CN111107872A - 有用于癌症免疫疗法的牛痘病毒突变体 - Google Patents

有用于癌症免疫疗法的牛痘病毒突变体 Download PDF

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CN111107872A
CN111107872A CN201880046090.4A CN201880046090A CN111107872A CN 111107872 A CN111107872 A CN 111107872A CN 201880046090 A CN201880046090 A CN 201880046090A CN 111107872 A CN111107872 A CN 111107872A
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L·邓
S·舒曼
N·杨
T·梅古布
J·沃尔乔克
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Memorial Sloan Kettering Cancer Center
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Abstract

本文公开了与治疗、预防和/或改善有需要的受试者的癌症相关的方法和组合物。在具体方面，本发明技术涉及痘病毒单独地或与免疫检查点阻断剂组合地作为溶瘤和免疫治疗组合物的用途，所述痘病毒包括具有牛痘宿主范围因子C7缺失的重组改良安卡拉牛痘(MVA)病毒或牛痘病毒(分别为MVAΔC7L和VACVΔC7L)。在一些实施方案中，本公开文本的技术涉及进一步修饰以表达人Fms样酪氨酸激酶3配体(Flt3L)的MVAΔC7L或VACVΔC7L病毒。

Description

有用于癌症免疫疗法的牛痘病毒突变体
相关申请的交叉引用
本申请要求2017年5月12日提交的美国临时申请号62/505,713的优先权，将其通过引用以其整体特此并入。
联邦资助研究声明
本发明是在由美国国立卫生研究院授予的AI073736、AI095692、AR068118和CA008748下在美国政府支持下完成的。政府拥有本发明的某些权利。
序列表
本申请含有以ASCII格式电子提交并且通过引用以其整体特此并入的序列表。在2018年5月8日创建的所述ASCII副本命名为115872-0781_SL.txt并且大小为492,760字节。
技术领域
本公开文本的技术总体上涉及肿瘤学、病毒学和免疫疗法领域。具体而言，本发明技术涉及痘病毒单独地或与免疫检查点阻断剂组合地作为溶瘤和免疫治疗组合物的用途，所述痘病毒包括具有牛痘宿主范围因子C7缺失的重组改良安卡拉牛痘(MVA)病毒或牛痘病毒(分别为MVAΔC7L和VACVΔC7L)。在一些实施方案中，本公开文本的技术涉及进一步修饰以表达人Fms样酪氨酸激酶3配体(hFlt3L)的MVAΔC7L或VACVΔC7L病毒。
背景技术
提供以下描述以帮助读者理解。所提供的信息或所引用的参考文献均不被承认是现有技术。
恶性肿瘤(如黑素瘤)固有地对常规疗法具有抗性，并且提出了重大的治疗挑战。免疫疗法是一个不断发展的研究领域，并且是治疗某些类型的癌症的另外的选择。免疫疗法方法所基于的基本原理是可以刺激免疫系统以识别肿瘤细胞，并且靶向它们进行破坏。尽管通过癌细胞呈递抗原，并且存在可能对肿瘤细胞潜在发生反应的免疫细胞，但是在许多情况下，免疫系统未被激活或肯定地被抑制。此现象的关键是肿瘤通过迫使免疫系统的细胞抑制免疫系统的其他细胞来保护自身免受免疫应答影响的能力。肿瘤发展出许多免疫调节机制来逃避抗肿瘤免疫应答。因此，需要改善的免疫治疗方法来增强宿主抗肿瘤免疫和靶向肿瘤细胞进行破坏。
发明内容
在一方面，本公开文本提供了一种工程化的改良安卡拉牛痘(MVA)病毒株，其包含C7L基因的破坏。在一些实施方案中，所述经破坏的C7L基因不编码全长野生型基因产物。在一些实施方案中，所述经破坏的C7L基因包含异源核酸序列到C7L基因的编码序列的插入。在一些实施方案中，所述经破坏的C7L基因包含一个或多个基因盒的插入。在一些实施方案中，所述经破坏的C7L基因包含一个或多个基因盒对至少一部分基因的替换。在一些实施方案中，所述经破坏的C7L基因包含一个或多个基因盒对整个C7L基因的替换。在一些实施方案中，所述一个或多个基因盒包含编码可选择标记的核苷酸序列。在一些实施方案中，所述一个或多个基因盒包含编码人Fms样酪氨酸激酶3配体(hFlt3L)的核苷酸序列。
在一方面，本公开文本提供了一种工程化的改良安卡拉牛痘(MVA)病毒株，其包含C7L基因的破坏，其中所述MVA毒株展现出以下特征中的一种或多种：(i)与感染相应的野生型毒株的树突细胞和THP-1细胞相比，诱导树突细胞和THP-1细胞中干扰素β(IFNB)表达水平升高；(ii)与感染相应的野生型毒株的树突细胞相比，诱导树突细胞中TBK1和IRF3磷酸化水平升高；(iii)与感染相应的野生型毒株的树突细胞相比，诱导树突细胞中ISG表达水平升高；(iv)与感染相应的野生型毒株的癌细胞相比，诱导癌细胞中IFNB、CCL4、CCL5和CXCL10中的至少一种水平升高；以及(v)与感染相应的野生型毒株的肿瘤相比，减小与所述工程化的MVA毒株接触的肿瘤的肿瘤体积。在一些实施方案中，所述癌细胞包含黑素瘤细胞。在一些实施方案中，所述肿瘤包含恶性黑素瘤。
在一方面，本公开文本提供了一种包含工程化的改良安卡拉牛痘(MVA)病毒株的免疫原性组合物，所述工程化的改良安卡拉牛痘(MVA)病毒株包含C7L基因的破坏。在一些实施方案中，所述免疫原性组合物还包含药学上可接受的载体。在一些实施方案中，所述免疫原性组合物还包含药学上可接受的佐剂。
在一方面，本公开文本提供了一种工程化的减毒牛痘病毒(VACV)株，其包含C7L基因的破坏。在一些实施方案中，所述经破坏的C7L基因不编码全长野生型基因产物。在一些实施方案中，所述经破坏的C7L基因包含异源核酸序列到C7L基因的编码序列的插入。在一些实施方案中，所述经破坏的C7L基因包含一个或多个基因盒的插入。在一些实施方案中，所述经破坏的C7L基因包含一个或多个基因盒对至少一部分基因的替换。在一些实施方案中，所述一个或多个基因盒包含编码可选择标记的核苷酸序列。在一些实施方案中，所述一个或多个基因盒包含编码人Fms样酪氨酸激酶3配体(hFlt3L)的核苷酸序列。在一些实施方案中，与感染相应的野生型毒株的小鼠相比，感染所述工程化的减毒VACV毒株的小鼠具有增加的感染后寿命。
在一方面，本公开文本提供了一种包含工程化的减毒牛痘病毒(VACV)株的免疫原性组合物，所述工程化的减毒牛痘病毒(VACV)株包含C7L基因的破坏。在一些实施方案中，所述免疫原性组合物还包含药学上可接受的载体。在一些实施方案中，所述免疫原性组合物还包含药学上可接受的佐剂。
在一方面，本公开文本提供了一种重组牛痘病毒(VACV)核酸序列，其中在SEQ IDNO:1的位置15,716和16,168之间的核酸序列被包含编码可选择标记的开放阅读框的异源核酸序列替换。在一些实施方案中，所述异源核酸序列的开放阅读框与能够指导所述可选择标记表达的启动子可操作地连接。在一些实施方案中，所述可选择标记是生物发光蛋白、荧光蛋白、化学发光蛋白、黄嘌呤-鸟嘌呤磷酸核糖基转移酶基因(gpt)或其任何组合。在一些实施方案中，所述可选择标记是绿色荧光蛋白(GFP)。在一些实施方案中，所述异源核酸序列还包含编码人Fms样酪氨酸激酶3配体(hFlt3L)的开放阅读框。
在一方面，本公开文本提供了一种重组改良安卡拉牛痘(MVA)病毒核酸序列，其中在SEQ ID NO:2的位置18,407和18,859之间的核酸序列被包含编码可选择标记的开放阅读框的异源核酸序列替换。在一些实施方案中，所述异源核酸序列的开放阅读框与能够指导所述可选择标记表达的启动子可操作地连接。在一些实施方案中，所述可选择标记是生物发光蛋白、荧光蛋白、化学发光蛋白、黄嘌呤-鸟嘌呤磷酸核糖基转移酶基因(gpt)或其任何组合。在一些实施方案中，所述可选择标记是绿色荧光蛋白(GFP)。在一些实施方案中，所述异源核酸序列还包含编码人Fms样酪氨酸激酶3配体(hFlt3L)的开放阅读框。
在一方面，本公开文本提供了一种用于治疗有需要的受试者的实体瘤的方法，所述方法包括将包含有效量的包含C7L基因的破坏的工程化的改良安卡拉牛痘(MVA)病毒株(MVAΔC7L)和/或基因工程化以表达hFlt3L的MVAΔC7L病毒(MVAΔC7L-hFlt3L)的组合物递送至肿瘤。在一些实施方案中，所述破坏包含C7L基因的缺失。在一些实施方案中，治疗包含以下中的一种或多种：在所述受试者体内诱导针对所述肿瘤的免疫应答或者在所述受试者体内增强或促进针对所述肿瘤的正在进行的免疫应答、减小所述肿瘤的大小、根除所述肿瘤、抑制所述肿瘤的生长、抑制所述肿瘤的转移性生长、诱导肿瘤细胞的凋亡或延长所述受试者的存活期。在一些实施方案中，所述免疫应答的诱导、增强或促进包含以下中的一种或多种：(i)与感染相应的野生型毒株的树突细胞和THP-1细胞相比，树突细胞和THP-1细胞中干扰素β(IFNB)表达的水平升高；(ii)与感染相应的野生型毒株的树突细胞相比，树突细胞中TBK1和IRF3磷酸化的水平升高；(iii)与感染相应的野生型毒株的树突细胞相比，树突细胞中ISG表达的水平升高；以及(iv)与感染相应的野生型毒株的肿瘤细胞相比，肿瘤细胞中IFNB、CCL4、CCL5和CXCL10中的至少一种的水平升高。在一些实施方案中，所述组合物通过瘤内或静脉内注射或者瘤内和静脉内注射的同时或顺序组合来给予。在一些实施方案中，所述肿瘤是黑素瘤、结肠癌、乳腺癌或前列腺癌。在一些实施方案中，所述组合物还包含一种或多种免疫检查点阻断剂。在一些实施方案中，所述免疫检查点阻断剂选自：CTLA-4、CD80、CD86、PD-1、PDL1、PDL2、LAG3、B7-H3、B7-H4、TIM3、ICOS、II DLBCL抑制剂、BTLA、伊匹单抗、纳武单抗、派姆单抗、皮地利珠单抗(pidilizumab)、AMP-224、MPDL3280A、BMS-936559、MED14736、MSB 00107180及其任何组合。
在一方面，本公开文本提供了一种用于治疗有需要的受试者的实体瘤的方法，所述方法包括将包含有效量的包含C7L基因的破坏的工程化的牛痘病毒(VACV)株(VACVΔC7L)和/或基因工程化以表达hFlt3L的VACVΔC7L病毒(VACVΔC7L-hFlt3L)的组合物递送至肿瘤。在一些实施方案中，所述破坏包含C7L基因的缺失。在一些实施方案中，治疗包含以下中的一种或多种：在所述受试者体内诱导针对所述肿瘤的免疫应答或者在所述受试者体内增强或促进针对所述肿瘤的正在进行的免疫应答、减小所述肿瘤的大小、根除所述肿瘤、抑制所述肿瘤的生长、抑制所述肿瘤的转移性生长、诱导肿瘤细胞的凋亡或延长所述受试者的存活期。在一些实施方案中，所述免疫应答的诱导、增强或促进包含以下中的一种或多种：(i)与感染相应的野生型毒株的树突细胞和THP-1细胞相比，树突细胞和THP-1细胞中干扰素β(IFNB)表达的水平升高；(ii)与感染相应的野生型毒株的树突细胞相比，树突细胞中TBK1和IRF3磷酸化的水平升高；(iii)与感染相应的野生型毒株的树突细胞相比，树突细胞中ISG表达的水平升高；以及(iv)与感染相应的野生型毒株的肿瘤细胞相比，肿瘤细胞中IFNB、CCL4、CCL5和CXCL10中的至少一种的水平升高。在一些实施方案中，所述组合物通过瘤内或静脉内注射或者瘤内和静脉内注射的同时或顺序组合来给予。在一些实施方案中，所述肿瘤是黑素瘤、结肠癌、乳腺癌或前列腺癌。在一些实施方案中，所述组合物还包含一种或多种免疫检查点阻断剂。在一些实施方案中，所述免疫检查点阻断剂选自：CTLA-4、CD80、CD86、PD-1、PDL1、PDL2、LAG3、B7-H3、B7-H4、TIM3、ICOS、II DLBCL抑制剂、BTLA、伊匹单抗、纳武单抗、派姆单抗、皮地利珠单抗、AMP-224、MPDL3280A、BMS-936559、MED14736、MSB00107180及其任何组合。
在一方面，本公开文本提供了一种刺激免疫应答的方法，其包括向受试者给予包含工程化的改良安卡拉牛痘(MVA)病毒株的免疫原性组合物，所述工程化的改良安卡拉牛痘(MVA)病毒株包含C7L基因的破坏。
在一方面，本公开文本提供了一种刺激免疫应答的方法，其包括向受试者给予包含工程化的减毒牛痘病毒(VACV)株的免疫原性组合物，所述工程化的减毒牛痘病毒(VACV)株包含C7L基因的破坏。
附图说明
图1A-1D是数据的一系列图形表示，其显示牛痘C7抑制STING、TBK1或IRF3介导的IFNB基因表达。图1A：将24孔板中的HEK293T细胞(2x 105)用表达IFNB-luc报告物、STING、如所指示的C7L的质粒转染。转染后24h进行双萤光素酶测定。通过将在IFNB启动子下的萤火虫萤光素酶活性相对于来自对照质粒pRL-TK的海肾萤光素酶活性归一化，以任意单位表示相对萤光素酶活性。通过将相对萤光素酶活性除以背景水平来计算诱导倍数。数据是均值±SEM(n＝3)。图1B-1D：将HEK293T细胞(2x 105)用表达TBK1、IRF3或IRF3-5D的质粒(表达或不表达渐增量的C7(10、50或250ng))转染。IRF3-5D是磷酸化活性突变型IRF3。数据是均值±SEM(n＝3)。(*P<0.05；**P<0.01；***P<0.001，t检验)。
图1E和1F是显示牛痘C7与转录因子IRF3相互作用的印迹。将HEK293T细胞单独地或组合地用Flag标记的人IRF3或C7L共转染。图1E：将全细胞裂解物(WCL)用抗Flag和抗C7抗体印迹。图1F：将全细胞裂解物用抗C7抗体免疫沉淀(IP：抗C7)，并且用抗Flag抗体免疫印迹。
图2A-2C是数据的一系列图形表示，其显示牛痘C7抑制聚IC/TLR3和TRIF介导的INFB启动子激活。图2A：将HEK293T细胞(2x 105)用表达TLR3、IFN-β-luc报告物的质粒和渐增量的C7表达质粒(10、50或250ng)转染。24h后，将细胞用聚IC(5μg/ml)处理。聚IC处理后24h测定萤光素酶活性。数据是均值±SEM(n＝3)。图2B：将HEK293T细胞(2x 105)用表达TRIF、IFNB-luc报告物和渐增量的C7(10、50或250ng)的质粒转染。转染后24h进行双萤光素酶测定。数据是均值±SEM(n＝3)。图2C：将HEK293T细胞(2x 105)用表达MAVS、IFNB-luc报告物和渐增量的C7(10、50或250ng)的质粒转染。转染后24h进行双萤光素酶测定。数据是均值±SEM(n＝3)。(*P<0.05；**P<0.01；***P<0.001，t检验)。
图3A-3D是数据的一系列图形表示，其显示巨噬细胞中牛痘C7的过表达抑制通过多种刺激物诱导的IFNB基因表达。将表达C7或具有空载体(EV)的RAW264.7稳定细胞系(2x106)分别用仙台病毒(SeV)(10HA单位/ml)感染，或用聚IC(5μg/ml)转染(图3A)，或用热灭活的MVA(H-MVA)(相当于10的MOI)处理，或用ISD(10μg/ml)转染(图3B)。24h后，通过定量实时PCR测量IFNB基因表达水平。图3C-3D：将表达C7或具有空载体的THP-1稳定细胞系(2x106)用(PMA；20ng/ml)分化3天，然后按(图3A-3B)处理。数据是均值±SEM(n＝3)。(**P<0.01；***P<0.001，t检验)。
图4A是在质粒DNA pC7L-GFP载体和MVA病毒基因组DNA之间在C7基因基因座处的同源重组的示意图。使用pC7L-GFP质粒将在牛痘合成早期和晚期启动子(PsE/L)控制下的特定目的基因(SG)(如人Flt3L(hFlt3L))插入C7L基因座中。在这种情况下，将在牛痘p7.5启动子控制下的GFP用作选择标记。将表达盒两侧侧接C7L基因侧翼区域(C7-L和C7-R)的部分序列。图4B示出了表达GFP的MVAΔC7L病毒的噬斑纯化。将BHK21细胞(1x 106)用MVA以0.2的MOI感染。感染1-2h后，将细胞用pC7L-GFP与lipofectamine2000转染。在质粒DNA和MVA基因组DNA的C7L基因座处发生的同源重组导致将GFP表达盒插入MVA基因组DNAC7基因座中，以从MVA基因组中缺失整个C7L基因，并且导致重组病毒MVAΔC7L的产生。将重组病毒基于GFP表达富集，并且将GFP+噬斑纯化4-5轮，直到获得所需的重组病毒而不污染MVA。图4C提供了重组病毒MVAΔC7L的PCR验证。重组病毒的PCR分析证明成功产生了MVAΔC7L。将病毒基因组DNA通过PCR分析以验证C7L的缺失。
图5A-5D是数据的一系列图形表示，其显示与MVA相比，MVAΔC7L在骨髓衍生的树突细胞(BMDC)和THP-1细胞中诱导更强的先天免疫应答。将1x 106个BMDC(图5A)或THP-1(图5C)用MVA或MVAΔC7L以10的MOI感染。在指定的时间点，进行IFNB mRNA的定量实时PCR分析。数据是均值±SEM(n＝3)。图5B：与(图5A)相同，将BMDC用WT VACV、MVA或MVAΔC7L以10的MOI感染。在感染后22h收集上清液。通过ELISA确定IFN-β的浓度。数据是均值±SEM(n＝3)。图5D：将BMDC(1x 106)用MVA或MVAΔC7L以10的MOI感染。在感染后2、4和8h收集细胞。使用抗磷酸-TBK1、抗TBK1、IRF3的抗磷酸丝氨酸-396和抗IRF3进行Western印迹分析。将β-肌动蛋白用作上样对照。
