcatgca tttgtccttg ccacagcaga aaacgagaaa gcctttgggc 128220tgcaaagctt cacaggctcc tcttctcccg actccatgga aacagctaca aagagcaggc 128280ccagtagagc ttaattcatg aaaatgagta ataaacttga actggaacag tatcgacttt 128340ttagaaacgg cagcaaagtg tataaaaaat attcaccaga acaatatttc caaacgatga 128400gatgagaatt tcagccaagt aatcctccat ggatagaaaa taatgaaggg attggattta 128460tgaaggaaaa tcatggagct caaatacaag aaaagagaat caaaaatgaa caggaggaga 128520taaaatatgg tttggccaaa gttacaaaat aaatttttta aaaacccttc atcatggcaa 128580gtagaaagag cgagaggaaa aacagatccc gtggaagaca caaataggac atggggagaa 128640aaatgaatga gatgaaacag agcagaaata aaattttacg gaactaaaga caagtgatct 128700gaacctgcct ggggcctggg ggacctcgcc accctgaagg gaaagaacat gcctggctgg 128760ctttgccacc tgctcattgc agagccccac agcttgcaac aaacataggc ggtagccagg 128820gagtggttac agcaggcctt gagcaagacc cagtgttgtg ctgacttcag gtctgaccca 128880gcactgtcat agtggtggtg tccatagtgg tagtgggggt gcttgtgtca ctccaccccc 128940atctccagga ggctcagaac agacagagag agactccatt tgtttgggag aaagtaaggg 129000atgagaacaa gagtctctgc ctggtaatcc agagaattat tctagatctt ggccaagatt 129060atcaaagcag tacctctatg agtcttttgg gcttggagtc cccctaaagc agatatagct 129120aagatcacaa cacccaagtc cttttgaata tgtgggaaga cttcccaagg acaggagcaa 129180acaaacaagc ccagactgca aaaaaacaag ccgagactgc aataaacacc tcactcttca 129240atgcccaggc actgaagaac atctcctagc agcaacacca tccaggaaaa catggcctca 129300accagtgaac taaataaggc accagggacc agtctcggag aaatagaggt atgttatctt 129360tcagagaatt caaagtagct ttgttgagga aactcaaaga aattcaagat aacacagtga 129420aggaattcag aatcctatcc gataaattta acagagattg aagcaattaa aaagaattaa 129480gcagaaatta tggagctgaa aaatgcaatt ggcatactga aaaatgcatc agagtatttt 129540catagcctca tatatcaagt agaagaaaga attagtgagc ttgaaaacag gctatttgga 129600aaagcacgat aaaaggagac aaaagagaaa agaataaata acaatgaagc atatctacag 129660gatctagaaa atagcctcaa aaggccaaat ctaagaatta ttagccttaa agaggaggta 129720gagaaagagg gatggagagt ttattcaaag ggataataac agaaaacttc ccaaacctag 129780agaaagatat caatatccaa atgcaagaag gatgtagtac accaaggaga tttaatgcaa 129840agaagactac ctcaaggcat tcaatactca aactcccata tgacaaggac tttaaaaaga 129900tcctaaaagc agcaaaagaa aagaaatgaa taaaatacta tggagctcca atatgtctgg 129960cagcagactt ttcagtgaag actttatatg ccaggagaga gtgtcataat ggatttaaag 130020tgctgaagga aaaaactttt accctcgaac agtatagctg gtgaaattat ccttcaaaca 130080tgaaggagaa ataatttgtt tccagacaaa tgttgaggga tttcatgaac accagacctg 130140tcttttaaga aatgctaaag ggagtacttc aatcagaaag aaacacgtta gtgaacaata 130200agaaatcatc tgaaggcaca aaactcaccg gtaatagtaa gtacacagaa aaacacagaa 130260tattataaca ctgtaactgt ggtgtgtaaa ctccttttgt ttgtttgttt gtttgtttgt 130320ttgtttttgt ttttagacgg agttttgctc cagcccaggc tggagtgcaa tggcacaatc 130380tcagctcact gcaacttcca cctcccgggt tcaagcaatt ctcctgcctc agcctcccaa 130440gtagctggga ttacaggcat gtgctaccat gtccagctaa ttttgtattt tagtagagac 130500ggtgtttcac catgttggtc aggctagcct tatcttgagt agaaaaacta aatgatgaag 130560caatgaaaaa taataactac aacttttcaa gacatagtac aataagatat aaatcataac 130620aaaaagttaa aaggtggagg gatgaagtta aggcatagag tctttattag ttttcttttt 130680acttgtctgt ttatgcaaac agtgttaagt tgtcatcagt ttaaaataat gggtcataag 130740atactatttg caagcctcat ggtaacgtca aaccaaaagc aatacaacag atacacaaaa 130800aacaaaaagc aagaagctaa attacgtcat cagagaaaat caccttcact aaaaggaaga 130860cggagaaaag aatgaagaga gagaagacca aaagcaaata gcaatatggc aggagtaagt 130920ccttacttat caataatacc attgaatgta aatggactaa actctccaat caaaagacat 130980agagtggctg aatcaattaa agaaaaaaca agacccattg atctgttgtc cacaagaaac 131040acactttatc tataaagaca cacatagact gaaaacaaag ggatggaaaa agatactcca 131100cgccaatgga aaccaaagaa agagcaggag tagctacact tatatcaggc aaaatagatt 131160tcaagacaaa aactataaga agagacaagg tcactaatga taaacaggtc aattcagcaa 131220gaggatataa caattgtaaa tatatatgca cccaatgctg gagcacccag atatataaag 131280caagtattta ctagagctaa agagagaaat agactccaat gcaataatag ctggagattt 131340caacatccca ctttcaacat tgaacagatc ctccagatag aaaatcaaca aagaaatatt 131400ggacttaatc tgcactatcg accaaatgga tctaacagat atttacagaa catttcatcc 131460aacagctgca gaacacacat tcttttcctc agcacataga tcattctcaa ggatagacca 131520tatgttgggt cacaaaacaa gttttaaaat attcaaatac attgaaataa tatcaagcat 131580cttctgtgac cacaatggac taaaactaga aatcaataac aagaggaatt ttggaaacta 131640tataaatata tggaaattaa tgaatgctga gtgggtcaat gaagcaatta agaaggaaac 131700tgaaattttt cttggaacga atgatcatgg aaacagaaaa taccaaaacc tatgggatac 131760agcaaaagca gtactaagag ggaagtttac agctacaaat