图6A-6B是数据的一系列图形表示，其显示牛痘C7减弱I型IFN诱导的JAK-STAT信号传导途径。图6A：牛痘ORF(C1L-C10L)抑制I型IFN诱导的干扰素刺激应答元件(ISRE)活性的能力的筛选。将HEK293T细胞(2x 105)用表达ISRE-luc报告物的质粒和对照质粒pRL-TK以及如所指示的牛痘ORF(C1L-C10L)转染，所述ISRE-luc报告物在ISRE一旦被激活时即表达萤火虫萤光素酶，并且所述对照质粒pRL-TK在ISRE一旦被激活时即表达海肾萤光素酶。转染后24h，将细胞用人IFN-β以1000U/ml的终浓度处理。IFN-β处理后24h进行双萤光素酶测定。通过将萤火虫萤光素酶活性相对于海肾萤光素酶活性归一化，以任意单位表示相对萤光素酶活性。数据是均值±SEM(n＝3)。(**P<0.01，t检验)。图6B：按图6A进行条件和分析，不同的是将HEK293T细胞用渐增量的含有C7L基因的质粒(10、50或250ng)转染。数据是均值±SEM(n＝3)。(*P<0.05；**P<0.01；***P<0.001，t检验)。
图7A和7B是数据的一系列图形表示，其显示HEK293T和鼠巨噬细胞中牛痘C7的过表达抑制I型IFN诱导的ISG15基因表达。将表达C7或具有空载体的HEK293T(图7A)或RAW264.7(图7B)稳定细胞系(1x 106)用人(图7A)或鼠(图7B)IFN-β以1000U/ml的终浓度处理16h。通过定量实时PCR测量ISG15 mRNA水平。数据是均值±SEM(n＝3)。(***P<0.001，t检验)。
图8A和8B是数据的一系列图形表示，其显示与MVA相比，MVAΔC7L在BMDC中诱导更高水平的干扰素刺激基因(ISG)表达。将BMDC(1x 106)用MVA或MVAΔC7L以10的MOI感染。感染后12和24h，收获细胞并且进行ISG15(图8A)或Mx1(图8B)mRNA的定量实时PCR分析。数据是均值±SEM(n＝3)。(***P<0.001，t检验)。
图9A和9B是数据的一系列图形表示，其显示MVAΔC7L无法表达C7蛋白并且不能抑制IFN-β诱导的STAT2磷酸化。(A)将HeLa细胞(2x 105)用MVA或MVAΔC7L以10的MOI感染。在感染后4和12h收集细胞。使用抗C7抗体进行Western印迹分析。将GAPDH用作上样对照。(B)在用鼠IFN-β以1000U/ml的终浓度处理指定的时间之前，将TBK1-/-MEF用MVA或MVAΔC7L以10的MOI感染6h。使用抗pSTAT2或抗C7抗体进行Western印迹分析。将GAPDH用作上样对照。
图10A和10B是数据的一系列图形表示，其显示牛痘C7蛋白与STAT2相互作用。将HEK293T细胞(1.5x 107)用2.5μg的Flag标记的人STAT1或STAT2与HA标记的C7共转染，然后用人IFN-β以1000U/ml的终浓度处理或假处理45min。图10A示出了使用抗FLAG和抗HA抗体的全细胞裂解物(WCL)的western印迹，证明了在转染细胞中STAT1或STAT2和C7-HA的表达。将β-肌动蛋白用作上样对照。用抗HA抗体免疫沉淀全细胞裂解物后，然后用抗Flag抗体探测与C7-HA蛋白相互作用的蛋白质。图10B示出了使用抗Flag抗体的抗HA免疫沉淀物的western印迹，证明通过抗C7-HA从全细胞裂解物中仅下拉了Flag标记的STAT2。
图11A和11B示出了重组病毒VACVΔC7L的PCR分析，证明从牛痘基因组成功缺失了C7基因。使用pC7L-GFP质粒将特定目的基因插入C7基因座中。在这种情况下，将在牛痘p7.5启动子控制下的GFP用作选择标记(图4A)。将BSC40细胞(1x 106)用MVA以0.2的MOI感染。感染1-2h后，将细胞用pC7-GFP与lipofectamine 2000转染。在质粒DNA和VACV基因组DNA的C7L基因座处发生的同源重组导致将GFP表达盒插入VACV基因组DNAC7基因座中，以从VACV基因组中缺失整个C7L基因，并且导致重组病毒VACVΔC7L的产生。通过PCR分析病毒基因组DNA。图11A显示在VACVΔC7L病毒中，从VACV基因组中缺失了C7基因。在感染WT VACV或VACVΔC7L的HeLa细胞中进行Western印迹分析。图11B显示牛痘C7蛋白未由VACVΔC7L感染的细胞表达。
图12A和12B是图像和图形表示，其显示VACVΔC7L具有比WT VACV小的噬斑大小，并且对IFN抑制更敏感。图12A示出了WT VACV和VACVΔC7L在感染前用人IFN-β以1000U/ml的终浓度预处理或假处理12h的BSC40细胞(非洲绿猴肾细胞系)上的噬斑测定。左上角显示了基于病毒滴度的每个孔中预期的噬斑形成单位(pfu)。初次接种后，在将细胞用结晶紫染料染色之前，如所指示，将细胞用或不用人IFN-b以1000U/ml的终浓度继续接种48h。图12B是在存在或不存在人IFN-β的情况下WT VACV和VACVΔC7L的多步生长曲线。将BSC40细胞用人IFN-β以1000U/ml的终浓度预处理或假处理12h。然后，如所指示，在存在或不存在IFN-β的情况下，将细胞用WT VACV或VACVΔC7L以0.05的MOI感染。在指定的时间收集感染的细胞，并且通过在BSC40细胞上的噬斑测定来确定病毒滴度。
图13A-13D是数据的一系列图形表示，其显示在鼠鼻内感染模型中VACVΔC7L被高度减毒。图13A是在WT C57BL/6J小鼠中用WT VACV以渐增的剂量(包括2x 103、2x 104、2x105或2x 106个噬斑形成单位(PFU))鼻内感染后随天数变化的初始重量％的图。图13B是感染渐增剂量的WT VACV的小鼠的Kaplan-Meier存活曲线。每组中n＝10。图13C是在WTC57BL/6J小鼠中用VACVΔC7L以渐增的剂量(包括2x 105、2x 106或2x 107PFU)鼻内感染后随天数变化的初始重量％的图。图13D是感染渐增剂量的VACVΔC7L的小鼠的Kaplan-Meier存活曲线。每组中n＝10。
图14A-14D是数据的图形表示，其显示WT VACV在Sting缺陷型(STINGGt/Gt)小鼠中获得了毒力，然而在鼠鼻内感染模型中VACVΔC7L在STINGGt/Gt小鼠中仍然没有致病性。图14A是在STINGGt/Gt小鼠和WT年龄匹配的C57BL/6J对照中用WT VACV以2x 105PFU鼻内感染后随天数变化的初始重量％的图。图14B是感染WT VACV的STINGGt/Gt和WT小鼠的Kaplan-Meier存活曲线。每组中n＝6。图14C是在STINGGt/Gt小鼠和WT年龄匹配的C57BL/6J对照中用VACVΔC7L以2x 105PFU鼻内感染后随天数变化的初始重量％的图。图14D是感染VACVΔC7L的STINGGt/Gt和WT小鼠的Kaplan-Meier存活曲线。每组中n＝10。
图15A-15B是数据的图形表示，其显示WT和STINGGt/Gt小鼠在VACVΔC7L感染中均存活，发展了针对致死性WT VACV感染的抗病毒免疫。图15A是在用WT VACV以2x 106PFU攻击的用VACVΔC7L感染中存活的STINGGt/Gt和WT小鼠鼻内感染后随天数变化的初始重量％的图。将从未感染VACVΔC7L的初试小鼠也用WT VACV以相同剂量攻击。图15B是STINGGt/Gt和WT小鼠的Kaplan-Meier存活曲线，所述小鼠最初感染VACVΔC7L并且在VACVΔC7L感染中存活，然后用WT VACV以2x 106PFU攻击。
图16A-16G是数据的图形表示，其显示在鼠鼻内感染模型中在STAT2-/-或IFNAR1-/-小鼠中，VACVΔC7L病毒获得了毒力。图16A是在STAT2-/-、IFNAR1-/-、MDA5-/-小鼠和WT年龄匹配的C57BL/6J对照中用VACVΔC7L以2x 107pfu鼻内感染后随天数变化的初始重量％的图。图16B是感染VACVΔC7L病毒的STAT2-/-、IFNAR1-/-、MDA5-/-小鼠和WT对照小鼠的Kaplan-Meier存活曲线。每组中n＝5。图16C是感染后4h收获的每克组织的病毒滴度(Log pfu)的图。每组中n＝3。图16D是在STAT2-/-小鼠中用VACVΔC7L以2x 102、2x103、2x 104或2x105pfu鼻内感染后随天数变化的初始重量％的图。图16E是用VACVΔC7L以2x 102、2x 103、2x 104或2x 105pfu病毒感染的STAT2-/-的Kaplan-Meier存活曲线。每组中n＝5。图16F是在IFNAR1-/-小鼠中用VACVΔC7L以2x 102、2x 103或2x 105pfu鼻内感染后随天数变化的初始重量％的图。图16G是用VACVΔC7L以2x 102、2x 103或2x 105pfu病毒感染的STAT2-/-的Kaplan-Meier存活曲线。每组中n＝5。
图17A-17B是数据的图形表示，其显示在鼠鼻内感染模型中在MDA5-/-STINGGt/Gt小鼠中，VACVΔC7L病毒获得了毒力。图17A：在STINGGt/Gt、MDA5-/-STINGGt/Gt小鼠和WT年龄匹配的C57BL/6J对照中用VACVΔC7L以2x 107pfu鼻内感染后随天数变化的初始重量％。图17B：感染VACVΔC7L病毒的STINGGt/Gt、MDA5-/-STINGGt/Gt小鼠和WT对照的Kaplan-Meier存活曲线。每组中n＝5。
图18A-18M是数据的图形表示，其显示VACVΔC7L感染导致树突细胞(DC)、嗜中性粒细胞、CD8+和CD4+T细胞流入被感染的肺的支气管肺泡腔中。将C57BL/6J小鼠用WT VACV以2x 105pfu或用VACVΔC7L以2x 107pfu鼻内感染。在感染后3和6天收集BALF。通过FACS分析细胞。图18A：在支气管肺泡灌洗液(BAL)中Siglec F+CD11c+肺泡巨噬细胞的点状图；图18B：在BAL中肺泡巨噬细胞占CD45+细胞的百分比；图18C：在BAL中肺泡巨噬细胞的绝对数量。图18D：感染后第3天和第6天在BAL中CD11c+MHC-IIhi常规树突细胞(cDC)的点状图；图18E：在BAL中cDC占CD45+细胞的百分比；图18F：在BAL中cDC的绝对数量。图18G：感染后第3天和第6天在BAL中Ly6G+Ly6C+嗜中性粒细胞的点状图；图18H：在BAL中Ly6G+Ly6C+嗜中性粒细胞占CD45+细胞的百分比；图18I：在BAL中Ly6G+Ly6C+嗜中性粒细胞的绝对数量。图18J：感染后第6天在BAL中CD8+T细胞的点状图；图18K：在BAL中CD8+T细胞占CD45+细胞的百分比和CD8+T细胞的绝对数量。图18L：感染后第6天在BAL中CD4+T细胞的点状图；图18M：在BAL中CD4+T细胞占CD45+细胞的百分比和CD4+T细胞的绝对数量。
图19A-19B是数据的图形表示，其显示在STAT2-/-或IFNAR1-/-小鼠中，VACVΔC7L诱导的CD8+T细胞募集减少。图19A：在WT、STAT2-/-或IFNAR-/-小鼠中，用PBS假感染或用VACVΔC7L(2x 105pfu)感染后第6天，在BAL中CD8+T细胞的点状图。图19B：在感染后第6天，在BAL中CD8+T细胞占CD45+细胞的百分比。
图20A-20B是数据的图形表示，其显示鼻内感染VACVΔC7L导致CD8+和CD4+T细胞募集进入肺实质中。将WT C57BL6/J小鼠用WT VACV或用VACVΔC7L以2x 105pfu感染。在感染后第6天收集肺并且用胶原酶D消化。将单细胞悬浮液用抗CD45、抗CD3、抗CD4和抗CD8抗体染色，并且通过FACS分析。图20A：感染后第6天在肺中CD8+T细胞的点状图；在肺中CD8+T细胞占CD45+细胞的百分比。图20B：感染后第6天在肺中CD4+T细胞的点状图；在肺中CD4+T细胞占CD45+细胞的百分比。
图21A-21B是数据的图形表示，其显示鼻内感染VACVΔC7L导致牛痘病毒B8R特异性CD8+T细胞的产生并且募集进入肺和支气管肺泡腔中。将WTC57BL6/J小鼠用WT VACV或用VACVΔC7L以2x 105pfu鼻内感染。感染后5天收集BAL和肺。收集肺并且用胶原酶D消化。将单细胞悬浮液在布雷菲德菌素A(5μg/ml)的存在下与SIINFEKL(SEQ ID NO:7)或TS YKFESV(SEQID NO:8)肽脉冲的BMDC一起孵育6h，然后用抗CD45、抗CD3、抗CD8和抗IFN-γ抗体染色，并且通过FACS分析。
图22A-22B是数据的图形表示，其显示宿主防御急性VACVΔC7L鼻内感染不需要CD8+T细胞。将WT C57BL6/J小鼠用VACVΔC7L以2x 107pfu鼻内感染。在病毒感染前1天和感染后1、3和5天，腹膜内注射200μg的抗CD8+耗竭抗体(克隆2.43.BioXCell)。图22A是鼻内感染VACVΔC7L后随天数变化的初始重量％的图。图22B是感染VACVΔC7L的小鼠的Kaplan-Meier存活曲线。每组中n＝5。
图23A-23B是数据的图形表示，其显示鼻内感染VACVΔC7L导致IFN-β、促炎细胞因子和趋化因子释放到支气管肺泡腔中。将C57BL/6J小鼠用WTVACV以2x 105pfu或用VACVΔC7L以2x 107pfu鼻内感染。在感染后1和3天收集BAL。图23A是通过ELISA确定的BAL中IFN-β的浓度。图23B是通过Luminex分析(Cytokine 20-Plex Mouse Panel，ThermoFisher)确定的BAL中的细胞因子和趋化因子概况。
图24提供了数据的图形表示，其显示在IFNβ/YFP报告小鼠中，VACVΔC7L感染诱导从II型肺泡上皮细胞(AECII)产生IFN-β。将IFNβ/YFP报告小鼠或WT C57BL/6J WT对照用VACVΔC7L鼻内感染(每只小鼠2x 107pfu)。48h后，收集肺，并且在将肺切成小块之前，在室温下为其输注在低熔点琼脂糖(1％)中的分散酶(1U/ml)持续30min。产生单细胞悬浮液并且通过FACS分析。右上方显示的是来自WT和IFNβ/YFP报告小鼠的肺中的CD45+细胞。右中间显示的是来自WT和IFNβ/YFP报告小鼠的肺中的CD45-细胞。右下方显示的是来自WT和IFNβ/YFP报告小鼠的肺中的CD45-CD31-Tla-细胞(不包括CD31+内皮细胞和Tla+I型AEC)。
图25A-25D是数据的图形表示，其显示VACVΔC7L感染诱导从肺II型肺泡上皮细胞(ACEII)产生IFN-β、CCL4和CCL5。图25A：将谱系阴性的上皮干/祖细胞(LNEP)定义为CD45-CD16-CD32-CD31-EpCAMhiCD104+细胞，将其经FACS分选用于体外培养。图25B：将LNEP在角质形成细胞生长因子的存在下在基质胶包被平板上生长培养4天后，在分化的原代肺II型肺泡上皮细胞(AEC)中对SPC(表面活性剂C)进行免疫荧光染色。图25C：在WT VACV或VACVΔC7L感染(以10的MOI)12h后，在原代肺II型AEC中的IFNB、CCL4和CCL5的RT-PCR分析。图25D：在WT VACV或VACVΔC7L感染24h后，来自原代肺II型AEC上清液的IFN-β、CCL4和CCL5的ELISA分析。
图26A-26B是数据的图形表示，其显示IFN-β的鼻内施用使小鼠免于致死性VACV感染。将WT C57BL6/J小鼠用WT VACV以2x 106pfu鼻内感染。12h后，为小鼠鼻内注射1μg重组小鼠IFN-β。图26A是鼻内感染WT VACV后随天数变化的初始重量％的图。图26B是感染WTVACV的小鼠的Kaplan-Meier存活曲线。每组中n＝5。
图27A-D是数据的图形表示，其显示在B16-F10黑素瘤细胞中，MVAΔC7L是比MVA更强的先天免疫应答诱导剂。将B16-F10细胞用MVA或MVAΔC7L以10的MOI感染，并且在感染后8和48h收集细胞。示出了Ifnb(图27A)、Ccl4(图27B)、Ccl5(图27C)、Cxcl10(图27D)基因表达的定量实时PCR分析。
图28A-D是数据的图形表示，其显示在双侧B16-F10肿瘤植入模型中瘤内注射MVAΔC7L比MVA更有效。图28A是B16-F10双侧肿瘤植入模型的肿瘤植入和处理方案。简言之，将B16-F10黑素瘤细胞皮内植入C57B/6J小鼠的左右侧腹(右侧腹5x 105，左侧腹1x 105)。肿瘤植入后8天，我们将2x 107pfu的MVA或MVAΔC7L瘤内注射进右侧腹较大的肿瘤内。每周两次测量肿瘤大小并且注射肿瘤。监测小鼠的存活。图28B是用PBS、MVA或MVAΔC7L处理的荷瘤小鼠的Kaplan-Meier存活曲线图(n＝10，*P<0.05；***P<0.001；Mantel-Cox检验)。图28C和28D是数据的图形表示，其示出了在注射PBS、MVA或MVAΔC7L之后随天数变化的注射的(图28C)和未注射的(图28D)肿瘤的体积。