gcttacatta aaaaagaaga 131820aaaacttcaa taaaaaaacc taacaatgca tcttaaagaa ctagaaaagc aagaggaaat 131880caaatccaaa attagtagaa gaaaacagta aaggtcagag cagaaataag taaaattgaa 131940atgaagaaaa caatacaaaa gatcaataaa acaacaggtt gttttcttga aaagttaaac 132000aaaattgaca aacctttagc cagactaaga aaaaaagaca gaagatccaa ataaataaaa 132060tcagagatga aaaaggtgac attacaactt acaccacaga aattcaaagg atcattagtg 132120gctactataa gcaactatat gccaataaat tggaaaatct agaagaaatg cagaaattcc 132180tagacacata caacctccca agattaaacc aagaagaaat tcaaaacctg aacagactga 132240taacaagtaa tgagatcaaa gccgtaataa aaagcctccc agtaaagaga agcccaggac 132300ccgacggctt cactgctgaa ttctaccaaa catttaaagt agaactaata ccaatcctac 132360tcaaactatt ccaaaaaata gaggtggaag gaatacttca aaactcatta tacgaggcca 132420gtattaacct gacaccaaaa ctagacaaag acacatgaaa aaaagaaaac tacaggccaa 132480tatgtctgat gaatattgac acaaaaatcc tcaacaaaat actagcaaac caaattcaac 132540tacacattag aaagttcact catcatgacc aagtggaatt tatctaactt gggatgcaaa 132600gatggttcaa catatgcaaa tcaatcaatg tgatacatca tatcaacaga atgaacaaca 132660aaaaccattt gatcatttaa ttgatactga aaaagcattt gataaaattc aacattcctt 132720cataataaaa attctcttct atactaggta caaaagaaac ttacctcaac ataataaagc 132780catatatgac agtcccacag tatgatacta aatgaggaaa aactgagagc ctttcctcta 132840cgatctggaa catgacaaag atgcccactt tcatcactgt tattcaacat agtactggaa 132900gtcctagctg gagcgatcag acaagagaaa gatataaaag acatccaaat tggaaaggaa 132960taagtcaaat tatcctcatt tgcatatggt atgatcttct atttagagct aactaaagac 133020tccaccaaaa aaagttatta gaactgacga acaaattcag taaagctgca ggatacaaaa 133080tcaacataca aaaatcagta gcatttctat atgccaacaa tgaccaatgt gaaaaagaaa 133140ttaaaaagta accctattta caataaccac aaataaacac ctaggaatta accaaagagg 133200taaaagattt ctgtaatgaa aactataaaa cactgatgaa agaaattgaa gagtacacca 133260aaaaatggaa agcaattgca tgttcatgga ttagaagaat cagtgttgtt ataatgtcca 133320tactatccaa agcaatctac agattcaatg caatccttat caaaatacca atgacatcat 133380tcacagaaat agaaaaaaaa aatcctaaaa tttacgtgga accacaaaga cccagaatag 133440ccaaagctct cctaagcaaa aagaacgaaa ctgtaggaat gacattgcct gtcttcaaat 133500tctactacag agctatagat agtaaccaaa acagcgtggt actggcataa aaacagacac 133560agagacaaac agaacaaaat ttaaaaaccc agaaataaat ccacacacct acagcaaatt 133620catttttgac aaagttgcca agaacatact ctggggaata gataatgata tctcttcaat 133680aaatagtgtg gggaaaactg gatatccata tacataacag tgaaactaga cccctctctc 133740tctcactata tacaaaaatc aaatcaaaat tgtttaagga cttaaatcta agacctcata 133800ctatgaaacc actgcaagac aaccttggcg gaaactctcc aagacatcag tccaggcaaa 133860gatttcttga gtaatatccc acaagcacag acaaccaaag caaaaatgga caaatgggat 133920cacatcaagt taaaaagctt ctgcacagta agggaaacaa ccaacaaaat gaagagacaa 133980cccacagaat gggagaaaat atttgaaaaa tacccatctg gcaagggatt aaaaaccaga 134040atatatgcag aatatataag gagctcaaac agtgctatag aaaaaaaaat ctaataatct 134100gatttaaaaa tgggaaaaat gttagaatag acatttctta aaataagaca tacagatggc 134160aaaccgacat ggaacggtgc tcaacatcat ggattatcac agaaacacaa tcaatcaaaa 134220ctaaaactaa aatgtgctat catctcaccc cagttaaaat ggctgatatc cagaagacag 134280gcaataacaa atgctggcaa ggatgtgggg aaaagggagc ccccatacac tgttgctggg 134340attgtaaatt agtacaacca ctgtggagag cagcatgaaa gttcctcaaa aaactgaaag 134400aaagctacca taggatccag caatcccact gctgtgtata tactacaaaa gaaaggaagt 134460cagtatatga agaggtatct gcactcccat gtttgttgca gccctgttca caacagccaa 134520gatttggaag caacctaagt gtccatcagc agttgaatgt ataaagaaaa tgtggtgcat 134580atacacaatg gagtattatt caataataaa aaggaatgag attgagtcat ttgcaacaac 134640atggatggaa ctggagatca ttatgtgaag tgaaataagc caggcacaga aagacaaaca 134700ttacaatgtt cttacttatt aatgagatct aaaaatcaaa acaattgcac ccatgttcat 134760aaagagtaaa aggatggtta ccagatgctg agaacggtgg tggggggata gggaaaggtg 134820gcagtggtta acgggtacaa aaaaatagaa agaatgaata agacttgcta cttgatagca 134880cagcaaggtg gctatagtca gtaatttagt tgtatatttt taataatgaa aggtgtataa 134940ttggattgtt tctaacacaa aggataatgc ttaagaggat ggatacccca ttttccatga 135000tgtgattatt tcacattgca cgcctagatc aaaacatcca atgtacccca taaatatata 135060catcttctat gtacccataa aaattctgta aaataaaata tataaaaaga ggtgacagat 135120atggaagaca ggcaaagaag agacgacatc cacataatcc gagtacctaa gaaagaatgg 135180agtccagtgc atctcaggag ccaccattct aagccaattt tctctggttc tctcagtcac 135240cctaccaata cgtgggcaat cttgttttat ttcaggatag agtttttgaa attatagatt 135300taagtatgct ttctgttcta ttacttttgg taattaattt tagaaagaac taatttgggc 135360acaaatttga aaaaattcta aatccaaaaa aaaaaagaaa aaaacacaca cacaatcatc