图29A-D是数据的图形表示，其显示与MVA相比，瘤内注射MVAΔC7L诱导更强的CD8+和CD4+免疫应答。图29A是在用MVA、MVAΔC7L或PBS处理的小鼠的注射的肿瘤中，肿瘤浸润的淋巴细胞的FACS分析图。示出了在用PBS(n＝4)或MVA(n＝4)或MVAΔC7L(n＝5)处理的小鼠的注射的肿瘤内颗粒酶B+CD8+T细胞、颗粒酶B+CD4+T细胞的百分比、CD8+/Treg的比率(*P<0.05；****P<0.0001，t检验)。图29B是FACS分析数据的图，其示出了在用PBS(n＝4)或MVA(n＝4)或MVAΔC7L(n＝5)处理的小鼠的未注射的肿瘤内颗粒酶B+CD8+T细胞、颗粒酶B+CD4+T细胞的百分比、CD8+/Treg的比率(*P<0.05；**P<0.01；***P<0.001；****P<0.0001，t检验)。图29C是FACS数据的图，其示出了在用PBS(n＝4)或MVA(n＝4)或MVAΔC7L(n＝5)处理的小鼠的TDLN中的酪氨酸酶相关蛋白2(TRP2)四聚体阳性CD8+T细胞。图29D是FACS数据的图，其示出了在用PBS(n＝4)或MVA(n＝4)或MVAΔC7L(n＝5)处理的小鼠的非引流LN中的TRP-2四聚体阳性CD8+T细胞(*P<0.05；**P<0.01；***P<0.001)。
图30A-C是显示重组MVAΔC7L-hFlt3L产生的数据的图形表示。图30A：显示通过在C7侧翼序列(C6L和C8L)进行同源重组产生MVAΔC7L-hFlt3L重组病毒的示意图。简言之，插入侧接C6和C8序列的具有在牛痘p7.5启动子控制下的GFP和在牛痘合成早期和晚期启动子(PsE/L)控制下的hFlt3L基因的单个盒，以替换MVA基因组中的C7基因。图30B：用于扩增插入物的引物和重组病毒的PCR验证。图30C：在CEF和BHK21细胞中MVAΔC7L-hFlt3L的复制曲线。将细胞用MVAΔC7L-hFlt3L以0.05的MOI感染，并且在感染后1、24、36、48和72h收集细胞。在BHK21细胞上通过滴定来确定病毒滴度。通过比较感染后72h的病毒滴度与感染后1h的病毒滴度来计算变化倍数。
图31.通过MVAΔC7L-hFlt3L-GFP感染的细胞表达hFlt3L。将细胞用MVAΔC7L-GFP或MVAΔC7L-hFlt3L-GFP以10的MOI感染细胞，并且在感染后24h收集细胞。使用抗hFlt3L抗体通过FACS分析评估hFlt3L表达。
具体实施方式
应当理解，为了提供对本发明技术的实质性理解，在各个细节层次上描述了本发明技术的某些方面、模式、实施方案、变型和特征。
I.定义
下文提供了如本说明书中使用的某些术语的定义。除非另外定义，否则本文使用的所有技术和科技术语均通常具有与本发明技术所属的领域中的普通技术人员通常所理解的相同含义。
如在本说明书和所附权利要求书中所用，单数形式“一种/一个”(“a”)、“一种/一个”(“an”)和“所述”(“the”)包括复数指示物，除非上下文另外明确说明。例如，提及“一个细胞”包括两个或更多个细胞的组合等。
如本文所用，术语“约”涵盖可能在测量中发生的并且对于熟练技术人员而言清楚的实验误差范围。
如本文所用，如与病毒结合使用的“减毒的”是指病毒与非减毒的对应物相比具有降低的毒力或致病性，但是仍是有活力的或存活的。通常，与非减毒的病毒相比，减毒使致病因子(如病毒)对受感染的对象具有较小的危害或毒力。这与被杀死的病毒或完全灭活的病毒形成对照。
如本文所用，“联合给予”是指与MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L组合地给予第二治疗方法。例如，与MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L在时间上非常接近地给予免疫检查点阻断剂。例如，可以与MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L同时(如上所述，当瘤内地或全身地给予MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L时，通过静脉内或瘤内注射)或者在MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L给予之前或之后，给予PD-1/PDL-1抑制剂和/或CTLA4抑制剂(在更具体的实施方案中，抗体)。在一些实施方案中，如果MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L给予和免疫检查点阻断剂给予的间隔为1-7天或甚至间隔长达三周，这将仍在如本文所述的“在时间上非常接近地”，因此这样的给予将被视为“联合的”。
在本文使用术语“相应的野生型毒株”以指代衍生出工程化的MVA或VACV毒株的野生型MVA或牛痘病毒(VACV)株。如本文所用，野生型MVA或VACV毒株是尚未被工程化以破坏或缺失(敲除)C7基因的毒株。工程化的MVA或VACV毒株可能已经过修饰以破坏或缺失(敲除)C7基因。
如本文所用，术语“递送”意指使本公开文本的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L沉积在肿瘤微环境中，无论这是通过向肿瘤局部给予(瘤内)还是通过例如静脉内途径完成的。所述术语侧重于到达肿瘤本身的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L。在一些实施方案中，“递送”与给予是同义的，但是记住它与特定的给予地点一起使用(例如，瘤内)。
术语“破坏”和“突变”在本文中可互换使用，以指代在遗传物质中可检测到且可遗传的变化。突变可以包括插入、缺失、取代(例如，转换、颠换)、转座、倒位、敲除及其组合。突变可能仅涉及单个核苷酸(例如，点突变或单核苷酸多态性)或多个核苷酸。在一些实施方案中，突变是沉默的，即未检测到突变的表型效应。在其他实施方案中，突变导致表型变化，例如，改变编码产物的表达水平，或者改变编码产物本身。在一些实施方案中，与野生型毒株相比，破坏或突变可能会产生基因产物(例如，蛋白质或RNA)表达水平降低的破坏的基因。在其他实施方案中，与野生型毒株表达的蛋白质的活性相比，破坏或突变可能导致表达的蛋白质具有较低的活性。
如本文所用，“有效量”或“治疗有效量”是指足够量的药剂，当以一个或多个剂量并且持续一段时间给予时，其足以在缓解、治愈或减轻疾病方面提供所需的生物学结果。在本公开文本中，MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的有效量是(当持续合适的时间段并且以合适的频率给予时)减少癌细胞数量；或减小肿瘤大小或根除肿瘤；或抑制(即，减慢或停止)癌细胞向外周器官的浸润；抑制(即，减慢或停止)转移性生长；抑制(稳定或阻止)肿瘤生长；允许治疗肿瘤；和/或诱导和促进针对肿瘤的免疫应答的量。根据本公开文本，本领域普通技术人员可以使用常规实验来确定在任何个别情况下的适当的治疗量。这种确定将开始于在体外发现有效的量和在动物中发现有效的量。治疗有效量将首先基于发现对培养细胞赋予益处的一种或多种浓度来确定。有效量可以从细胞培养物内的数据推断出来，并且可以基于诸如本文详述的因素上调或下调。尽管可以给予更低或更高的剂量，病毒构建体的有效量通常在约105至约1010个噬斑形成单位(pfu)的范围内。在一些实施方案中，剂量是约106-109pfu。在一些实施方案中，单位剂量以在从1到10ml范围内的体积来给予。根据所使用的特定pfu滴定方法，pfu与病毒颗粒的等效性可能有所不同。通常，pfu等于约5至100个病毒颗粒。能以一个或多个分剂量持续规定的时间段并且以规定的给予频率来给予治疗有效量的带有hFlt3L转基因的病毒。例如，根据本公开文本的带有hFlt3L的病毒的治疗有效量可以根据诸如受试者的疾病状态、年龄、性别、体重和一般状况以及病毒构建体在特定受试者体内针对特定癌症引起所需免疫应答的效力等因素而变化。
特别提及本文公开的基于病毒的免疫刺激剂，“有效量”或“治疗有效量”是指包含MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的组合物的如下量，其足以减少、抑制或消除肿瘤细胞的生长，从而减少或根除肿瘤，或者其足以抑制、减少或消除体外、离体或受试者体内的转移扩散，或者其足以引起和促进针对肿瘤的免疫应答，所述免疫应答视情况而定最终将导致转移扩散的减少、抑制和/或消除中的一种或多种。肿瘤细胞生长的减少、抑制或根除可能是坏死、细胞凋亡或免疫应答或前述两种或更多种的组合的结果(然而，例如细胞凋亡的沉淀可能不是由于与溶瘤病毒观察到的相同因素)。在治疗上有效的量可以取决于诸如组合物中使用的特定病毒、被治疗受试者的年龄和状况、肿瘤形成的程度、存在或不存在其他治疗方法等因素而变化。类似地，待给予的组合物的剂量及其给予的频率将取决于多种因素，如活性成分的效力、给予后其活性持续时间、给予途径、受试者的体型、年龄、性别和身体状况、不良反应的风险以及医师的判断。以多种剂型(如可注射溶液)给予组合物。
特别提及与免疫检查点抑制剂的组合疗法，免疫检查点阻断剂的“有效量”或“治疗有效量”意指免疫检查点阻断剂的足以逆转或减少肿瘤微环境中的免疫抑制作用以及足以激活或增强被治疗的受试者的宿主免疫的量。免疫检查点阻断剂包括但不限于针对CD28抑制剂的抑制性抗体如CTLA-4(细胞毒性T淋巴细胞抗原4)(例如，伊匹单抗)、抗PD-1(程序性死亡1)抑制性抗体(例如，纳武单抗、派姆单抗、皮地利珠单抗、拉姆布罗力珠单抗(lambrolizumab))和抗PD-L1(程序性死亡配体1)抑制性抗体(MPDL3280A、BMS-936559、MEDI4736、MSB 00107180)以及针对LAG-3(淋巴细胞激活基因3)、TIM3(T细胞免疫球蛋白和粘蛋白3)、B7-H3和TIGIT(具有Ig和ITIM结构域的T细胞免疫受体)的抑制性抗体。由于已经完成了一些给药临床试验，因此前述的剂量范围是已知的或容易地在本领域技术范围内的，从而外推到其他可能的药剂。
在一些实施方案中，肿瘤表达特定的检查点，但是在本发明的上下文中，这并不是严格必要的，因为免疫检查点阻断剂更通常地阻断由肿瘤细胞、基质细胞和肿瘤浸润的免疫细胞引起的肿瘤内的免疫抑制机制。
例如，当在黑素瘤中作为手术后的辅助疗法给予时，CTLA4抑制剂伊匹单抗在90分钟内以1-2mg/mL给予，每三周的总输注量为3mg/kg，共4剂。这种疗法通常伴随着严重的甚至危及生命的免疫介导的不良反应，这限制了耐受剂量以及可以给予的累积量。预期当将伊匹单抗与MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L联合给予时，可以降低伊匹单抗的剂量和/或累积量。具体而言，根据下文所述的实验结果，预期如果向肿瘤直接联合给予CTLA4抑制剂与一种或两种前述MVA病毒，则可以进一步降低CTLA4抑制剂的剂量。因此，上文为伊匹单抗提供的量可以是用于确定联合给予时待给予患者的特定剂量和累积量的起点。
作为另一个例子，开具派姆单抗的处方为作为黑素瘤的辅助疗法稀释至25mg/mL给予。每三周在30分钟内以2mg/kg的剂量给药。这可以是用于确定在MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的联合给予中剂量和给予的起点。
纳武单抗也可以作为确定与MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L组合给予的检查点抑制剂的剂量和给予方案的起点。开具纳武单抗的处方为每2周在60分钟内以3mg/kg作为静脉输注给予。
免疫刺激剂(如激动剂抗体)也已被探究作为癌症的免疫疗法。例如，抗ICOS抗体与ICOS的胞外域结合，从而导致ICOS信号传导激活和T细胞激活。抗OX40抗体可以与OX40结合并且增强T细胞受体信号传导，从而导致T细胞激活、增殖和存活。其他例子包括针对4-1BB(CD137)、GITR的激动剂抗体。
免疫刺激性激动剂抗体可以与MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的瘤内注射组合地全身地使用。可替代地，免疫刺激性激动剂抗体可以经由瘤内递送同时地或顺序地与MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L联合使用。
在本文使用术语“工程化的”以指代生物体已经被操纵以在基因上改变、修饰或变化，例如通过破坏基因组。例如，“工程化的牛痘病毒株”或“工程化的改良安卡拉牛痘病毒”是指已经被操纵以在基因上改变、修饰或变化的牛痘或改良安卡拉牛痘毒株。
在本文使用术语“基因盒”以指代编码并且能够表达一个或多个目的基因(例如，hFlt3L、可选择标记或其组合)的DNA序列，其可以在DNA序列的一个或多个选定的限制位点之间插入。在一些实施方案中，插入基因盒会产生破坏的基因。在一些实施方案中，基因的破坏涉及用基因盒替换至少一部分基因，所述基因盒包括编码目的基因(例如，hFlt3L、可选择标记或其组合)的核苷酸序列。
如本文所用，“免疫检查点抑制剂”或“免疫检查点阻断剂”或“免疫检查点阻断抑制剂”是指完全或部分降低、抑制、干扰或调节一种或多种检查点蛋白活性的分子。检查点蛋白调节T细胞激活或功能。检查点蛋白包括但不限于CD28受体家族成员CTLA-4及其配体CD80和CD86；PD-1及其配体PD-L1和PD-L2；LAG3、B7-H3、B7-H4、TIM3、ICOS、II DLBCL、BTLA或前述两种或更多种的任何组合。预期本文所用的非限制性例子包括伊匹单抗、纳武单抗、派姆单抗、皮地利珠单抗、AMP-224、MPDL3280A、BMS-936559、MEDI4736、MSB 00107180或其任何组合。
如本文所用，“免疫应答”是指淋巴细胞、抗原呈递细胞、吞噬细胞、粒细胞和由以上细胞或肝产生的可溶性大分子(包括抗体、细胞因子和补体)中的一种或多种的如下作用，其导致选择性损毁、破坏或消除人体的癌性细胞、转移性肿瘤细胞等。免疫应答可以包括细胞应答(如T细胞应答)，其是细胞即T细胞功能的改变(调节，例如显著增强、刺激、激活、损害或抑制)。T细胞应答可以包括特定类型的T细胞或T细胞亚群(例如，效应CD4+、CD4+辅助、效应CD8+、CD8+细胞毒性或自然杀伤(NK)细胞)的产生、增殖或扩增或刺激。可以通过检测一种或多种细胞受体或细胞表面分子(例如，CD或分化分子簇)来鉴定此类T细胞亚群。T细胞应答还可以包括影响其他细胞的分化或增殖的细胞因子(如可溶性介体(例如，细胞因子、淋巴因子、细胞因子结合蛋白或白细胞介素))的表达改变(统计上显著的增加或减少)。例如，I型干扰素(IFN-α/β)是先天免疫的关键调节剂(Huber等人Immunology132(4):466-474(2011))。动物和人类研究已经显示了IFN-α/β在抗原识别和抗肿瘤免疫应答的初始阶段期间直接影响CD4+和CD8+T细胞的命运的作用。响应于树突细胞的激活而诱导I型IFN，这进而是先天免疫系统的前哨。免疫应答还可以包括体液(抗体)应答。
在本文使用术语“免疫原性组合物”以指代将在已经暴露于组合物的哺乳动物中引起免疫应答的组合物。在一些实施方案中，免疫原性组合物包含单独的或与免疫检查点阻断抑制剂组合的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和/或VACVΔC7L-hFlt3L。
“敲除的基因”或“基因缺失”是指包括无效突变的基因(例如，通过基因编码的野生型产物不表达，表达水平低至无作用，或是无功能的)。在一些实施方案中，敲除的基因包括基因本身的异源序列或基因工程化的无功能序列，这使得基因无功能。在其他实施方案中，敲除的基因缺少一部分野生型基因。例如，在一些实施方案中，缺失了至少约10％、至少约20％、至少约30％、至少约40％或至少约60％的野生型基因序列。在其他实施方案中，敲除的基因缺少至少约70％、至少约75％、至少约80％、至少约90％、至少约95％或至少约100％的野生型基因序列。在其他实施方案中，敲除的基因可能包括多达100％的野生型基因序列(例如，可能缺失野生型基因序列的一些部分)，但是也包括插入其中的一个或多个异源和/或无功能核酸序列。