135420tataaggggg atgatgacca gtcctagatt tctcaccagc cacattcaag atcagtaaat 135480ggtaggacaa aacctgtagg gtccttaagg gggaaagaag tagtggatag tccagagtct 135540atatacagcc aactgttctt gaagaaaaaa ggctgctgaa aaggagttcc aaacattcta 135600taatccataa tctcatgatg aaactactag aggaagacca ccagccatca aaaggtgctt 135660ggagaaccca gggccaagaa ccaaaagtaa atattaagtg tccttaactg cgagactaag 135720atagaaatga ctgtggggga ccatgtggcc tcaacagagg tgaaatggtg tctgcctgac 135780aaagtggaca ttttacaatg atcaaaacac agaatatgag atagagagca cttctgaatt 135840actgcctcac tccaaataac tctcagccaa aggacttcag taaaaccaaa ttgggcatat 135900tagacagtac aaacaaattc taagaaaata atattactga ttacaatcac atgatgctag 135960agatggaggg gaaaaggaag aggaaaccag gtaatttcat actcgtatat agtaaagaac 136020taaagtacat tgtccaaaga agaacaaaga atattttgga aagttataaa ggtagccact 136080acacatagaa gatagcaaag aacaagaaaa cttaagatgg aaaacttttt ggaagcataa 136140gaatagaaaa tataaactac taagataaga ttgaagccaa acagatctat gaaaacaaca 136200aacatcaatg gccttaactt gcctattaaa aggaagagac tttcaaattg gaccacaaga 136260taaaacccaa ctctatatag catatgagta ttacacacaa aatgggaaaa gctgaaaaaa 136320cttgggcaaa attcacccca agcaaattcc actgtttcct ttgggacaaa atgccaagct 136380ccatgccagg gaagatgatt ctcctcagac cttctcctca ctctcccagt cctcttaggg 136440aaggaattgg gtgttagagg agggagactc tgtcgattat cagctgaagc agtggtgtgc 136500tcctgcgttg cttctgacct gggaaatgaa gcagcaagac tctttctgct gtgtctttgc 136560ccagaagggc catcccccca gagcagagta cccaggccgg caggagcagt ggtggaagcg 136620tggaaaccac gtctcctaca gcagagacca tcagaagcgg agcctcgggt ataagggaaa 136680caacgcgttc tccctaacct gggagtgaca gacagcgtca ttcctcacag tgataccctg 136740tgttctagcc atctggccca tgacagagcc agcccagagc cagcccagag ccagcccctc 136800accatcctgg agcctggcca gctcgccaag ctgcaccata ggcctggaag gcgtggagac 136860ctgcggcagt gccctgtcct cccgtgaggc ctgccatccc tgccaggggt cgcctctggc 136920ttctccttct ccaggaccgc acggtccaga ggctcagtgc ctggagtagg tgttgcctcc 136980ctgcttctag gcccagaccc tcccttgttc ctgaccccgg gcctttccct ctggcttgga 137040catccagggc cctgtctcag ctggggagct gctcctgctc aaggactgtc ttccgcggga 137100tcgaaaggcc gcgtcctgaa caatgcgtgg gccacgtaag cggagcaggc tctaaaggcc 137160gcgtcctaaa cagtgcgtgg gccacgtgag cggagcaggc tctaaaggcc gcgtcctaaa 137220cagtgcgtgg gccacgtgag cggagcaggc tctaaaggcc gcgtcctaaa cagtgcgtgg 137280gccacgtgag cggagcaggc tctaaaggcc gcgtcctaaa cagtgcgtgg gccacgtgag 137340cggagcaggc tctaaaggcc gcgtcctaaa cagtgcgtgg gccacgtgag cggagcaggc 137400tctaaaggcc gcgtcctaaa cagtgcgtgg gccacgtgag cggagcaggc tctaaaggcc 137460gcgtcctaaa cagtgcgtgg gccacgtgag cggagcaggc tctaaaggcc gcgtcctaaa 137520cagtgcgtgg gccacgtgag cggagcaggc tctaaaggcc gcgtcctaaa cagtgcgtgg 137580gccacgggag cggagcagac tctaaaggcc gcgtcctaaa cagtgtgtgg gccacgtgag 137640cggagcgccc tctccactgc cctcggggcc gcagctccca gctcagctcc cagccctgct 137700cagggcagcc aggccaggag gtaccatcca ggctaagtga ccctcagggg ggacaggtgc 137760cccaggagat gccagctgtt gggagaggct gggggaccaa ctcgacctgg cctgtgggcc 137820ctgccctggc cacccattgt aggatccagc cgccacgcct gtgacactcg tgtgctttcc 137880ctggtgtgtg cttgtggcag gtgggggcag agggtcctca ggccagagag ccactccccc 137940agcgccagac caccctcttc ctcactcccc cacctcaccc cctcacaggt gcctcccagg 138000ccatcagggc ccaaccaccc ctaaacaaat gggttctcgg cccctcgtgg ctggaggtgg 138060gttctctcac cattcccagc ctaagactcc atccccatgc tggcagctgt tcaaccatgt 138120ctagagagat ccactgtccc agacagcacc tcagggtccc ccgtcctgcc tggaaccctg 138180taggaaactc cacaaaccgc cgccattctg tccacacccc tacaggagcc ccaaccctct 138240ccccacatcc aggcttccct cccagacccc tcatccctgc ccgcacggtg cctgaggggg 138300ccttcttggg cagcgcctaa gcaagccccc agcacccttc ggccccttca aggcacacag 138360gccccctttc cacccagcct caggaaacca cctgtgtcct ccaacgacag gtcccagcct 138420cccagccttt gccttgcctg ttcctctccc tggaactctg ccccgacaca gaccctcccc 138480agcaagcccg caggggcacc tcccctgccc ccagacaccc tgtgcccgtc agttcatccc 138540cagcagaggc cctcaccagg cacaccccca tgctcacacc tggccccagg cctcagcctc 138600cctgagggcc ccacccagcc cgcgtctggc cagtggtgcg tgcaaagccc ctcacccaga 138660ctcggcggaa ggcagccagt gcaggcctgg ggaggggctc tccttagacc accttgcacc 138720ttccctggca cccaccatgg gaagagctga gactcactga ggaccagctg aggctcagag 138780aagggaccca gcactggtgg acacgcaggg agcccacgcc agggcgccgt ggtgagtgag 138840gcccagtgcc acccactgag gcctcccgtt cagtgggacg acggtgaaca ggtggaacca 138900accaggcaac ccccgccggg ccccacagac gggatcagag caggaaaggc ttcctgcccc 138960tgcaggccag cgaggagccc tggcgggggc cgtggccctc caggcgagga ggctcccctg 139020gccaccgcca cccgggcctc tctgctgctg ggaaaacaag tcagaaagca agtggatgag 139080aggtggcgtg acagacccag cttcagatct gctctaattt acaaaagaaa aggaaaaaca 139140cacttggcag ccttcagcac tctaatgatt cttaacagca gcaaattatt ggcacaagac 139200tccagagtga ctggcagggt tgagggctgg ggtctcccac gtgttttggg gctaacagcg 139260gaagggagag cactggcaaa ggtgctgggg gcccctggac ccgacccgcc ctggagaccg 139320cagccacatc agcccccagc cccacaggcc ccctaccagc cgcagggttt tggctgagct 139380gagaaccact gtgctaactg gggacacagt gattggcagc tctacaaaaa ccatgctccc 139440ccgggacccc gggctgtggg tttctgtagc ccctggctca gggctgactc accgtggctg 139500aatacttcca gcactggggc cagggcaccc tggtcaccgt ctcctcaggt gagtctgctg 139560tctggggata gcggggagcc aggtgtactg ggccaggcaa gggctttggc ttcagacttg 139620gggacaggtg ctcagcaaag gaggtcggca ggagggcgga gggtgtgttt ttgtatggga 139680gaagcaggag ggcagaggct gtgctactgg tacttcgatc tctggggccg tggcaccctg 139740gtcactgtct cctcaggtga gtcccactgc agccccctcc cagtcttctc tgtccaggca 139800ccaggccagg tatctggggt ctgcagccgg cctgggtctg gcctgaggcc acaccagctg 139860ccatccctgg ggtctccgcc atgggctgca tgccagagcc ctgctgtcac ttagccctgg 139920ggccagctgg agcccccaag gacaggcagg gaccccgctg ggcttcagcc ccgtcaggga 139980ccctccacag gtagcaagca ggccgagggc agggacggga aggagaagtt gtgggcagag 140040cctgggctgg ggctgggcgc tggctgttca tgtgccgggg accaggcctg cgctttagtg 140100tggctacaag tgcttggagc actggggcca gggcagcccg gccaccgtct ccctgggaac 140160gtcacccctc cctgcctggg tctcagcccg ggggtctgtg tggctgggga cagggacgcc 140220ggctgcctct gctctgtgct tgggccatgt gacccattcg agtgtcctgc acgggcacag 140280gtttgtgtct gggcaggaac agggactgtg tccctgtgtg atgcttttga tatctggggc 140340caagggacaa tggtcaccgt ctcttcaggt aagatggctt tccttctgcc tcctttctct 140400gggcccagcg tcctctgtcc tggagctggg agataatgtc cgggggctcc ttggtctgcg 140460ctgggccatg tggggccctc cggggctcct tctccggctg tttgggacca cgttcagcag 140520aaggcctttc tttgggaact gggactctgc tgctggggca aagggtgggc agagtcatgc 140580ttgtgctggg gacaaaatga ccttgggaca cggggctggc tgccacggcc ggcccgggac 140640agtcggagag tcaggttttt gtgcacccct taatggggcc tcccacaatg tgactacttt 140700gactactggg gccagggaac cctggtcacc gtctcctcag gtgagtcctc acaacctctc 140760tcctgcttta actctgaagg gttttgctgc atttttgggg ggaaataagg gtgctgggtc 140820tcctgccaag agagccccgg agcagcctgg ggggctcagg aggatgccct gaggcaacag 140880cggccacaca gacgaggggc aagggctcca gatgctcctt cctcctgagc ccagcagcac 140940gggtctctct gtggccaggg ccaccctagg cctctggggt ccaatgccca acaacccccg 141000ggccctcccc gggctcagtc tgagagggtc ccagggacgt agcggggcgc cagttcttgc 141060ctggggtcct ggcattgttg tcacaatgtg acaactggtt cgacccctgg ggccagggaa 141120ccctggtcac cgtctcctca ggtgagtcct caccaccccc tctctgagtc cacttaggga 141180gactcagctt gccagggtct cagggtcaga gtcttggagg cattttggag gtcaggaaag 141240aaagccgggg agagggaccc ttcgaatggg aacccagcct gtcctcccca agtccggcca 141300cagatgtcgg cagctggggg gctccttcgg ctggtctggg gtgacctctc tccgcttcac 141360ctggagcatt ctcaggggct gtcgtgatga ttgcgtggtg ggactctgtc