在本文使用术语“MVAΔC7L”以指代如下改良安卡拉牛痘(MVA)突变型病毒或包含所述病毒的疫苗，在其中C7基因不表达，表达水平低至无作用，或表达的蛋白质无功能(例如，是无效突变)。如本文所用，“MVAΔC7L”涵盖不表达功能性C7蛋白的重组MVA病毒。在一些实施方案中，ΔC7L突变体包括代替全部或大部分C7L基因序列的异源核酸序列。例如，如本文所用，“MVAΔC7L”涵盖重组MVA核酸序列，其中将对应于MVA基因组中C7的位置(例如，SEQ ID NO:2的位置18,407至18,859)的核酸序列用包含编码特定目的基因(SG)的开放阅读框的异源核酸序列替换，所述目的基因是如人Fms样酪氨酸激酶3配体(hFlt3L)(“MVAΔC7L-hFlt3L”)。在一些实施方案中，异源核酸序列还包含编码可选择标记的开放阅读框。在一些实施方案中，可选择标记是GFP蛋白。如本文所用，“MVAΔC7L”意指缺少功能性C7L基因且具有感染性但无复制性的MVA缺失突变体，并且其逃避宿主免疫系统的能力进一步受损。在本文使用术语“VACVΔC7L”以指代如下牛痘突变型病毒或包含所述病毒的疫苗，在其中C7基因不表达，表达水平低至无作用，或表达的蛋白质无功能(例如，是无效突变)。如本文所用，“VACVΔC7L”涵盖不表达功能性C7蛋白的重组牛痘病毒(VACV)。在一些实施方案中，牛痘病毒衍生自Western Reserve(WR)毒株。在一些实施方案中，ΔC7L突变体包括代替全部或大部分C7L基因序列的异源序列。例如，如本文所用，“VACVΔC7L”涵盖重组牛痘病毒核酸序列，其中将对应于VACV基因组中C7的位置(例如，SEQ ID NO:1的位置15,716至16,168)的核酸序列用包含编码特定目的基因(SG)的开放阅读框的异源核酸序列替换，所述目的基因是如人Fms样酪氨酸激酶3配体(hFlt3L)基因(“VACVΔC7L-hFlt3L”)。在一些实施方案中，异源核酸序列还包含编码可选择标记的开放阅读框。在一些实施方案中，可选择标记是GFP蛋白。
如本文所用，“转移”是指癌症从其原发部位扩散到体内的相邻组织或远端位置。癌细胞(包括癌症干细胞)可以脱离原发性肿瘤，穿透淋巴管和血管，在血流中循环，并且在体内其他部位的正常组织中生长。转移是一个顺序过程，取决于肿瘤细胞(或癌症干细胞)从原发性肿瘤中脱落、穿过血流或淋巴管并且在远端部位停止。一旦到达另一个部位，癌细胞就会重新穿透血管或淋巴管壁，继续繁殖并且最终形成新的肿瘤(转移性肿瘤)。在一些实施方案中，将这种新的肿瘤称为转移性(或继发性)肿瘤。
如本文所用，“MVA”意指“改良安卡拉牛痘”，并且是指衍生自安卡拉毒株并且开发用作疫苗和疫苗佐剂的牛痘的高度减毒的毒株。通过连续传代鸡胚细胞从野生型安卡拉毒株中分离出原始的MVA。如此处理后，它失去了约15％的野生型牛痘基因组，包括其在灵长类动物(包括人)细胞中有效复制的能力。(Mayr等人,Zentralbl Bakteriol B 167,375-390(1978))。天花疫苗接种株MVA：标记，遗传结构，肠胃外疫苗接种获得的经验以及在防御机制减弱的生物体中的行为。MVA被认为是适合作为重组载体开发的候选物，用于针对传染性疾病或肿瘤的基因或疫苗接种递送。(Verheust等人,Vaccine30(16),2623-2632(2012))。MVA具有长度为178kb的基因组并且其序列首先公开于Antoine等人,Virol.244(2):365-396(1998)。序列还公开于Genbank U94848.1(SEQ ID NO:2)。临床级MVA可从丹麦的Bavarian Nordic A/S Kvistgaard商购和公开获得。此外，MVA可从马里兰州罗克维尔的ATCC和法国巴黎的CMCN(巴斯德国家微生物研究所(Institut Pasteur CollectionNationale des Microorganismes))获得。
如本文所用，“溶瘤病毒”是指优先感染癌细胞，在此类细胞中复制并且通过其复制过程诱导癌细胞裂解的病毒。天然存在的溶瘤病毒的非限制性例子包括水泡性口炎病毒、呼肠孤病毒以及工程化以具有肿瘤选择性的病毒，如腺病毒、新城疫病毒和单纯疱疹病毒(参见例如，Nemunaitis,J.Invest New Drugs.17(4):375-86(1999)；Kirn,DH等人NatRev Cancer.9(1):64-71(2009)；Kirn等人Nat.Med.7:781(2001)；Coffey等人Science282:1332(1998))。牛痘病毒感染许多类型的细胞，但是由于肿瘤细胞具有促进复制的新陈代谢，展现出某些途径的激活(其也有利于复制)并且创造出逃避先天免疫系统的环境的事实，因此优先在肿瘤细胞中复制。
如本文所用，当在治疗性物质或组合物的给予的背景下使用时，“肠胃外”包括除通过消化道给予以外的任何给予途径。与本文公开的方法特别相关的是静脉内(包括例如通过肝门静脉进行肝递送)、瘤内或鞘内给予。
如本文所用，“药学上可接受的载体和/或稀释剂”或“药学上可接受的赋形剂”包括但不限于任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。此类介质和试剂用于生物学活性物质的用途是本领域熟知的。下文提供了赋形剂的进一步细节。补充活性成分(如抗微生物剂，例如抗真菌剂)也可以掺入组合物中。
如本文所用，“药学上可接受的赋形剂”是指当给予动物或人时不产生不利、过敏或其他不良反应的物质和组合物。如本文所用，所述术语包括所有惰性的、无毒的、液体或固体的填充剂或稀释剂(只要它们不以不适当的负面方式与本发明的治疗性物质反应)、溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂、防腐剂等，例如液体药物载体(例如，无菌水、盐水、糖溶液、Tris缓冲液、乙醇和/或某些油)。
如本文所用，障碍或病症的“预防”(“prevention”、“prevent”或“preventing”)是指如下一种或多种化合物，其在统计学样品中，相对于未治疗的对照样品降低所治疗样品中的障碍或病症的发生率，或者相对于未治疗的对照样品延迟障碍或病症的一种或多种症状的发作。
如本文所用，“实体瘤”是指除血液系统癌症(如淋巴瘤、白血病和多发性骨髓瘤)以外的所有肿瘤性细胞生长和增殖以及所有癌前和癌性细胞和组织。实体瘤的例子包括但不限于：软组织肉瘤如纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、成骨性肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因瘤和其他骨瘤(例如，骨肉瘤、恶性纤维组织细胞瘤)、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝细胞瘤、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、肾母细胞瘤(Wilms’tumor)、宫颈癌、睾丸瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、脑/CNS肿瘤(例如，星形胶质细胞瘤、神经胶质瘤、胶质母细胞瘤、儿童肿瘤如非典型畸胎瘤/横纹肌样瘤、生殖细胞瘤、胚胎瘤、室管膜瘤)、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤、黑素瘤、神经母细胞瘤和视网膜母细胞瘤。本公开文本的组合物和方法将有用的一些最常见的实体瘤包括：头颈癌、直肠腺癌、神经胶质瘤、成神经管细胞瘤、尿路上皮癌、胰腺癌、子宫(例如，子宫内膜癌、输卵管癌)卵巢癌、宫颈癌、前列腺癌、非小细胞肺癌(鳞状和腺癌)、小细胞肺癌、黑素瘤、乳腺癌、导管原位癌、肾细胞癌和肝细胞癌、肾上腺肿瘤(例如，肾上腺皮质癌)、食道癌、眼癌(例如，黑素瘤、视网膜母细胞瘤)、胆囊癌、胃肠道癌、肾母细胞瘤、心癌、头颈癌、喉癌和下咽癌、口腔癌(例如，嘴、口、唾液腺)、鼻咽癌、神经母细胞瘤、腹膜癌、垂体癌、卡波西肉瘤(Kaposi’s sarcoma)、小肠癌、胃癌、睾丸癌、胸腺癌、甲状腺癌、甲状旁腺癌、阴道肿瘤和前述任一种的转移瘤。
如本文所用，术语“受试者”、“个体”或“患者”可以是个体生物体、脊椎动物、哺乳动物或人。在一些实施方案中，“受试者”意指可能患有癌症并且当由此痛苦时需要治疗的任何动物(哺乳动物、人或其他)患者。
如本文所用，“协同治疗效果”是指由至少两种药剂的组合产生，并且超过原本由单独给予药剂产生的治疗效果的大于累加的治疗效果。例如，较低剂量的一种或多种药剂可以用于治疗疾病或障碍，从而导致治疗功效增加和副作用降低。
如本文所用的“治疗”(“treating”、“treat”、“treated”或“treatment”)涵盖治疗受试者(如人)的本文所述的疾病或障碍，并且包括：(i)抑制疾病或障碍，即阻止其发展；(ii)缓解疾病或障碍，即引起障碍的消退；(iii)减缓障碍的进展；和/或(iv)抑制、缓解或减缓疾病或障碍的一种或多种症状的进展。
还应当理解，所述的医学疾病和病症的各种治疗或预防模式旨在意指“实质性的”，其包括完全的以及少于完全的治疗或预防，并且其中实现一些生物学或医学上相关的结果。
如本文所用，“肿瘤免疫”是指肿瘤逃避免疫系统的识别和清除的一个或多个过程。因此，作为治疗概念，当减轻或消除这种逃避时，“治疗”肿瘤免疫，并且肿瘤被免疫系统识别并且攻击(后者在本文中称为“抗肿瘤免疫”)。肿瘤识别的一个例子是肿瘤结合，并且肿瘤攻击的例子是肿瘤减小(数量、大小或二者)和肿瘤清除。
如本文所用，“T细胞”是指胸腺衍生的淋巴细胞，其参与多种细胞介导的适应性免疫反应。
如本文所用，“辅助T细胞”是指CD4+T细胞；辅助T细胞识别与MHC II类分子结合的抗原。辅助T细胞至少有两种类型，Th1和Th2，它们产生不同的细胞因子。
如本文所用，“细胞毒性T细胞”是指通常在其表面带有CD8分子标记(CD8+)并且通过破坏在其表面具有特异性抗原分子的靶T细胞而在细胞介导的免疫中起作用的T细胞。细胞毒性T细胞还会释放颗粒酶，一种丝氨酸蛋白酶，它可以经由穿孔素形成的孔进入靶T细胞并且诱导细胞凋亡(细胞死亡)。颗粒酶作为细胞毒性表型的标记。细胞毒性T细胞的其他名称包括CTL、细胞溶解性T细胞、细胞溶解性T淋巴细胞、杀伤性T细胞或杀伤性T淋巴细胞。细胞毒性T细胞的靶标可以包括病毒感染的细胞、被细菌或原生动物寄生虫感染的细胞或癌细胞。大多数细胞毒性T细胞在其细胞表面具有CD8蛋白存在。CD8被吸引到I类MHC分子部分。通常，细胞毒性T细胞是CD8+细胞。
如本文所用，“肿瘤浸润的白细胞”是指患有癌症(如黑素瘤)的受试者的如下白细胞，其驻留于循环中或以其他方式已经离开循环(血液或淋巴液)并且已经迁移到肿瘤中。
如本文所用，“载体”包括当与适当的控制元件结合时能够复制并且可以在细胞之间转移基因序列的任何遗传元件，如质粒、噬菌体、转座子、粘粒、染色体、人工染色体、病毒、病毒体等。因此，所述术语包括克隆和表达运载体以及病毒载体。在一些实施方案中，预期有用的载体是待转录的核酸区段位于启动子的转录控制下的那些载体。“启动子”是指被细胞的合成机器或引入的合成机器识别的启动基因的特异性转录所需的DNA序列。短语“可操作地定位”、“可操作地连接”、“在控制之下”或“在转录控制之下”意指启动子相对于核酸而言处于正确的位置和方向，以控制基因的RNA聚合酶的启动和表达。术语“表达载体或构建体”意指含有核酸的任何类型的遗传构建体，其中部分或全部核酸编码序列能够被转录。在一些实施方案中，表达包括核酸的转录，例如以从转录的基因产生生物学活性多肽产物或抑制性RNA(例如，shRNA、miRNA)。在SEQ ID NO:4中显示了根据本发明技术的pCB-C7L-GFP载体的非限制性例子。
在本文使用术语“毒力”以指代病原体引起疾病的相对能力。在本文使用术语“减弱的毒力”或“降低的毒力”以指代病原体引起疾病的相对能力降低。
II.免疫系统和癌症
恶性肿瘤固有地对常规疗法具有抗性，并且提出了重大的治疗挑战。免疫疗法已经成为一个不断发展的研究领域，并且是治疗某些类型的癌症的另外的选择。免疫疗法方法所基于的基本原理是可以刺激免疫系统以识别肿瘤细胞，并且靶向它们进行破坏。
大量研究支持在癌症进展中免疫系统组成部分差异存在的重要性(Jochems等人,Exp Biol Med,236(5):567-579(2011))。临床数据表明，高密度的肿瘤浸润的淋巴细胞与改善的临床结果相联系(Mlecnik等人,Cancer Metastasis Rev.；30:5-12,(2011))。在多种类型的癌症中已经报道了在强大的淋巴细胞浸润和患者存活期之间的相关性，所述癌症包括黑素瘤、卵巢癌、头颈癌、乳腺癌、尿路上皮癌、结直肠癌、肺癌、肝细胞癌、胆囊癌和食道癌(Angell等人,Current Opinion in Immunology,25:1-7,(2013))。肿瘤免疫浸润物包括巨噬细胞、树突细胞(DC)、单核细胞、嗜中性粒细胞、自然杀伤(NK)细胞、幼稚和记忆淋巴细胞、B细胞和效应T细胞(T淋巴细胞)，主要负责识别肿瘤细胞表达的抗原和随后通过细胞毒性T细胞破坏肿瘤细胞。
尽管通过癌细胞呈递抗原，并且存在可能对肿瘤细胞潜在发生反应的免疫细胞，但是在许多情况下，免疫系统未被激活或肯定地被抑制。此现象的关键是肿瘤通过迫使免疫系统的细胞抑制免疫系统的其他细胞来保护自身免受免疫应答影响的能力。肿瘤发展出许多免疫调节机制来逃避抗肿瘤免疫应答。例如，肿瘤细胞分泌免疫抑制性细胞因子(如TGF-β)或者在肿瘤病变中诱导免疫细胞(如CD4+T调节性细胞和巨噬细胞)分泌这些细胞因子。肿瘤还具有使CD4+T细胞偏向表达调节表型的能力。总的结果是T细胞应答受损和细胞凋亡诱导受损或CD8+细胞毒性T细胞的抗肿瘤免疫能力降低。此外，MHC I类在肿瘤细胞表面的肿瘤相关表达改变使它们对免疫应答“不可见”(Garrido等人CancerImmunol.Immunother.59(10),1601-1606(2010))。抑制抗原呈递功能和树突细胞(DC)此外有助于逃避抗肿瘤免疫(Gerlini等人Am.J.Pathol.165(6),1853-1863(2004))。
此外，肿瘤微环境的局部免疫抑制性质以及免疫编辑可以导致不表达靶抗原的癌细胞亚群逃逸。因此，找到能促进免疫系统的抗肿瘤活性的保存和/或恢复的方法将具有重大的治疗益处。
免疫检查点已经牵涉肿瘤介导的抗肿瘤免疫的下调，并且用作治疗靶标。已经证明T细胞功能障碍与抑制性受体CTLA-4和程序性死亡1多肽(PD-1)(CD28受体家族的成员)的诱导表达同时发生。PD-1是CD28受体家族的抑制性成员，所述家族除了PD-1外还包括CD28、CTLA-4、ICOS和BTLA。然而，尽管抗CTLA-4(伊匹单抗)和抗PD-1药物(例如，派姆单抗和纳武单抗)的临床使用、甚至监管审批强调了关于在黑素瘤的治疗中免疫疗法的使用的承诺，但是患者对这些免疫疗法的反应有限。专注于阻断T细胞中的这些抑制性信号(例如，CTLA-4、PD-1和PD-1的配体PD-L1)的临床试验显示，逆转T细胞抑制对于成功的免疫疗法至关重要(Sharma等人,Science 348(6230),56-61(2015)；Topalian等人,Curr OpinImmunol.24(2),202-217(2012))。这些观察结果强调了需要开发利用免疫系统对抗癌症的新型治疗方法。
III.痘病毒
痘病毒(如工程化的牛痘病毒)在转移癌的溶瘤疗法方面处于最前沿(Kirn等人,Nature Review Cancer 9,64-71(2009))。牛痘病毒是大的DNA病毒，其具有快速的生命周期和到远端组织的有效血源性播散(Moss,在Fields Virology(Lippincott Williams&Wilkins,2007),第2905-2946页)。痘病毒非常适合作为在癌细胞中表达多个转基因并且因此增强治疗功效的载体(Breitbach等人,Current pharmaceutical biotechnology 13,1768-1772(2012))。临床前研究和临床试验已经证明了使用溶瘤性牛痘病毒和其他痘病毒用于治疗传统疗法难以治疗的晚期癌症的功效(Park等人,Lacent Oncol 9,533-542(2008)；Kirn等人,PLoS Med 4,e353(2007)；Thorne等人,J Clin Invest117,3350-3358(2007))。基于痘病毒的溶瘤疗法的优势在于通过细胞裂解、细胞凋亡和坏死的组合杀死癌细胞。它还会触发先天免疫传感途径，这促进免疫细胞向肿瘤的募集和抗肿瘤适应性免疫应答的形成。目前处于临床试验的溶瘤性牛痘毒株(例如JX-594)是复制性毒株。它们使用如下野生型牛痘，其具有胸苷激酶的缺失以增强肿瘤选择性，并且具有转基因(如粒细胞巨噬细胞集落刺激因子(GM-CSF))的表达以刺激免疫应答(Breitbach等人,Curr PharmBiotechnol 13,1768-1772(2012))。然而，许多研究显示，野生型牛痘对抗原呈递细胞(APC)具有免疫抑制作用(Engelmayer等人,J Immunol 163,6762-6768(1999)；Jenne等人,Gene therapy 7,1575-1583(2000)；P.Li等人,J Immunol 175,6481-6488(2005)；Deng等人,J Virol 80,9977-9987(2006))，并且因此增加了肿瘤本身的免疫抑制和免疫逃避作用。
牛痘病毒(Western Reserve毒株；WR)基因组序列在SEQ ID NO:1中列出，并且由GenBank登录号AY243312.1给出。
IV.改良安卡拉牛痘(MVA)