ccgctccaag 141420gcacccgctc tctgggacgg gtgccccccg gggtttttgg actcctgggg gtgacttagc 141480agccgtctgc ttgcagttgg acttcccagg ccgacagtgg tctggcttct gaggggtcag 141540gccagaatgt ggggtacgtg ggaggccagc agagggttcc atgagaaggg caggacaggg 141600ccacggacag tcagcttcca tgtgacgccc ggagacagaa ggtctctggg tggctgggtt 141660tttgtggggt gaggatggac attctgccat tgtgattact actactacta cggtatggac 141720gtctggggcc aagggaccac ggtcaccgtc tcctcaggta agaatggcca ctctagggcc 141780tttgttttct gctactgcct gtggggtttc ctgagcattg caggttggtc ctcggggcat 141840gttccgaggg gacctgggcg gactggccag gaggggacgg gcactggggt gccttgagga 141900tctgggagcc tctgtggatt ttccgatgcc tttggaaaat gggactcagg ttgggtgcgt 141960ctgatggagt aactgagcct ctagactgag cattgcagac taatcttgga tatttgtccc 142020tgagggagcc ggctgagaga agttgggaaa taaactgtct agggatctca gagcctttag 142080gacagattat ctccacatct ttgaaaaact aagaatctgt gtgatggtgt tggtggagtc 142140cctggatgat gggataggga ctttggaggc tcatttgagg gagatgctaa aacaatccta 142200tggctggagg gatagttggg gctgtagttg gagattttca gtttttagaa taaaagtatt 142260agctgcggaa tatacttcag gaccacctct gtgacagcat ttatacagta tccgatgcat 142320agggacaaag agtggagtgg ggcactttct ttagatttgt gaggaatgtt ccacactaga 142380ttgtttaaaa cttcatttgt tggaaggaga gctgtcttag tgattgagtc aagggagaaa 142440ggcatctagc ctcggtctca aaagggtagt tgctgtctag agaggtctgg tggagcctgc 142500aaaagtccag ctttcaaagg aacacagaag tatgtgtatg gaatattaga agatgttgct 142560tttactctta agttggttcc taggaaaaat agttaaatac tgtgacttta aaatgtgaga 142620gggttttcaa gtactcattt ttttaaatgt ccaaaattct tgtcaatcag tttgaggtct 142680tgtttgtgta gaactgatat tacttaaagt ttaaccgagg aatgggagtg aggctctctc 142740ataacctatt cagaactgac ttttaacaat aataaattaa gtttcaaata tttttaaatg 142800aattgagcaa tgttgagttg gagtcaagat ggccgatcag aaccagaaca cctgcagcag 142860ctggcaggaa gcaggtcatg tggcaaggct atttggggaa gggaaaataa aaccactagg 142920taaacttgta gctgtggttt gaagaagtgg ttttgaaaca ctctgtccag ccccaccaaa 142980ccgaaagtcc aggctgagca aaacaccacc tgggtaattt gcatttctaa aataagttga 143040ggattcagcc gaaactggag aggtcctctt ttaacttatt gagttcaacc ttttaatttt 143100agcttgagta gttctagttt ccccaaactt aagtttatcg acttctaaaa tgtatttaga 143160attcattttc aaaattaggt tatgtaagaa attgaaggac tttagtgtct ttaatttcta 143220atatatttag aaaacttctt aaaattactc tattattctt ccctctgatt attggtctcc 143280attcaattct tttccaatac ccgaagcatt tacagtgact ttgttcatga tcttttttag 143340ttgtttgttt tgccttacta ttaagacttt gacattctgg tcaaaacggc ttcacaaatc 143400tttttcaaga ccactttctg agtattcatt ttaggagaaa gacttttttt ttaaatgaat 143460gcaattatct agacttattt cagttgaaca tgctggttgg tggttgagag gacactcagt 143520cagtcagtga cgtgaagggc ttctaagcca gtccacatgc tctgtgtgaa ctccctctgg 143580ccctgcttat tgttgaatgg gccaaaggtc tgagaccagg ctgctgctgg gtaggcctgg 143640actttgggtc tcccacccag acctgggaat gtatggttgt ggcttctgcc acccatccac 143700ctggctgctc atggaccagc cagcctcggt ggctttgaag gaacaattcc acacaaagac 143760tctggacctc tccgaaacca ggcaccgcaa atggtaagcc agaggcagcc acagctgtgg 143820ctgctgctct taaagcttgt aaactgtttc tgcttaagag ggactgagtc ttcagtcatt 143880gctttagggg gagaaagaga catttgtgtg tcttttgagt accgttgtct gggtcactca 143940catttaactt tccttgaaaa actagtaaaa gaaaaatgtt gcctgttaac caataatcat 144000agagctcatg gtactttgag gaaatcttag aaagcgtgta tacaattgtc tggaattatt 144060tcagttaagt gtattagttg aggtactgat gctgtctcta cttcagttat acatgtgggt 144120ttgaattttg aatctattct ggctcttctt aagcagaaaa tttagataaa atggatacct 144180cagtggtttt taatggtggg tttaatatag aaggaattta aattggaagc taatttagaa 144240tcagtaagga gggacccagg ctaagaaggc aatcctggga ttctggaaga aaagatgttt 144300ttagttttta tagaaaacac tactacattc ttgatctaca actcaatgtg gtttaatgaa 144360tttgaagttg ccagtaaatg tacttcctgg ttgttaaaga atggtatcaa aggacagtgc 144420ttagatccga ggtgagtgtg agaggacagg ggctggggta tggatacgca gaaggaaggc 144480cacagctgta cagaattgag aaagaataga gacctgcagt tgaggccagc aggtcggctg 144540gactaactct ccagccacag taatgaccca gacagagaaa gccagactca taaagcttgc 144600tgagcaaaat taagggaaca aggttgagag ccctagtaag cgaggctcta aaaagcacag 144660ctgagctgag atgggtgggc ttctctgagt gcttctaaaa tgcgctaaac tgaggtgatt 144720actctgaggt aagcaaagct gggcttgagc caaaatgaag tagactgtaa tgaactggaa 144780tgagctgggc cgctaagcta aactaggctg gcttaaccga gatgagccaa actggaatga 144840acttcattaa tctaggttga atagagctaa actctactgc ctacactgga ctgttctgag 144900ctgagatgag ctggggtgag ctcagctatg ctacgctgtg ttggggtgag ctgatctgaa 144960atgagatact ctggagtagc tgagatgggg tgagatgggg tgagctgagc tgggctgagc 145020tagactgagc tgagctaggg tgagctgagc tgggtgagct gagctaagct ggggtgagct 145080gagctgagct tggctgagct agggtgagct gggctgagct ggggtgagct gagctgagct 145140ggggtaagct gggatgagct ggggtgagct gagctgagct ggagtgagct gagctgggct 145200gagctggggt gagctgggct gagctgggct gagctgggct gagctggggt gagctgagct 145260ggggtgagct gagctgagct ggggtgagct gagctgagct ggggtgagct ggggtgagct 145320gagctggggt gagctgagct gagctggggt gagctgagct ggggtgagct gagctgagct 145380ggggtgagct gagctgagct gagctgagct gagctggggt gagctgagct gagctgagct 145440ggggtgagct ggggtgagct gagctgagct ggagtgagct gagctgggct gagctggggt 145500gagctgggct gagctggggt gagctgagct gagctgagct gagctggggt gagctgagct 145560gagctggggt gagctgagct ggggtgagct gggctgagct gagctgagct gagctgagct 145620gagctgagct gagctgagct gagctgagct gagctgagct gagctgagct gagctgagct 145680ggggtgagct gagctgagct gggctgagct ggggtgagct gggctgagct gggctgagct 145740gggctgagct ggggtgagct gagctggggt gagctgagct gagctgggct gagctgagct 145800gagctggggt gagctgagct gagctggggt gagctgagct gagctgagct ggggtgagct 145860gagctgagct gggctgagca gggctgagct ggggtgagct gagctgagct ggggtgagct 145920gggctgagct gggctgagct gagctgagct gggctgagct gggctgagct gggctgagct 145980gggctgagct gggctgagct ggggtgagct gagctggggt gagctggggt gagctgagct 146040ggggtgagct gagctggggt gagctgagct gagctggggt gagctgagct ggggtgagct 146100gagctgagct ggggtgagct gagctgagct ggggtgagct gagctagggt gaactgggct 146160gggtgagctg gagtgagctg agctgaggtg aactggggtg agccgggatg ttttgagttg 146220agctggggta agatgagctg aactggggta aactgggatg agctgtggtg agcggagctg 146280gattgaactg agctgtgtga gctgagctgg ggtcagctga gcaagagtga gtagagctgg 146340ctggccagaa ccagaatcaa ttaggctaag tgagccagat tgtgctggga tcagctgtac 146400tcagatgagc tgggatgagg taggctggga tgagctgggc tagctgacat ggattatgtg 146460aggctgagct agcatgggct ggcctagctg atgagctaag cttgaatgag cggggctgag 146520ctggactcag atgtgctaga ctgagctgta ctggatgatc tggtgtaggg tgatctggac 146580tcaactgggc tggctgatgg gatgcgccag gttgaactag gctcagataa gttaggctga 146640gtagggcctg gttgagatgg ttcgggatga gctgggaaaa gatggactcg gaccatgaac 146700tgggctgagc tgggttggga gaccatgaat tgagctgaac tgagtgcagc tgggataaac 146760tgggttgagc taagaataga ctacctgaat tgtgccaaac tcggctggga tcaattggaa 146820attatcagga tttagatgag ccggactaaa ctatgctgag ctggactggt tggatgtgtt 146880gaactggcct gctgctgggc tggcatagct gagttgaact taaatgagga aggctgagca 146940aggctagcct gcttgcatag agctgaactt tagcctagcc tgagctggac cagcctgagc 147000tgagtaggtc taaactgagt taaaaatcaa cagggataat ttaacagcta atttaacaag 147060cctgaggtct gagattgaat gagcagagct gggatgaact gaatgagttt caccaggcct 147120ggaccagtta ggctaggacc tcgttctata gaggcagact gtgtgctaca gtggagtttc 147180aagatgattc catgagtcct ccccgccccc aacataaccc accttcctcc taccctacac 147240gcctgtctgg tgtgtaaatc ccagctttgt gtgctgatac agaagcctga gcccctcccc 147300cacctccacc tacctattac tttgggatga gaatagttct cccagccagt gtctcagagg 147360gaagccaagc aggacaggcc caaggctact tgagaagcca ggatctaggc