改良安卡拉牛痘(MVA)病毒是痘病毒科中正痘病毒属的成员。MVA是通过在牛痘病毒的安卡拉毒株(CVA)的鸡胚成纤维细胞(CEF)上连续进行大约570次传代而产生的(Mayr等人,Infection 3,6-14(1975))。这些长期传代的结果是，所得的MVA病毒含有大量的基因组缺失，并且宿主细胞高度限于禽类细胞(Meyer等人,J.Gen.Virol.72,1031-1038(1991))。在各种动物模型中都显示出所得的MVA是显著无毒性的(Mayr等人,Dev.Biol.Stand.41,225-34(1978))。
MVA的安全性和免疫原性已经在临床试验中进行了广泛的测试和记录，特别是针对人类天花病。这些研究包括超过120,000名个体，并且已经证明在人中具有出色的功效和安全性。此外，与其他基于牛痘的疫苗相比，MVA具有减弱的毒力(传染性)，同时其触发良好的特异性免疫应答。因此，由于诱导特异性免疫应答的能力，已经将MVA建立为安全的疫苗载体。
由于上述特征，MVA成为了开发工程化的MVA载体(用于重组基因表达和疫苗)的有吸引力的候选物。作为疫苗载体，已经针对多种病理病症对MVA进行了研究，所述病理病症包括HIV、结核病和疟疾以及癌症(Sutter等人,Curr Drug Targets Infect Disord 3:263-271(2003)；Gomez等人,Curr Gene Ther 8:97-120(2008))。
已经证明，人单核细胞衍生的树突细胞(DC)的MVA感染会导致DC激活，其特征在于共刺激分子的上调和促炎细胞因子的分泌(Drillien等人,J Gen Virol 85:2167-2175(2004))。在此方面，MVA与标准野生型牛痘病毒(WT-VAC)不同，后者无法激活DC。树突细胞可以分为两种主要的亚型：常规树突细胞(cDC)和浆细胞样树突细胞(pDC)。前者(特别是CD103+/CD8α+亚型)特别适合将抗原交叉呈递至T细胞；后者是I型IFN的强大生产者。
人细胞的病毒感染导致由I型干扰素(尤其是干扰素-α(α))介导的先天免疫应答(第一道防线)的激活。这通常会导致免疫学“级联”的激活，激活的T细胞(CTL和辅助细胞)的募集和增殖，并且最终产生抗体。然而，病毒表达抑制宿主免疫应答的因子。MVA是比WT-VAC更好的免疫原，并且在哺乳动物细胞中复制能力很差。(参见例如，Brandler等人,J.Virol.84,5314-5328(2010))。
然而，MVA不是完全无复制性的，并且含有一些残留的免疫抑制活性。然而，已经显示出MVA可延长所治疗受试者的存活期。
MVA基因组序列在SEQ ID NO:2中列出，并且由GenBank登录号U94848.1给出。
V.牛痘病毒C7蛋白和具有C7缺失的MVA(MVAΔC7L)
牛痘病毒C7蛋白是在哺乳动物细胞中牛痘病毒的生命周期的重要宿主范围因子。在几乎所有感染哺乳动物宿主的痘病毒中都存在C7L同源物。宿主范围基因C7L和K1L二者的缺失使得病毒不能在人细胞中复制(Perkus等人,Virology,1990)。当敲除SAMD9时，缺乏K1L和C7L二者的突变型病毒获得了在人HeLa细胞中复制的能力(Sivan等人,mbio,2015)。已经发现K1和C7二者均与SAMD9相互作用(Sivan等人,mbio,2015)。IRF1的过表达导致C7L和K1L双缺失的牛痘病毒的宿主限制性(Meng等人Journal of Virology,2012)。C7和K1二者在体外均与SAMD9相互作用(Sivan等人,mbio,2015)。C7是否直接调节IFN的产生或信号传导尚不清楚。I型IFN在病毒感染的宿主防御中起重要作用，但是，C7在IFN途径的免疫调节中的作用尚不清楚。
不希望受理论的束缚，据信牛痘C7是I型IFN诱导和IFN信号传导的抑制剂。TANK结合激酶1(TBK1)是丝氨酸/苏氨酸激酶，其在诱导对各种病原体相关分子模式(PAMP)(包括核酸)的先天免疫应答中起关键作用。一方面，RIG-I样受体(如RIG-I和MDA5，其分别检测5'三磷酸RNA和dsRNA)与线粒体蛋白质IPS-1或MAVS相互作用，从而导致TBK1的激活和磷酸化。内体dsRNA与Toll样受体3(TLR3)结合，这导致TRIF和TRAF3的募集以及TBK1的激活。另一方面，胞质DNA可以通过胞质DNA传感器环状GMP-AMP合酶(cGAS)检测，这导致环状GMP-AMP(cGAMP)的产生。cGAMP进而与内质网(ER)定位衔接子STING结合，从而导致TBK1的募集和激活。TBK1磷酸化转录因子IRF3，其易位至细胞核以激活IFNB基因表达。不希望受理论的束缚，据信C7抑制通过多种刺激进行的IFNB诱导，所述刺激物包括RNA病毒、DNA病毒、聚(I:C)、免疫刺激DNA(ISD)。C7可能在TBK1/IRF3复合物水平上发挥其抑制作用。一旦被分泌，I型IFN就与IFNAR结合，这导致JAK/STAT信号传导途径的激活。磷酸化的STAT1和STAT2易位至细胞核，在其中它们与IRF9一起激活IFN刺激基因(ISG)的表达。不希望受理论的束缚，据信除了具有抑制IFNB诱导的能力外，C7还可以通过其与STAT2的相互作用来阻断IFNAR信号传导，从而防止IFN-β诱导的STAT2磷酸化。不希望受理论的束缚，据信牛痘C7具有I型IFN产生和信号传导的双重抑制作用。如本文所述，从WT牛痘缺失C7L(VACVΔC7L)导致病毒的减毒，并且从MVA缺失C7L(MVAΔC7L)导致与MVA相比免疫刺激功能的增强。
在一方面，本公开文本证明异位C7表达阻断STING、TBK1或IRF3诱导的IFNB和ISRE(干扰素刺激应答元件)启动子激活。在另一方面，本公开文本显示过表达C7的鼠或人巨噬细胞细胞系对DNA或RNA刺激物或者DNA或RNA病毒感染具有减弱的先天免疫应答。在一些实施方案中，C7的过表达也减弱由IFN-β处理诱导的ISG基因表达。在一些实施方案中，具有C7L缺失的MVA(MVAΔC7L)感染cDC比MVA诱导更高水平的I型IFN。在一些实施方案中，C7经由阻止Stat2磷酸化来阻断IFN-β诱导的Janus激酶/信号转导蛋白和转录激活子(JAK/STAT)信号传导途径。通过举例的方式而是通过限制的方式，如共免疫沉淀研究所证明，显示C7与Stat2直接相互作用。
下文提供了由GenBank登录号AAB96405.1(SEQ ID NO:3)给出的说明性全长牛痘病毒C7宿主范围蛋白。
1 mgiqhefdii ingdialrnl qlhkgdnygc klkiisndyk klkfrfiirp dwseidevkg
61 ltvfannyav kvnkvddtfy yviyeavihl ynkkteiliy sddenelfkh yypyislnmi
121 skkykvkeen ysspyiehpl ipyrdyesmd
VI.Fms样酪氨酸激酶3配体(Flt3L)
在1994年克隆出了人Flt3L(Fms样酪氨酸激酶3配体)，它是刺激骨髓细胞增殖的I型跨膜蛋白(Lyman等人,1994)。已经在多种临床前和临床环境中探究了hFlt3L的用途，所述临床前和临床环境包括干细胞动员以准备进行骨髓移植、癌症免疫疗法(如树突细胞的扩增)以及疫苗佐剂。已经在超过500名人类受试者中测试了重组人Flt3L(rhuFlt3L)并且其是具有生物活性的、安全的以及良好耐受的(Fong等人,1998；Maraskovsky等人,2000；Shackleton等人,2004；He等人,2014；Anandasabapathy等人,2015)。在理解生长因子Flt3L在DC子集(包括CD8α+/CD103+DC和pDC)的发育中的关键作用方面已经取得了很大的进展(McKenna等人,2000；Waskow等人,2008；Liu等人,2007；2009；Naik等人,2006；Ginhoux等人,2009)。
自发交叉引发肿瘤抗原特异性CD8+T细胞需要CD103+/CD8α+DC(Hildner等人,2008；Ginhoux等人,2009；Zhang等人,2015；Spranger等人,2015)。Broz等人报道CD103+DC稀疏地存在于肿瘤内，并且它们与大量的肿瘤相关巨噬细胞竞争肿瘤抗原。CD103+DC能够独特地刺激幼稚以及激活的CD8+T细胞，并且对于过继性T细胞疗法的成功至关重要(Broz等人Cancer Cell,26(5):638-52,2014)。Spranger等人报道致癌性信号传导途径WNT/β-连环蛋白的激活导致肿瘤内CD103+DC和抗肿瘤T细胞的减少(Spranger等人,2015)。Flt3L培养的骨髓衍生的树突细胞(BMDC)的瘤内递送导致对抗CTLA-4和抗PD-L1免疫疗法的组合的反应性(Spranger等人,2015)。全身给予Flt3L(CD103+DC的生长因子)和瘤内注射聚I:C(TLR3激动剂)扩增并且激活了肿瘤内的CD103+DC群体，并且克服了鼠黑素瘤和MC38结肠癌模型中的免疫疗法抗性，或增强了对所述免疫疗法的反应性(Salmon等人,2016；Sanchez-Paulete等人,2016)。
在各种实体瘤中肿瘤新抗原的最新发现指示，实体瘤带有通常因人而异的独特的新抗原(Castle等人,Cancer Res 72,1081-1091(2012)；Schumacher等人,Science 348,69-74(2015))。本文公开的重组病毒不通过表达肿瘤抗原发挥其活性。本发明的重组MVA病毒的瘤内递送允许肿瘤新抗原的有效交叉呈递和肿瘤内抗肿瘤适应性免疫的产生(并且还全身地扩展)，并且因此在产生针对肿瘤的免疫应答方面导致利用肿瘤分化抗原和通过肿瘤细胞表达的新抗原进行“原位癌症疫苗接种”。
尽管肿瘤内存在通过体细胞突变产生的新抗原，但是肿瘤抗原特异性T细胞的功能通常受到多种抑制机制的约束(Mellman等人,Nature 480,480-489(2011))。例如，激活的T细胞上的细胞毒性T淋巴细胞抗原4(CTLA-4)的上调可以与T细胞共刺激物CD28竞争，以与树突细胞(DC)上的CD80(B71)/CD86(B7.2)相互作用，从而抑制T细胞激活和增殖。CTLA-4也在调节性T(Treg)细胞上表达，并且在介导Treg的抑制功能中起重要作用(Wing等人,Science 322,271-275(2008)；Peggs等人,J Exp Med 206,1717-1725(2009))。另外，PD-L/PD-L2在肿瘤细胞上的表达可能导致CD28家族抑制性受体PD-1的激活，从而导致T细胞枯竭。利用针对抑制性受体(如CTLA-4和程序性死亡1多肽(PD-1))的抗体的免疫疗法在动物研究中显示出显著的临床前活性并且在患有转移性癌症的患者中显示出临床反应，并且已经获得FDA的批准用于转移性黑素瘤、非小细胞肺癌以及肾细胞癌的治疗(Leach等人,Science 271,1734-1746(1996)；Hodi等人,NEJM 363,711-723(2010)；Robert等人,NEJM364,2517-2526(2011)；Topalian等人,Cancer Cell27,450-461(2012)；Sharma等人,Science 348(6230),56-61(2015))。
VII.黑素瘤
黑素瘤(最致命的癌症之一)是美国和全球增长最快的癌症。在大多数情况下，晚期黑素瘤对常规疗法(包括化学疗法和放射)具有抗性。因此，患有转移性黑素瘤的人具有非常差的预后，预期寿命只有6到10个月。约50％的黑素瘤在BRAF(关键的促肿瘤基因)中具有突变的发现为这种疾病的靶向疗法打开了大门。使用BRAF抑制剂的早期临床试验显示，在有BRAF突变的黑素瘤患者中反应显著，但不幸的是无法持续。因此，迫切需要针对这些患者以及无BRAF突变的其他黑素瘤患者的替代治疗策略。
人类病理学数据指示黑素瘤病变内T细胞浸润物的存在与更长的患者存活期正相关(Oble等人Cancer Immun.9,3(2009))。免疫系统在针对黑素瘤的保护中的重要性进一步得到了免疫疗法(如免疫激活剂IFN-α2b和IL-2)的部分成功的支持(Lacy等人Expert RevDermatol 7(1):51-68(2012))，并且进一步得到了患有转移性黑素瘤的患者对免疫检查点疗法(包括抗CTLA-4和抗PD-1/PD-L1，单独的药剂或组合疗法)的空前临床反应的支持(Sharma和Allison,Science 348(6230),56-61(2015)；Hodi等人,NEJM 363(8),711-723(2010)；Wolchok等人,Lancet Oncol.11(6),155-164(2010)；Topalian等人,NEJM 366(26),2443-2454(2012)；Wolchok等人,NEJM 369(2),122-133(2013)；Hamid等人,NEJM 369(2),134-144(2013)；Tumeh等人,Nature515(7528),568-571(2014))。然而，许多患者对仅免疫检查点阻断疗法无反应。
VIII.肿瘤免疫中的I型IFN和胞质DNA传感途径
I型IFN在宿主抗肿瘤免疫中起重要作用(Fuertes等人,Trends Immunol 34,67-73(2013))。IFNAR1缺陷型小鼠在植入肿瘤细胞后更容易患上肿瘤；自发的肿瘤特异性T细胞启动在IFNAR1缺陷型小鼠中也存在缺陷(Diamond等人,J Exp Med 208,1989-2003(2011)；Fuertes等人,J Exp Med 208,2005-2016(2011))。最近的研究显示，胞质DNA传感途径在肿瘤衍生的DNA的先天免疫传感中很重要，所述先天免疫传感导致抗肿瘤CD8+T细胞免疫的形成(Woo等人,Immunity 41,830-842(2014))。此途径在放射诱导的抗肿瘤免疫中也起作用(Deng等人,Immunity 41,843-852(2014))。尽管可以在患有癌症的患者体内检测到自发的抗肿瘤T细胞应答，但是在大多数患者体内癌症最终克服了宿主抗肿瘤免疫。改变肿瘤免疫抑制性微环境的新型策略将有益于癌症疗法。
IX.免疫应答
除了通过上调特定的免疫系统活性(如抗体和/或细胞因子的产生、或细胞介导的免疫的激活)来诱导免疫应答外，免疫应答还可以包括抑制、减弱或任何其他下调可检测的免疫，以重建稳态并且防止对宿主自身器官和组织的过度伤害。在一些实施方案中，根据本公开文本的方法诱导的免疫应答产生效应CD8+(抗肿瘤细胞毒性CD8+)T细胞或激活的T辅助细胞或二者，它们可以直接或间接地导致肿瘤细胞死亡或肿瘤细胞丧失繁殖能力。
可以通过检测多种熟知的免疫学参数中的任一种来确定通过本公开文本的组合物和方法对免疫应答的诱导(Takaoka等人,Cancer Sci.94:405-11(2003)；Nagorsen等人,Crit.Rev.Immunol.22:449-62(2002))。因此，可以通过许多熟知的测定(包括免疫测定)中的任一种来证实免疫应答的诱导。此类测定包括但不必限于体内、离体或体外确定可溶性免疫球蛋白或抗体、可溶性介体(如细胞因子、趋化因子、激素、生长因子等)以及其他可溶性小肽、碳水化合物、核苷酸和/或脂质介体；如通过免疫系统的细胞的功能或结构特性改变确定的细胞激活状态变化，例如细胞增殖、运动性改变、细胞内阳离子梯度或浓度(如钙)改变；细胞多肽的磷酸化或去磷酸化；诱导专门的活性，如特定的基因表达或细胞溶解行为；免疫系统细胞的细胞分化，包括改变的表面抗原表达谱或细胞凋亡(程序性细胞死亡)的发作；或可以检测免疫应答的存在的任何其他标准。例如，可以通过与CD4+、CD8+或NK细胞结合的特异性抗体来检测区分免疫细胞类型的细胞表面标记。可以检测到的其他标记和细胞组分包括但不限于干扰素γ(IFN-γ)、肿瘤坏死因子(TNF)、IFN-α、IFN-β(IFNB)、IL-6和CCL5。用于检测免疫应答的常用方法包括但不限于流式细胞术、ELISA、免疫组织化学。进行这些和类似测定的程序是众所周知的，并且可以在例如Letkovits(Immunology MethodsManual:The Comprehensive Sourcebook of Techniques,Current Protocols inImmunology,1998)中找到。
X.本发明技术的药物组合物和制剂
本文公开了包含MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的药物组合物，其可以含有载体或稀释剂，所述载体或稀释剂可以是溶剂或分散介质，所述溶剂或分散介质含有例如水、盐水、Tris缓冲液、多元醇(例如，甘油、丙二醇和液体聚乙二醇等)、其合适的混合物和植物油。例如，通过使用包衣(如卵磷脂)、通过在分散液的情况下维持所需的粒度以及通过使用表面活性剂，可以维持适当的流动性。防止微生物的作用可以通过多种抗细菌剂和抗真菌剂和防腐剂(例如，对羟基苯甲酸酯、三氯叔丁醇、苯酚、山梨酸、硫柳汞等)来实现。在一些实施方案中，包括等渗剂(例如，糖或氯化钠)以及缓冲剂。通过在组合物中使用延迟吸收的试剂(例如，单硬脂酸铝和明胶或载体分子)可以实现可注射组合物的延长吸收。其他赋形剂可以包括润湿剂或乳化剂。通常，对于本领域技术人员清楚的是，可以包括适合于可注射制剂的赋形剂。
包含MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的药物组合物和制剂可以通过常规混合、溶解、制粒、乳化、封装、包埋或冻干过程来制造。可以使用一种或多种生理学上可接受的载体、稀释剂、赋形剂或助剂以常规方式配制药物病毒组合物，所述载体、稀释剂、赋形剂或助剂有助于配制适合于体外、体内或离体使用的病毒制剂。所述组合物可以与一种或多种另外的生物学活性剂(例如，GM-CSF的平行给予)组合，并且可以用药学上可接受的载体、稀释剂或赋形剂配制，以产生适合于肠胃外或瘤内给予的本公开文本的药物(包括生物)或兽药组合物。
如本领域技术人员所理解的，许多类型的配制品都是可能的。如本领域所公认的，所选择的具体类型取决于所选择的给予途径。例如，通常设计全身配制品用于通过注射(例如，静脉内)给予，并且设计那些配制品用于瘤内递送。在一些实施方案中，全身或瘤内配制品是无菌的。
根据需要，无菌可注射溶液是通过如下方式来制备：将MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L掺入所需量的具有本文列举的各种其他成分的适当溶剂中，然后进行合适的灭菌手段。通常，分散液是通过如下方式来制备：将各种无菌活性成分掺入无菌媒介物中，所述媒介物含有基础分散介质和来自上文所列举的那些成分的所需其他成分。在用于制备无菌可注射溶液的无菌粉末的情况下，优选的制备方法为真空干燥和冷冻干燥技术，其由先前无菌过滤的溶液产生病毒和任何另外的所需成分的粉末。
在一些实施方案中，可以将本公开文本的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L组合物配制在水性溶液中，或者配制在生理相容性溶液或缓冲液(如汉克氏溶液、林格氏溶液、甘露糖醇溶液或生理盐水缓冲液)中。在某些实施方案中，MVAΔC7L或MVAΔC7L-hFlt3L组合物中的任一种均可以含有配方剂，如悬浮剂、稳定剂、渗透剂或分散剂、缓冲剂、冻干保护剂或防腐剂，如聚乙二醇、聚山梨醇酯80、1-十二烷基六氢-2H-氮杂卓-2-酮(月桂氮酮(laurocapran))、油酸、柠檬酸钠、Tris HCl、右旋糖、丙二醇、甘露糖醇、聚山梨醇酯聚乙烯脱水山梨醇单月桂酸酯(
Figure BDA0002361606670000341
-20)、异丙基肉豆蔻酸酯、苯甲醇、异丙醇、乙醇、蔗糖、海藻糖和可以用于本公开文本的任何组合物中的本领域通常已知的其他此类配方剂。(Pramanick等人,Pharma Times 45(3),65-76(2013))。
可以配制本公开文本的生物或药物组合物，以允许在将组合物给予受试者后，所述组合物中所含的病毒可以用于感染肿瘤细胞。可以通过多种完善的技术(如基于抗体的测定(例如，ELISA、免疫组织化学等))监测在给予后血清、肿瘤和其他组织(如果需要)中的病毒水平。
可以将本发明的重组病毒以在约10mM Tris、140mM NaCl(pH 7.7)中配制的3.5x107PFU/ml的滴度在-80℃下保存。为了制备疫苗注射液，例如，可以将102-108或102-109个病毒颗粒在安瓿瓶(优选玻璃安瓿瓶)中在2％蛋白胨和1％人白蛋白的存在下在100ml的磷酸盐缓冲盐水(PBS)中冻干。可替代地，可以通过逐步冷冻干燥配制品中的重组病毒来产生可注射制剂。此配制品可以含有另外的添加剂，如甘露糖醇、葡聚糖、糖、甘氨酸、乳糖或聚乙烯吡咯烷酮或其他添加剂，如适合于体内给予的抗氧化剂或惰性气体、稳定剂或重组蛋白质(例如，人血清白蛋白)。然后将玻璃安瓿瓶密封，并且可以在4℃和室温之间保存几个月。在一些实施方案中，将安瓿瓶在低于-20℃的温度下保存。
为了治疗，可以将冻干物溶解于水性溶液(如生理盐水或Tris缓冲液)中，并且全身地或瘤内地给予。给予的模式、剂量和给予次数可以由本领域技术人员优化。
根据本公开文本的药物组合物可以包含另外的佐剂。如本文所用，“佐剂”是指增强、增加或加强宿主对肿瘤抗原的免疫应答的物质。典型的佐剂可以是铝盐(如氢氧化铝或磷酸铝)、Quil A、细菌细胞壁肽聚糖、病毒样颗粒、多糖、toll样受体、纳米珠粒等(Aguilar等人(2007),Vaccine 25:3752-3762)。
XI.包含重组MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L病毒的 试剂盒
本公开文本提供了包含一种或多种组合物的试剂盒，所述组合物包含本文所述的重组MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L病毒中的一种或多种。所述试剂盒可以包含重组MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的一个或多个容器或小瓶以及向待治疗的受试者给予重组MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的说明书。所述说明书可以指示用于给予一种或多种如下文提供的组合物的剂量方案。
在一些实施方案中，所述试剂盒还可以包含另外的组合物，其包含用于与重组MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L组合物联合给予的检查点抑制剂。
XII.MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的有效量和剂 量
通常，尽管可以给予更低或更高的剂量，向受试者给予在约106至约1010个噬斑形成单位(pfu)范围内的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L剂量。在一些实施方案中，剂量范围是从约102至约1010pfu。在一些实施方案中，剂量范围是从约103至约1010pfu。在一些实施方案中，剂量范围是从约104至约1010pfu。在一些实施方案中，剂量范围是从约105至约1010pfu。在一些实施方案中，剂量范围是从约106至约1010pfu。在一些实施方案中，剂量范围是从约107至约1010pfu。在一些实施方案中，剂量范围是从约108至约1010pfu。在一些实施方案中，剂量范围是从约109至约1010pfu。在一些实施方案中，剂量是约107至约109pfu。根据所使用的特定pfu滴定方法，pfu与病毒颗粒的等效性可能有所不同。通常，pfu等于约5至100个病毒颗粒，而0.69PFU是约1TCID50。能以一个或多个分剂量持续规定的时间段并且以规定的给予频率来给予治疗有效量的M MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L。
例如，对于本领域技术人员清楚的是，根据本公开文本的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的治疗有效量可以根据诸如受试者的疾病状态、年龄、性别、体重和一般状况以及MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L在特定受试者体内引起所需免疫应答的能力(受试者对疗法的反应)等因素而变化。在将MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L递送给受试者时，剂量也将取决于诸如一般医疗状况、以前的病史、疾病类型和进展、肿瘤负担、肿瘤中存在或不存在肿瘤浸润的免疫细胞等因素而变化。
在一些实施方案中，以剂量单位形式配制本公开文本的组合物可能是有利的，以便于给予和剂量均匀。如本文所用的“剂量单位形式”是指适合作为待治疗的哺乳动物受试者的单位剂量的物理上离散的单位；每个单位含有经计算与所需的药学上或兽医学上可接受的载体联合可产生所需治疗效果的预定量的活性材料。
XIII.MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的给予和治疗 方案
通常将药物组合物配制为与其预期的给予途径相容。可以使用不止一种途径来实现MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的给予。给予途径的例子包括但不限于肠胃外(例如，静脉内、肌内、腹膜内、皮内、皮下)、瘤内、鞘内、鼻内、全身、透皮、离子电渗疗法、皮内、眼内或局部给予。在一个实施方案中，在需要直接的局部反应的情况下，例如通过瘤内注射将MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L直接给予至肿瘤。此外，MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的给予途径可以变化，例如使用瘤内注射进行第一次给予，并且经由静脉内注射进行随后的给予或其任何组合。可以持续规定的时间段并且以规定的给予频率来给予治疗有效量的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L注射剂。在某些实施方案中，可以与其他治疗性治疗结合使用MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L。例如，针对患有大块原发性肿瘤的受试者，可以在新辅助(术前)或辅助(术后)环境中给予MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L。预期这样优化的治疗方案将诱导针对肿瘤的免疫应答，并且在诸如手术等首发治疗之前或之后减轻受试者的肿瘤负担。此外，可以与其他治疗性治疗(如化学疗法或放射)结合给予MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L。
在某些实施方案中，至少每周或每月给予一次MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L病毒，但是可以根据需要更频繁地给予，如每周两次持续数周、数月、数年或甚至无限期，只要益处持续存在。如果可以耐受并且如果它们产生持续或增加的益处，则考虑更频繁的给予。本发明方法的益处包括但不限于以下：减少癌细胞数量、减小肿瘤大小、根除肿瘤、抑制癌细胞向外周器官的浸润、抑制或稳定或根除转移性生长、抑制或稳定肿瘤生长以及稳定或改善生活质量。此外，益处可以包括诱导针对肿瘤的免疫应答、激活效应CD4+T细胞、增加效应CD8+T细胞或减少调节性CD4+细胞。例如，在黑素瘤的背景下，或者益处可以是黑素瘤初次诊断的一、二、三、四、五年或更多年之内没有复发或转移。可以对结肠癌和其他实体瘤进行类似的评估。
在某些其他实施方案中，在体内、离体或在体外用MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L治疗肿瘤块或肿瘤细胞。
XIV.载体
在一些实施方案中，使用基于pCB质粒的载体插入在牛痘合成早期和晚期启动子(PsE/L)控制下的特定目的基因(SG)(如鼠GM-CSF(mGM-CSF)或人Flt3L(hFlt3L))。已经描述了构建载体的方法(参见M.Puhlmann,C.K.Brown,M.Gnant,J.Huang,S.K.Libutti,H.R.Alexander,D.L.Bartlett,Vaccinia as a vector for tumor-directed genetherapy:Biodistribution of a thymidine kinase-deleted mutant.Cancer GeneTherapy,7(1),66-73(2000))。说明性pCB-C7L-GFP载体核酸序列在SEQ ID NO:4中给出。将在牛痘P7.5启动子控制下的绿色荧光蛋白(GFP)用作可选择标记。在一些实施方案中，这些表达盒的两侧侧接C7基因的部分序列。除了C7基因座外，还可以使用病毒内其他合适的基因座。在质粒DNA和MVAΔC7L基因组DNA的C7基因座处发生的同源重组导致将SG和GFP表达盒插入MVAΔC7L基因组DNAC7基因座中，以产生MVAΔC7L-hFlt3L。在一些实施方案中，将MVA基因组序列(SEQID NO:2)的位置18,407至18,859用包含一个或多个开放阅读框的异源核酸序列替换，所述开放阅读框编码可选择标记(如GFP)和目的基因(SG)(如hFlt3L)。类似地，在一些实施方案中，在质粒DNA和VACVΔC7L基因组DNA的C7基因座处发生的同源重组导致将SG和GFP表达盒插入VACVΔC7L基因组DNAC7基因座中，以产生VACVΔC7L-hFlt3L。在一些实施方案中，将VACV基因组序列(SEQ ID NO:1)的位置15,716至16,168用包含一个或多个开放阅读框的异源核酸序列替换，所述开放阅读框编码可选择标记(如GFP)和目的基因(SG)(如hFlt3L)。通过GFP选择富集重组病毒并且进行4-5轮噬斑纯化，直到获得适当的没有污染的MVAΔC7L或VACVΔC7L的重组病毒。
应当理解，可以使用适合于整合到MVAΔC7L或VACVΔC7L基因组中的任何其他表达载体，以及MVA的替代启动子、调节元件、可选择标记、切割位点、非必需插入区。在一些实施方案中，可选择标记是报告蛋白，其中所述报告蛋白是生物发光蛋白、荧光蛋白或化学发光蛋白。在一些实施方案中，报告蛋白是绿色荧光蛋白(GFP)。在一些实施方案中，可选择标记是黄嘌呤-鸟嘌呤磷酸核糖基转移酶基因(gpt)。MVA编码在线性基因组的末端的许多免疫调节基因，包括C11、C7、K3、F1、F2、F4、F6、F8、F9、F11、F14.5、J2、A46、C16。可以缺失这些基因以潜在地增强病毒的免疫激活特性，并且允许插入转基因。
实验性实施例
通过以下实施例进一步说明本发明技术，所述实施例不应被解释为以任何方式进行限制。
一般材料和方法
病毒和细胞系。使牛痘病毒(VACV)的Western Reserve(WR)毒株繁殖，并且在37℃下在BSC40(非洲绿猴肾细胞)单层上确定病毒滴度。将BSC40细胞在补充有5％胎牛血清(FBS)的杜氏改良伊格尔培养基中培养。MVA病毒由Gerd Sutter(慕尼黑大学)慷慨提供，并且使其在BHK-21(幼仓鼠肾细胞，ATCC CCL-10)细胞中繁殖。MVA可商购和/或公开获得。将病毒通过36％的蔗糖垫纯化。将BHK-21在含有10％FBS、0.1mM非必需氨基酸(NEAA)和50mg/ml庆大霉素的伊格尔最小必需培养基(伊格尔MEM，可以从Life Technologies购买，Cat#11095-080)中培养。最初从I.Fidler(MD Anderson Cancer Center)获得鼠黑素瘤细胞系B16-F10。将B16-F10细胞维持在RPMI 1640培养基中，所述培养基补充有10％FBS、100单位/ml青霉素、100μg/ml链霉素、0.1mM NEAA、2mM L-谷氨酰胺、1mM丙酮酸钠和10mM HEPES缓冲液。使所有细胞在37℃下在5％CO2培养箱中生长。人胚肾293T细胞来自美国典型培养物保藏中心(ATCC)。使它们在补充有10％FBS的DMEM中生长。使RAW264.7鼠巨噬细胞细胞系在补充有10％FBS的DMEM中生长。使THP-1细胞在补充有10％FBS的RPMI 1640中生长。为了使THP-1分化为巨噬细胞，在使其经受实验条件之前，将它们用PMA(10ng/ml)处理48h。
除非另外指示，否则本文所用的细胞和细胞系可商购或公开获得。
WT VACV和VACVΔC7L的多步生长曲线。将BSC40细胞用IFN-β以1000U/ml的终浓度处理或假处理12h。然后将细胞用WT VACV或VACVΔC7L以0.05的MOI感染。然后将细胞刮入培养基中并且在指定的时间收集。在三个循环的冻融和后续超声处理之后，通过在BSC40细胞上的噬斑测定来确定收集的样品中的病毒滴度。
C7表达质粒的构建。IFN-β报告质粒(pIFN-β-luc)和ISRE报告质粒(p-ISRE-luc)由Michaela Gack(芝加哥大学)提供。通过PCR从VACV WR基因组扩增VACV C7L，并且将其亚克隆到pcDNA3.1和PQCXIP中。为了构建flag标记的C7表达质粒，将flag序列插入C7的C末端中并且亚克隆到pcDNA3.1.中。
双重萤光素酶报告物测定。根据制造商的说明(Promega)，使用双重萤光素酶报告物测定系统测量萤光素酶活性。简言之，将包括萤火虫萤光素酶报告构建体、海肾萤光素酶报告构建体以及其他表达构建体的表达质粒转染到HEK293T细胞中。转染后24h，收集细胞并且使其裂解。将20μl细胞裂解物与50μl的LARII一起孵育以测量萤火虫萤光素酶活性，然后与50μl的Stop&Glo试剂一起孵育以测量海参萤光素酶活性。通过将在IFNB或ISRE启动子下的萤火虫萤光素酶活性相对于来自对照质粒pRL-TK的海肾萤光素酶活性归一化，以任意单位表示相对萤光素酶活性。通过将在某种测试条件下的相对萤光素酶活性除以在背景条件下的相对萤光素酶活性来计算诱导倍数。
表达牛痘C7的逆转录病毒的产生。将HEK293T细胞传代到6孔板中。第二天，将细胞用三种质粒与10μl lipofectamine 2000转染：VSVG(1μg)；gag/pol(2μg)；和PQCXIP-C7(2μg)。2天后，收集细胞上清液，并且通过0.45μm过滤器过滤并且在-80℃下保存。