ctctccctga 147420gaacgggtgt tcatgcccct agagttggct gaagggccag atccacctac tctagaggca 147480tctctccctg tctgtgaagg cttccaaagt cacgttcctg tggctagaag gcagctccat 147540agccctgctg cagtttcgtc ctgtatacca ggttcaccta ctaccatatc tagccctgcc 147600tgccttaaga gtagcaacaa ggaaatagca gggtgtagag ggatctcctg tctgacagga 147660ggcaagaaga cagattctta cccctccatt tctcttttat ccctctctgg tcctcagaga 147720gtcagtcctt cccaaatgtc ttccccctcg tctcctgcga gagccccctg tctgataaga 147780atctggtggc catgggctgc ctggcccggg acttcctgcc cagcaccatt tccttcacct 147840ggaactacca gaacaacact gaagtcatcc agggtatcag aaccttccca acactgagga 147900cagggggcaa gtacctagcc acctcgcagg tgttgctgtc tcccaagagc atccttgaag 147960gttcagatga atacctggta tgcaaaatcc actacggagg caaaaacaaa gatctgcatg 148020tgcccattcc aggtaagaac caaaccctcc cagcaggggt gcccaggccc aggcatggcc 148080cagagggagc agcggggtgg ggcttaggcc aagctgagct cacaccttga cctttcattc 148140cagctgtcgc agagatgaac cccaatgtaa atgtgttcgt cccaccacgg gatggcttct 148200ctggccctgc accacgcaag tctaaactca tctgcgaggc cacgaacttc actccaaaac 148260cgatcacagt atcctggcta aaggatggga agctcgtgga atctggcttc accacagatc 148320cggtgaccat cgagaacaaa ggatccacac cccaaaccta caaggtcata agcacactta 148380ccatctctga aatcgactgg ctgaacctga atgtgtacac ctgccgtgtg gatcacaggg 148440gtctcacctt cttgaagaac gtgtcctcca catgtgctgc cagtgagtgg cctgggctaa 148500gcccaatgcc tagccctccc agattaggga agtcctccta caattatggc caatgccacc 148560cagacatggt catttgctcc ttgaactttg gctccccaga gtggccaagg acaagaatga 148620gcaataggca gtagaggggt gagaatcagc tggaaggacc agcatcttcc cttaagtagg 148680tttgggggat ggagactaag cttttttcca acttcacaac tagatatgtc ataacctgac 148740acagtgttct cttgactgca ggtccctcca cagacatcct aaccttcacc atccccccct 148800cctttgccga catcttcctc agcaagtccg ctaacctgac ctgtctggtc tcaaacctgg 148860caacctatga aaccctgaat atctcctggg cttctcaaag tggtgaacca ctggaaacca 148920aaattaaaat catggaaagc cctcccaatg gcaccttcag tgctaagggt gtggctagtg 148980tttgtgtgga agactggaat aacaggaagg aatttgtgcg tactgtgact cacagggatc 149040tgccttcacc acagaagaaa ttcatctcaa aacccaatgg taggtatccc cccttccctt 149100cccctccaat tgcaggaccc ttcctgtacc tcatagggag ggcaggtcct cttccaccct 149160atcctcacta ctgtcttcat ttacagaggt gcacaaacat ccacctgctg tgtacctgct 149220gccaccagct cgtgagcaac tgaacctgag ggagtcagcc acagtcacct gcctggtgaa 149280gggcttctct cctgcagaca tcagtgtgca gtggcttcag agagggcaac tcttgcccca 149340agagaagtat gtgaccagtg ccccgatgcc agagcctggg gccccaggct tctactttac 149400ccacagcatc ctgactgtga cagaggagga atggaactcc ggagagacct atacctgtgt 149460tgtaggccac gaggccctgc cacacctggt gaccgagagg accgtggaca agtccactgg 149520taaacccaca ctgtacaatg tctccctgat catgtctgac acaggcggca cctgctattg 149580accatgctag cgctcaacca ggcaggccct gggtgtccag ttgctctgtg tatgcaaact 149640aaccatgtca gagtgagatg ttgcatttta taaaaattag aaataaaaaa aatccattca 149700aacgtcactg gttttgatta tacaatgctc atgcctgctg agacagttgt gttttgcttg 149760ctctgcacac accctgcata cttgcctcca ccctggccct tcctctacct tgccagtttc 149820ctccttgtgt gtgaactcag tcaggcttac aacagacaga gtatgaacat gcgattcctc 149880cagctacttc tagatatatg gctgaaagct tgcatgcctg caggtcgact ctagaggatc 149940cccgggtacc gagctcgaat tcgccctata gtgagtcgta ttacaattca ctggccgtcg 150000ttttacaacg tcgtgactgg gaaaaccctg gcgttaccca acttaatcgc cttgcagcac 150060atcccccttt cgccagctgg cgtaatagcg aagaggcccg caccgatcgc ccttcccaac 150120agttgcgcag cctgaatggc gaatggcgcc tgatgcggta ttttctcctt acgcatctgt 150180gcggtatttc acaccgcata tggtgcactc tcagtacaat ctgctctgat gccgcatagt 150240taagccagcc ccgacacccg ccaacacccg ctgacgcgaa ccccttgc 1502887123DNAArtificial Sequencesynthetic 71ggaaggtgtg cacaccgctg gac 237223DNAArtificial Sequencesynthetic 72ggaaggtgtg cacaccactg gac