稳定表达牛痘C7的HEK293T细胞系的产生。将HEK293T细胞传代到6孔板中。第二天，将细胞用表达C7的逆转录病毒以5的MOI感染。2天后，将培养基用含有1.2μg/ml的嘌呤霉素的新鲜DMEM培养基替换。一周后，存活细胞是稳定表达C7的细胞。使用抗C7抗体通过Western印迹分析验证了C7的表达。
稳定表达牛痘C7的RAW264.7细胞系的产生。将RAW264.7细胞传代到6孔板中。第二天，将细胞用表达C7的逆转录病毒以5的MOI感染。2天后，将培养基用含有5μg/ml的嘌呤霉素的新鲜DMEM培养基替换。一周后，存活细胞是稳定表达C7的细胞。使用抗C7抗体通过Western印迹分析验证了C7的表达。
稳定表达牛痘C7的THP-1细胞系的产生。将THP-1细胞传代到6孔板中。第二天，将细胞用表达C7的逆转录病毒以5的MOI感染。2天后，将培养基用含有5μg/ml的嘌呤霉素的新鲜RPMI-1640培养基替换。三周后，存活细胞是稳定表达C7的细胞。使用抗C7抗体通过Western印迹分析验证了C7的表达。
重组VACVΔC7病毒的产生。将BSC40细胞传代到6孔板中。第二天，将细胞用牛痘病毒WR株以0.2的MOI感染。1-2h后，将细胞用0.75μg pC7-GFP与2μl lipofectamine 2000转染。2天后，收集细胞并且冻融三次。为了选择纯VACVΔC7，将BSC40细胞用上述病毒混合物感染，然后在显微镜下基于GFP表达选择噬斑。在几轮选择之后，所有噬斑均为GFP阳性。进行PCR以确认不存在C7。
重组MVAΔC7L病毒的产生。将BHK21细胞传代到6孔板中。第二天，将细胞用MVA以0.2的MOI感染。1-2h后，将细胞用0.75μg pC7-GFP与2μl lipofectamine 2000转染。2天后，收集细胞并且冻融三次。为了选择纯MVAΔC7，将BHK21细胞用上述收集的病毒原液感染，然后在显微镜下基于GFP表达选择噬斑。在4-6轮选择之后，所有噬斑均为GFP阳性。扩增GFP阳性MVAΔC7L克隆，并且通过PCR分析确认C7L基因的检测。PCR引物序列如下：正向引物5’-ATGGGTATACAGCACGAATTC-3’(SEQ ID NO:5)和反向引物5’-TTAATCCATGGACTCATAATC-3’(SEQ ID NO:6)。
骨髓衍生的树突细胞(BMDC)的产生。通过如下方式来收集来自小鼠胫骨和股骨的骨髓细胞：首先从骨骼中除去肌肉，然后使用0.5cc U-100胰岛素注射器(BectonDickinson)用含10％FCS的RPMI冲洗细胞。离心后，将细胞重悬于ACK裂解缓冲液(Lonza)中，以便通过将细胞在冰上孵育1-3min来裂解红细胞。然后将细胞收集，重悬于新鲜培养基中，并且通过40μm细胞滤器(BD Biosciences)过滤。计数细胞数量。为了产生GM-CSF-BMDC，将骨髓细胞(每15cm细胞培养皿中500万个细胞)在GM-CSF(30ng/ml，由Sloan KetteringInstitute的Monoclonal Antibody Core实验室生产)的存在下在CM中培养10-12天。CM是补充有10％胎牛血清(FBS)、100单位/ml青霉素、100μg/ml链霉素、0.1mM必需和非必需氨基酸，2mM L-谷氨酰胺、1mM丙酮酸钠和10mM HEPES缓冲液的RPMI 1640培养基。通过将50％的旧培养基用新鲜培养基替换，每2天饲喂细胞，并且每3-4天重新铺板以除去贴壁细胞。仅将非贴壁细胞用于实验。
Western印迹分析。骨髓衍生的树突细胞(BMDC)是根据方案(Dai等人,2014)产生的。将来自WT和KO小鼠的BMDC(1x 106)用MVA或MVAΔC7L以10的MOI(感染复数)感染。制备全细胞裂解物。使等量的蛋白质经受十二烷基硫酸钠-聚丙烯酰胺凝胶电泳，并且将多肽转移到硝酸纤维素膜上。使用各自的抗体(Cell Signaling)确定TBK-1的磷酸化、TBK-1、IRF3的磷酸化、IRF3和STING水平。将抗甘油醛-3-磷酸脱氢酶(GADPH)或抗β-肌动蛋白抗体(Cell Signaling)用作上样对照。
共免疫沉淀。将HEK293T细胞传代到10cm板中。第二天，将细胞用flag-STAT1或flag-STAT2与pcDNA3.1-C7-HA一起转染。两天后，将细胞在冰上的Pierce IP裂解缓冲液中裂解30min。对于IFN处理组，在细胞裂解之前，将细胞用1000U/ml IFNB处理45min。将HA抗体(Sigma H3663)添加到细胞裂解液中至终浓度1μg/ml，并且在4℃下孵育过夜。第二天，添加蛋白质A-琼脂糖，并且在4℃下孵育2h。将琼脂糖用IP裂解缓冲液洗涤三次。最后，将蛋白质在98℃下变性5min。
小鼠。从Jackson Laboratory购买6和10周龄之间的雌性C57BL/6J小鼠，并且将其用于制备骨髓衍生的树突细胞，并且作为体内实验的对照小鼠。将这些小鼠饲养在SloanKettering Institute的动物实验室中。严格按照美国国立卫生研究院的实验动物的护理和使用指南(Guide for the Care and Use of Laboratory Animals)中的建议执行所有程序。所述方案得到了Sloan-Kettering Cancer Institute的动物实验伦理委员会(Committee on the Ethics of Animal Experiments)的批准。STINGGt/Gt小鼠是在RussellVance实验室(加利福尼亚大学伯克利分校)中产生的。
WT C57BL/6小鼠和STINGGt/Gt小鼠的WT VACV或VACVΔC7L鼻内感染。每组中麻醉10只WT小鼠，并且用WT VACV以2x 103、2x 104、2x 105或2x 106pfu，以及用VACVΔC7L以2x105、2x 106或2x 107pfu的渐增剂量进行鼻内感染，各自以10μl接种至两个鼻孔。监测小鼠并且每天称重。将STINGGt/Gt小鼠用WT VACV以2x 104pfu或用VACVΔC7L以2x 105pfu感染。对失去30％初始重量的小鼠实施安乐死。确定Kaplan-Meier存活曲线。
双侧肿瘤植入模型和瘤内注射重组MVAΔC7L或MVA。简言之，将B16-F10黑素瘤细胞皮内植入C57BL/6小鼠的左右侧腹(右侧腹5x 105，左侧腹1x 105)。肿瘤植入后9天，为右侧腹较大的肿瘤瘤内注射2x 107pfu的MVA或MVAΔC7L。每周两次测量肿瘤大小并且重复注射肿瘤。监测小鼠的存活。
VACV C7特异性多克隆抗体的产生。将C7 cDNA克隆到细菌表达载体pET28-N-His-SUMO中。将C7表达质粒转化到大肠杆菌BL21(DE3)细胞中。使从单个转化体扩增的细菌培养物(2升)在37℃下在含有100μg/ml氨苄青霉素的LB肉汤中生长，直到A600达到0.8。将培养物调节至0.5mM异丙基-β-d-硫代吡喃半乳糖苷(IPTG)，然后在18℃下伴随恒定振荡孵育20h。通过离心收获细胞，并且将其重悬于缓冲液A(50mM Tris-HCl(pH 7.5)、500mM NaCl、20mM咪唑、10％甘油)中。通过超声处理将细胞裂解，并且通过以15000rpm离心45min将不溶性材料除去。将上清液与5ml的Ni-NTA树脂(Qiagen)(其已经用缓冲液A平衡)混合1h。将树脂倒入重力流柱中，然后用60ml的缓冲液A洗涤。将吸附的蛋白质用在缓冲液A中的300mM咪唑逐步洗脱。通过SDS-PAGE监测洗脱级分的多肽组成，并且合并含有每种重组蛋白质的峰级分。将洗脱液在含有50mM Tris-HCl(pH 8)、200mM NaCl、2mM DTT、2mM EDTA、10％甘油和0.1％Triton X-100的缓冲液中透析，然后在-80℃下保存。在Pocono Rabbit Farm andLaboratory(PRF&L)中进行兔免疫以产生C7特异性兔抗体。为兔皮下注射不完全弗氏佐剂(IFA)中的100μg的纯化的C7蛋白加Mighty快速免疫刺激剂，四次，间隔两周，持续两个月。使用亲和纯化从兔血清中纯化C7抗体。
统计学。将双尾非配对学生t检验用于研究中两组的比较。通过对数秩(Mantel-Cox)检验分析存活数据。认为显著的p值在图中指示如下：*，p<0.05；**，p<0.01；***，p<0.001；****，p<0.0001。在每个图例中都讨论了研究中包含的动物数量。
实施例1：牛痘C7抑制STING、TBK1和IRF3介导的IFN基因诱导。
将双重萤光素酶测定系统用于评价牛痘C7在HEK293T细胞中的STING、TBK1或IRF3诱导的IFNB启动子激活的调节中的作用，所述HEK293T细胞是用SV40大T抗原转化的人胚肾细胞系。将HEK293T细胞用表达IFNB萤火虫萤光素酶报告物的质粒、表达海肾萤光素酶的对照质粒pRL-TK、STING和如所指示的牛痘C7L转染。转染后24h进行双萤光素酶测定。通过将萤火虫萤光素酶活性相对于海肾萤光素酶活性归一化，以任意单位表示相对萤光素酶活性。与在没有STING的对照样品中的IFNB启动子活性相比，STING的过表达导致IFNB启动子活性的30倍诱导。渐增量的C7L表达质粒的共转染导致STING诱导的IFNB启动子活性显著降低(图1A)。类似地，与对照相比，TBK1的过表达导致IFNB启动子活性的400倍诱导。渐增量的C7L表达质粒(250ng)的共转染导致TBK1诱导的IFNB启动子活性降低90％以上(图1B)。IRF3是干扰素调节转录因子(IRF)家族的成员，并且是IFNB启动子的必需转录因子。C7的过表达也导致IRF3诱导的IFNB启动子活性降低70％(图1C)，然而C7的过表达未能降低IRF3-5D诱导的IFNB启动子活性(图1D)。IRF3-5D是IRF3的磷酸化活性突变体。图1E和1F显示牛痘C7与转录因子IRF3相互作用。这些结果指示，C7在IRF3磷酸化中起抑制作用，并且C7不能阻断磷酸化的IRF3的活性。
实施例2：牛痘C7抑制聚I:C(TLR3)或TRIF介导的IFN基因诱导。
TBK1-IRF3轴对于从多种传感途径进行信号转导很重要，所述传感途径包括cGAS-cGAMP-STING、RIG-I或MDA5-MAVS、TLR3-TRIF和TLR4-TRIF。为了测试牛痘C7是否具有TRIF信号传导的抑制作用，诸位发明人用TLR3表达质粒、IFN-β-luc报告物和渐增量的C7表达质粒(10ng、50ng或250ng)转染了HEK293T细胞。24h后，将细胞用聚I:C(5μg/ml)处理。聚I:C处理后24h测定萤光素酶活性。与空载体对照相比，TLR3的转染和用聚I:C处理导致IFNB启动子活性的9倍诱导(图2A)。C7的过表达导致聚(I:C)/TLR3诱导的IFNB启动子活性降低多达90％(图2A)。为了测试C7是否也抑制TRIF诱导的IFNB启动子活性，将HEK293T细胞用TRIF表达质粒转染，与空载体对照相比，其导致IFNB启动子活性的500倍诱导(图2B)。C7的过表达导致TRIF诱导的IFNB启动子活性降低70％以上(图2B)。RIG-I或MDA5-MAVS信号传导对于RNA刺激的Ⅰ型IFN产生是必需的。MAVS过表达诱导高IFNB萤光素酶信号。与对照相比，它是约500倍的诱导。C7还将MAVS诱导的萤光素酶信号阻断了70％。这些结果指示，在HEK293T细胞中C7的过表达对STING、聚(I:C)、TRIF、TBK1和IRF3诱导的IFNB启动子活性发挥抑制作用。相比之下，C7的过表达不能抑制组成型地激活的磷酸化的IRF3-5D。由于TBK1/IRF3是这些不同的DNA和RNA传感途径的共同节点，因此C7可能靶向导致IRF3激活的步骤，从而导致IRF3磷酸化和核转位的失败。
实施例3：在免疫细胞中牛痘C7的过表达抑制IFNB基因诱导。
为了评估牛痘C7在免疫细胞中的IFNB基因诱导中的作用，我们产生了两种稳定表达牛痘C7的细胞系，包括鼠巨噬细胞RAW264.7和人THP-1。THP-1是人单核细胞白血病细胞系，其已经广泛用于研究人单核细胞和巨噬细胞的功能和免疫调节。简言之，将RAW264.7和THP-1用含有在CMV启动子和嘌呤霉素选择标记下的牛痘C7表达构建体的逆转录病毒转导。具有药物选择标记的空载体也用于产生对照细胞系。获得抗药性细胞并且将其用于以下实验。在将表达C7或具有空载体的THP-1稳定细胞系用于实验之前，使它们通过佛波醇-12-肉豆蔻酸酯-13-乙酸酯(PMA；20ng/ml)分化3天。将细胞用仙台病毒(SeV)、热灭活的MVA(H-MVA)感染，或用聚I:C孵育，或用ISD(Invivogen)转染。24h后，通过定量实时PCR测量IFNB基因表达水平。在RAW264.7和THP-1细胞中，SeV感染均诱导了最高水平的IFNB基因表达，并且牛痘C7的过表达导致IFNB基因表达降低了60％(图3A和C)。牛痘C7还使在RAW264.7和THP-1细胞中的聚(I:C)诱导的IFNB基因表达减弱50％以上。类似地，牛痘C7将在RAW264.7和THP-1细胞中热iMVA诱导的IFNB基因表达降低了60％。SeV是负义的单链RNA病毒，属于副粘病毒科。SeV可以通过细胞质RNA传感器视黄酸诱导型基因I(RIG-I)和黑素瘤分化相关基因5(MDA-5)来检测(Kato等人2005；Gitlin等人,2010)，这导致MAVS/TBK1/IRF3轴的激活。聚(I:C)激活内体dsRNA传感器TLR3，这导致TRIF/TBK1/IRF3轴的激活。H-MVA激活胞质DNA传感器cGAS，这导致第二信使环状GMP-AMP(cGAMP)的产生以及STING/TBK1/IRF3轴的激活(Dai等人,Science immunology,印刷中)。综上所述，这些结果指示牛痘C7抑制巨噬细胞中的多种先天免疫传感途径。
实施例4：重组MVAΔC7L病毒的产生。
为了进一步证实C7在免疫调节中的作用，设计了产生缺失了C7L基因的MVAΔC7L病毒的策略。构建pC7LGFP载体(SEQ ID NO:4)以将特定目的基因插入MVA的C7L基因座中。在这种情况下，将在牛痘P7.5启动子控制下的GFP用作选择标记。将表达盒两侧侧接C7侧翼区域(C7-L和C7-R)的部分序列(图4A)。将BHK21细胞用表达LacZ的MVA病毒以0.05的MOI感染1h，然后用上述质粒DNA转染。在48h收集感染的细胞。将重组病毒(GFP插入C7基因座中)通过绿色荧光鉴定(图4B)。将阳性克隆噬斑纯化4-5次。进行PCR分析以确认重组病毒MVAΔC7L已经丢失C7基因(图4C)。
实施例5：鼠cDC和人THP-1细胞的MVAΔC7L感染比MVA诱导更高水平的IFNB基因表 达和TBK1和IRF3的磷酸化。
常规树突细胞(cDC)的MVA感染已经显示经由cGAS/STING/IRF3依赖性机制诱导I型IFN。为了测试C7是否在胞质DNA传感途径的诱导中起抑制作用，分析了骨髓衍生的DC(BMDC)对MVAΔC7L与MVA的先天免疫应答。将BMDC用MVAΔC7L或MVA以10的MOI感染。在感染后3h和6h收集细胞。通过定量PCR分析确定IFNB基因表达水平。在感染后3h和6h，cDC中MVAΔC7L诱导的IFNB基因表达水平明显高于MVA(图5A)。来自MVAΔC7L感染的cDC的上清液中的IFN-β蛋白水平也高于来自MVA感染的cDC的上清液中的IFN-β蛋白水平(图5B)。Western印迹分析证明，MVAΔC7L感染诱导的TBK1和IRF3的磷酸化水平高于MVA，这表明TBK1可能是C7的靶标(图5D)。为了测试MVAΔC7L是否在人免疫细胞中诱导更高水平的IFNB基因激活，采用了广泛使用的分化的THP-1细胞。将THP-1细胞用MVAΔC7L或MVA以10的MOI感染，并且在感染后3h和6h收集细胞。在THP-1细胞中，MVAΔC7L感染诱导的IFNB基因表达水平高于MVA(图5C)。这些结果指示，C7是可能在TBK1水平上拮抗胞质DNA传感途径的抑制剂。因此，这些结果显示，MVAΔC7L有用于诱导先天免疫应答的方法。
实施例6：牛痘C7减弱I型IFN诱导的JAK-STAT信号传导途径。
分析了C7是否对IFN-β诱导的干扰素刺激基因(ISG)激活具有任何抑制作用。在此实施例中，使用了ISRE-luc报告物。简言之，将HEK293T细胞用ISRE-luc报告物和对照质粒pRL-TK以及渐增量的表达牛痘C7的质粒转染，所述ISRE-luc报告物在ISRE一旦被激活时即表达萤火虫萤光素酶，并且所述对照质粒pRL-TK在ISRE一旦被激活时即表达海肾萤光素酶。转染后24h，将细胞用IFN-β再处理24h。然后收集细胞，并且确定萤火虫萤光素酶相对于海肾萤光素酶的相对水平。将变化倍数定义为相对水平。C7的过表达导致ISRE激活减少高达75％(图6B)。
实施例7：牛痘C7的过表达拮抗IFN-β诱导的ISG表达。
分析了HEK293T细胞(图7A)或RAW264.7细胞(图7B)中过表达牛痘C7是否会拮抗IFN-β诱导的ISG基因表达。已经描述了表达牛痘C7的RAW264.7细胞(实施例3)。将HEK293T细胞用含有牛痘C7L和药物选择标记-嘌呤霉素的逆转录病毒转导。几轮药物选择后，产生了表达牛痘C7的稳定HEK293T细胞系。具有药物选择标记的空载体也用于产生对照细胞系。将表达C7或具有空载体的稳定细胞系用IFN-β处理16h。通过定量实时PCR测量ISG15 mRNA水平。与空载体对照细胞系相比，C7的异位表达导致ISG15基因表达减少。这些结果进一步支持牛痘C7下调IFN-β诱导的ISG表达。