237323DNAArtificial Sequencesynthetic 73ggaaggtgtg cacactgctg gac 237423DNAArtificial Sequencesynthetic 74agactgtgcg cacaccgctg gac 237522DNAArtificial Sequencesynthetic 75tcttatcaga cagggggctc tc 227622DNAArtificial Sequencesynthetic 76aagaagcaca cgactgaggc ac 227722DNAArtificial Sequencesyntheticvariation(12)..(12)w = a or t 77agtggataga cwgatggggg tg 227822DNAArtificial Sequencesynthetic 78agtggataga ccgatggggc tg 227922DNAArtificial Sequencesynthetic 79aagggataga cagatggggc tg 228022DNAArtificial Sequencesynthetic 80ggaagacatt tgggaaggac tg 228122DNAArtificial Sequencesynthetic 81ggaagatgga tacagttggt gc 22

Claims

1. A rat or mouse having a restricted immunoglobulin heavy chain locus characterized by the presence of a single human V.sub.H gene segment, one or more human D.sub.H gene segments, and one or more human J.sub.H gene segments.

2. The rat or mouse of claim 1, wherein the mouse comprises a deletion of all or substantially all endogenous V.sub.H, D.sub.H, and J.sub.H gene segments.

3. The mouse of claim 1, wherein the single human V.sub.H gene segment is selected from V.sub.H1-2, V.sub.H1-69, V.sub.H2-26, V.sub.H2-70, V.sub.H3-23.

4.-5. (canceled)

6. The rat or mouse of claim 1, wherein the single human V.sub.H gene segment is operably linked to a human or non-human immunoglobulin constant region gene.

7. The rat or mouse of claim 6, wherein the single human V.sub.H gene segment is operably linked to a mouse, rat, or human constant region gene.

8. The rat or mouse of claim 1, further comprising a one or more human immunoglobulin V.sub.L gene segments operably linked to one or more human J.sub.L gene segments.

9. The rat or mouse of claim 8, wherein the one or more human V.sub.L gene segments and/or the one or more human J.sub.L gene segments are selected from human .kappa. and human .lamda. gene segments.

10. The rat or mouse of claim 8, wherein the one or more human immunoglobulin V.sub.L gene segments and the one or more human J.sub.L gene segments are operably linked to a non-human light chain constant gene.

11. The rat or mouse of claim 10, wherein the non-human light chain constant gene is selected from a mouse .kappa. or .lamda. constant region gene.

12. A mouse comprising, in its germline, a replacement at an endogenous immunoglobulin heavy chain locus of all or substantially all endogenous V.sub.H, D.sub.H, and J.sub.H gene segments with single human V.sub.H gene segment and/or polymorphic variants thereof, one or more human D.sub.H gene segments and one or more human J.sub.H gene segments.

13. The mouse of claim 12, further comprising a replacement at an endogenous immunoglobulin light chain locus of all or substantially all endogenous V.sub.L and J.sub.L gene segments with one or more human V.sub.L and one or more human J.sub.L gene segments.

14. (canceled)

15. A cell or tissue derived from the rat or mouse of claim 1.

16. A method of making a nucleic acid sequence encoding a human V.sub.H domain, comprising (a) immunizing a rat or mouse of claim 1 with an antigen of interest; (b) allowing said mouse to mount an immune response to the antigen of interest; and, (c) obtaining a nucleic acid sequence encoding a human V.sub.H domain from said mouse.

17.-19. (canceled)

20. The method of claim 16, wherein the immunoglobulin V.sub.H region sequence is at least 95% identical to SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66 or SEQ ID NO: 68.

21. The method of claim 16, wherein the immunoglobulin V.sub.H region sequence comprises SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68. or a polymorphic variant thereof.

22. The method of claim 16, wherein the immunoglobulin V.sub.H region sequence encodes a protein that is at least 95% identical with SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67 or SEQ ID NO: 69.

23. The method of claim 16, wherein the method further comprises making a nucleic acid sequence encoding a human V.sub.L domain that is cognate with the human V.sub.H domain, comprising isolating a B cell encoding the human V.sub.H domain and the human V.sub.L domain from said mouse and obtaining therefrom the sequence of the heavy and light chain variable domains.

24. The method of claim 23, wherein the human V.sub.L domain is a V.sub..kappa. domain.

25. The method of claim 16, wherein the mouse comprises a deletion of the endogenous immunoglobulin heavy chain locus and the endogenous .kappa. light chain.

26. A rat or mouse comprising an endogenous immunoglobulin heavy chain locus, wherein the endogenous immunoglobulin heavy chain locus consists essentially of a) one or more polymorphic variants of a single human V.sub.H gene segment, b) one or more human D.sub.H gene segments, and c) one or more human J.sub.H gene segments, wherein the single human V.sub.H gene segment is a polymorphic V.sub.H gene segment associated with a high copy number in human populations, and wherein the single human V.sub.H gene segment, one or more human D.sub.H gene segments, and one or more J.sub.H gene segments are operably linked to a non-human immunoglobulin heavy chain constant region gene.

27. A cell or tissue derived from the rat or mouse of claim 26.

28. A method of making a nucleic acid sequence encoding a human V.sub.H domain, comprising (a) immunizing a rat or mouse of claim 26 with an antigen of interest; (b) allowing said mouse to mount an immune response to the antigen of interest; and, (c) obtaining a nucleic acid sequence encoding a human V.sub.H domain from said mouse.