实施例8：与MVA相比，在BMDC中MVAΔC7L诱导更高水平的ISG表达。
分析了MVAΔC7L是否比MVA诱导更高水平的干扰素刺激基因(ISG)表达。将BMDC用MVAΔC7L或MVA以10的MOI感染。在感染后12和24h收集细胞。提取mRNA，并且通过定量实时PCR确定ISG15和Mx1的表达水平。在感染后12和24h，MVAΔC7L感染比MVA诱导更高水平的ISG15和Mx1(图8A和B)。因此，这些结果显示，MVAΔC7L有用于诱导先天免疫应答的方法。
实施例9：MVAΔC7L不能表达C7并且不能抑制IFN-β诱导的STAT2磷酸化。
在大肠杆菌BL21(DE3)中表达和纯化牛痘C7蛋白，并且通过在兔中免疫产生抗C7多克隆兔抗体。将抗C7抗体通过亲和柱纯化。为了验证在MVA感染的细胞中C7的表达以及在MVAΔC7L感染的细胞中C7表达的损失，将HeLa细胞用MVA或MVAΔC7L以10的MOI感染。在感染后4和12h收集细胞。进行Western印迹分析。在感染后4和12h，MVA感染导致C7表达，然而MVAΔC7L感染的细胞没有可检测的C7蛋白(图9A)。这与图4C中的PCR结果一致，即C7L基因已从MVAΔC7L中缺失。
结合I型IFN后，IFNAR激活JAK/STAT途径，从而导致Stat1和Stat2转录因子的磷酸化和激活，这进而激活数百种ISG的表达，从而导致建立抗病毒状态。为了测试MVA感染是否抑制IFN-β诱导的JAK-STAT途径激活，使用了TBK1-/-MEF细胞。在MEF中MVA诱导的IFNB基因诱导依赖于TBK1。因此，在TBK1-/-细胞中，消除了MVA对IFNB基因诱导的影响。在用鼠IFN-β以1000U/ml的终浓度处理指定的时间之前，将TBK1-/-细胞用MVA或MVAΔC7L以10的MOI感染6h。IFN-β处理导致STAT2磷酸化的快速诱导，STAT2的磷酸化在MVA感染的细胞中减少，但是在MVAΔC7L感染的细胞中不受影响(图9B)。与在HeLa细胞中观察到的情况相似，在MVA感染的MEF中检测到C7，但是在MVAΔC7L感染的细胞中没有检测到。这些结果指示，C7通过防止STAT2磷酸化来抑制IFNAR介导的JAK-STAT途径激活。
实施例10：牛痘C7蛋白与STAT2相互作用。
进行共免疫沉淀测定以确定牛痘C7是否通过与Stat1或Stat2相互作用来下调此途径。简言之，将HEK293T细胞用Flag标记的人STAT1或STAT2与HA标记的C7共转染，然后用IFN-β处理或假处理45min。制备全细胞裂解物(WCL)，并且将其用抗FLAG和抗HA抗体印迹，证明了STAT1或STAT2和C7-HA在转染细胞中的表达(图10A)。用抗HA抗体免疫沉淀全细胞裂解物后，然后用抗Flag抗体探测与C7-HA蛋白相互作用的蛋白质。这些结果显示，仅Flag标记的STAT2被抗C7-HA从全细胞裂解物中拉下(图10B)。
实施例11：具有C7L缺失的重组牛痘病毒(VACVΔC7L)的产生。
使用pC7LGFP载体(SEQ ID NO:4)将在牛痘P7.5启动子控制下的GFP插入MVA的C7L基因座中。将表达盒两侧侧接C7侧翼区域(C7-L和C7-R)的部分序列。将BSC40细胞用表达的WT牛痘病毒以0.05的MOI感染1h，然后用上述质粒DNA转染。在48h收集感染的细胞。将重组病毒(GFP插入C7基因座中)通过绿色荧光鉴定。在BSC40细胞上将阳性克隆噬斑纯化4-5次。进行PCR分析以确认重组病毒VACVΔC7L已经丢失C7基因(图11A和11B)。
实施例12：VACVΔC7L具有比WT VACV小的噬斑大小，并且对IFN抑制敏感。
为了研究WT VACV和VACVΔC7L之间是否存在任何表型差异，以及它们是否对IFN抑制敏感，在用两种病毒以指定剂量(PFU)感染之前，将BSC40细胞用IFN-β(1000U/ml)预处理或假处理12h。在不存在IFN-β预处理的情况下，VACVΔC7L的噬斑大小比WT VACV小。在存在IFN-β预处理的情况下，WT VACV的噬斑大小有所减小，并且VACVΔC7L的噬斑大小进一步减小并且几乎不可见(图12A)。与WT VACV相比VACVΔC7L的噬斑大小减小可能是由于VACVΔC7L的复制能力降低或其扩散到邻近细胞的能力降低所致。为了区分这两种可能性，进行了多步生长实验，其中在用两种病毒以0.05的MOI感染之前，将BSC40细胞用IFN-β(1000U/ml)预处理或假处理12h。在不同时间收集细胞并且确定病毒滴度。在不存在IFN-β预处理的情况下，在感染48h期间，WT VACV的滴度从1.5x 105增加到7.0x 108(增加了1000倍以上)；然而在感染的前48h期间，VACVΔC7L的滴度从1.5x 105增加到4.5x 107(增加了约300倍)。在存在IFN-β预处理的情况下，在感染的48h期间，WTVACV的滴度从1.2x 105增加到9.0x 107(增加了700倍以上)；然而在感染的前48h期间，VACVΔC7L的滴度从6.0x 104增加到8.0x105(增加了约15倍)(图12B)。这些结果证明，VACVΔC7L在BSC40细胞上的复制能力降低，并且对IFN抑制敏感。
实施例13：VACVΔC7L在鼠鼻内感染模型中高度减毒。
将在鼻内感染不同剂量的WT VACV后C57BL/6J小鼠的重量减轻与在感染VACVΔC7L后C57BL/6J小鼠观察到的重量减轻进行比较。每只小鼠以2x103PFU进行WT VACV感染导致在感染后第7天重量减轻超过10％，并且在感染后第14天所有小鼠重量均增加并且恢复(图13A和13B)。每只小鼠以2x 104PFU进行WT VACV感染导致在感染后第7天和第8天重量减轻约20％，并且在感染后第14天所有小鼠重量均增加并且恢复(图13A和13B)。每只小鼠以2x105PFU进行WT VACV感染导致在感染后第8天和第9天重量减轻约30％，并且在感染后第14天，6/10的小鼠重量增加并且缓慢恢复大部分减轻的重量，然而4/10小鼠死亡(图13A和13B)。每只小鼠以2x 105PFU进行WT VACV感染导致100％致死率(图13A和13B)。相比之下，以最高剂量(2x 107PFU)进行VACVΔC7L感染导致重量减轻不到20％，并且所有小鼠在感染后11至12天均恢复了重量(图13C和13D)。这些结果指示，在鼠鼻内感染模型中，C7是毒力因子，而VACVΔC7L是高度减毒的。
实施例14：在STINGGt/Gt小鼠中，VACVΔC7L感染并未导致死亡率增加。
STINGGt/Gt小鼠更易受WT VACV感染。用WT VACV以2x 105PFU感染在WT C57BL/6J小鼠中导致50％的致死率，然而所有STINGGt/Gt小鼠均在此剂量下死于WT VACV感染(图14A和14B)。相比之下，与WT年龄匹配的对照小鼠相比，以2x 105PFU进行VACVΔC7L感染导致WT小鼠重量减轻不到5％，而STINGGt/Gt小鼠重量减轻略多。所有小鼠均在感染中存活(图14C和14D)。由于VACVΔC7L感染的衰减，可能会将VACVΔC7L感染限制在鼻内感染模型中的感染的肺组织上，而STING缺乏并没有显著影响感染的严重性或其向血液和远端器官的传播。
实施例15：VACVΔC7L感染的小鼠产生了针对致死性WT VACV攻击的免疫。
为了测试在WT或STINGGt/Gt小鼠中鼻内感染VACVΔC7L是否导致全身抗病毒免疫的形成，将存活的小鼠(初次感染后6周)和初试WT对照小鼠用WT VACV感染的致死剂量以2x106PFU攻击。所有初试WT小鼠均在感染后8或9天死亡，然而先前感染的WT或STINGGt/Gt小鼠均未减轻初始重量的5％以上，并且它们都在攻击中存活(图15A和B)。这些结果指示，在WT或STING缺陷型小鼠中先前感染VACVΔC7L导致全身抗病毒免疫的形成。
实施例16：在鼻内感染模型中，MVAΔC7L感染在STAT2-/-和IFNAR1-/-小鼠中获得了 毒力。
为了测试VACVΔC7L病毒是否在STAT2-/-或IFNAR1-/-小鼠中获得了毒力，将WT、STAT2-/-或IFNAR1-/-小鼠用VACVΔC7L以2x 107pfu的剂量鼻内感染，并且监测其重量减轻和随时间的存活。发现与WT小鼠相比，STAT2-/-和IFNAR1-/-小鼠对VACVΔC7L感染高度易感，重量迅速减轻，疾病严重和死亡(图16A和16B)。STAT2-/-和IFNAR1-/-小鼠的中值存活时间分别为7天和8天(图16B)。P＝0.0145(n＝5)时，此差异具有统计学意义。在用VACVΔC7L以2x107pfu感染后第4天，比较WT、STAT2-/-或IFNAR1-/-小鼠的各种组织中的病毒滴度。发现WT小鼠的VACVΔC7L感染导致肺部的局部感染，而没有病毒的传播或病毒血症。相比之下，在STAT2-/-或IFNAR1-/-小鼠中，VACVΔC7L感染导致肺中的病毒滴度更高。还观察到在感染后第4天，在STAT2-/-和IFNAR1-/-小鼠中，病毒血症和病毒向各个远端器官(包括肝、脾和脑)的传播(图16C)。与WT小鼠相比，MDA5-/-小鼠的VACVΔC7L病毒感染导致重量减轻更多，并且在感染后第4天MDA5-/-小鼠的肺中的病毒滴度是WT小鼠的肺中的病毒滴度的100倍(图16A和16C)。然而，所有MDA5-/-小鼠都逐渐增重，并且在感染中存活(图16A和16B)。
为了确定在STAT2-/-或IFNAR1-/-小鼠中VACVΔC7L病毒的LD50(50％的感染的小鼠死于感染的剂量)，将这些小鼠用各种剂量的VACVΔC7L鼻内感染。发现在VACVΔC7L的2x105pfu剂量下，5/5的STAT2-/-小鼠和5/5的IFNAR1-/-小鼠重量迅速减轻并且死亡。在VACVΔC7L的2x 103pfu剂量下，1/5的STAT2-/-小鼠和1/5的IFNAR1-/-小鼠在分别为9天和11天的中值存活时间死亡。在VACVΔC7L的2x 102pfu剂量下，5/5的STAT2-/-小鼠和5/5的IFNAR1-/-小鼠存活。估计STAT2-/-和IFNAR1-/-小鼠中VACVΔC7L的LD50约为1000pfu(图16D-16G)。
实施例17：在鼻内感染模型中在MDAS5-/-STINGGt/Gt小鼠中，VACVΔC7L感染获得了 毒力。
与WT对照相比，以2x 107pfu进行VACVΔC7L感染导致MDA5-/-或STINGGt/Gt小鼠重量减轻更多。为了测试VACVΔC7L病毒是否在MDA5-/-STINGGt/Gt小鼠中获得了毒力，将MDA5-/-STINGGt/Gt、STINGGt/Gt或WT年龄匹配的对照小鼠用VACVΔC7L病毒以2x 107pfu感染。观察到MDA5-/-STINGGt/Gt比STINGGt/Gt或WT小鼠的重量减轻更多(图17A)，并且5/5的小鼠死于VACVΔC7L感染(图17B)。这些结果指示，MDA5介导的胞质dsRNA传感途径和STING介导的胞质DNA传感途径在宿主防御VACVΔC7L感染中起协同作用。
实施例18：鼻内感染VACVΔC7L导致树突细胞(DC)、嗜中性粒细胞、CD8+和CD4+T细 胞流入被感染肺的支气管肺泡腔中。
为了理解在鼻内感染模型中VACVΔC7L与WT VACV相比毒力显著降低的情况，对WTVACV或VACVΔC7L感染的小鼠的支气管肺泡灌洗液(BAL)进行了免疫细胞分析。将小鼠用VACV以2x 105pfu或用VACVΔC7L以2x 107pfu感染，或用PBS假感染。在感染或PBS处理后3和6天收集BAL。观察到在PBS假感染的小鼠的BAL中，Siglec F+CD11c+肺部驻留肺泡巨噬细胞包含大部分的CD45+细胞。在感染后第6天，WT VACV感染导致Siglec F+CD11c+巨噬细胞的绝对数量减少，而不影响BAL中的其他骨髓细胞群(图18A-18C)。相比之下，在感染后第6天，VACVΔC7L感染导致CD45+骨髓细胞大量流入支气管肺泡腔中。观察到在VACVΔC7L感染后，cDC和嗜中性粒细胞被募集到支气管肺泡腔中，而在WT VACV感染的情况下未被募集(图18D-18I)。在感染后第6天，cDC的百分比从来自PBS假处理的小鼠的BAL中占CD45+细胞的1.7％增加到来自VACVΔC7L感染的小鼠的BAL中占CD45+细胞的16％(图18D-18F)。在VACVΔC7L感染的肺的BAL中，其他骨髓细胞(如嗜中性粒细胞)也有所增加(图18G-18I)。DC对于将病毒抗原呈递给幼稚T细胞以在引流淋巴结中产生抗病毒T细胞很重要。在VACVΔC7L感染后第6天，在BAL中，DC向肺泡腔募集增加与CD4+和CD8+T细胞的增加正相关。在病毒感染后第6天，CD4+T细胞占CD45+细胞的百分比从来自PBS假处理小鼠的BAL中的0.1％增加到来自VACVΔC7L感染的小鼠的BAL中的11％(图18L-18M)。最引人注目的是，与WT VACV感染的小鼠相比，VACVΔC7L感染导致更高百分比的CD8+T细胞的募集(在VACVΔC7L感染的小鼠中CD8+T细胞占CD45+T细胞的38％对比在WT VACV感染的小鼠中CD8+T细胞占CD45+的2％)(图18J-18K)。综上所述，这些结果指示，VACVΔC7L感染导致树突细胞、嗜中性粒细胞、CD8+和CD4+T细胞募集到被感染肺的支气管肺泡腔中，然而WT VACV感染则不会。
实施例19：I型IFN信号传导对于CD8 T细胞浸润到支气管肺泡腔是必需的。
在用VACVΔC7L以2x 105pfu感染后第5天，检查了WT、STAT2-/-或IFNAR1-/-小鼠的BAL中的CD8+T细胞群。发现尽管在WT小鼠中鼻内感染VACVΔC7L病毒导致CD8+T细胞募集进入BAL中，但是在STAT2-/-或IFNAR-/-小鼠中CD8+T细胞的数量却可忽略，这指示对于将CD8+T细胞募集到支气管肺泡腔中，与IFNAR1和JAK/STAT途径相比，I型IFN信号传导至关重要(图19A-19B)。
实施例20：鼻内感染VACVΔC7L导致CD8+和CD4+T细胞募集进入肺实质中。
为了检查鼻内感染WT VACV或VACVΔC7L对肺实质中CD8+和CD4+T细胞的影响，将WTC57BL6/J小鼠用WT VACV或VACVΔC7L以2x 105pfu感染。感染后6天收集肺，并且用胶原酶D消化。将单细胞悬浮液用抗CD45、抗CD3、抗CD4和抗CD8抗体染色，并且FACS分析显示VACVΔC7L感染导致肺实质中的CD8+T细胞增加了2倍以上，然而WT VACV感染导致CD8+T细胞占CD45+T细胞的百分比变化很小(图20A)。VACVΔC7L感染导致肺实质中CD4+T细胞占CD45+T细胞的百分比略有增加，然而WT VACV感染导致肺实质中CD4+T细胞占CD45+T细胞的百分比显著降低(图20B)。
实施例21：鼻内感染VACVΔC7L导致牛痘病毒B8R特异性CD8+T细胞的产生并且募 集进入肺和支气管肺泡腔中。
为了测试募集到BAL和肺实质的CD8+T细胞是否是病毒特异性的，将B8R20-27肽TSYKFESV(SEQ ID NO:8)脉冲的BMDC添加到来自用WT VACV以2x 105pfu或VACVΔC7L以2x105pfu感染的小鼠的肺的单细胞悬浮液中。在将细胞固定并透化并且用抗IFN-γ抗体染色之前，在布雷菲德菌素A(5μg/ml)的存在下将它们孵育6h。与WT VACV病毒感染相比，VACVΔC7L感染导致肺实质中的IFN-γ+CD8+T细胞百分比更高(图21A)。在将细胞固定并透化并且用抗IFN-γ抗体染色之前，在布雷菲德菌素A(5μg/ml)的存在下，将用B8R20-27 TSYKFESV(SEQ ID NO:8)或用OVA257-264 SIINFEKL(SEQ ID NO:7)脉冲的BMDC与来自VACVΔC7L感染的小鼠的BAL的细胞一起孵育6h。图21B显示BAL中的CD8+T细胞与B8R20-27 TSYKFESV(SEQ IDNO:8)反应，但不与无关肽OVA257-264 SIINFEKL(SEQ ID NO:7)反应。这些结果指示，VACVΔC7L感染导致病毒特异性T细胞的产生并且将它们募集进入肺实质和BAL中。
实施例22：宿主防御急性VACVΔC7L鼻内感染不需要CD8+T细胞。
为了测试宿主防御急性VACVΔC7L感染是否需要CD8+T细胞，我们通过在第-1、+1、+3和+5天时腹膜内递送抗CD8抗体(200μg/小鼠)耗竭了CD8+T细胞，并且在第0天将小鼠用VACVΔC7L病毒以2x 107pfu感染。CD8+T细胞耗竭的效率通过CD8+T细胞耗竭或假耗竭小鼠的外周血的FACS分析来验证。观察到CD8+T细胞耗竭并不影响小鼠的重量减轻或存活(图22A和22B)，这指示针对急性VACVΔC7L感染的保护不需要CD8+T细胞。
实施例23：鼻内感染VACVΔC7L导致IFN-β、促炎细胞因子和趋化因子释放到支气 管肺泡腔中。
鉴于T细胞介导的适应性免疫可能在宿主针对急性VACVΔC7L感染的保护中没有发挥重要作用，分析了对WT VACV或VACVΔC7L感染的先天免疫应答。在鼻内感染后1和3天收集BAL，并且通过ELISA测试IFN-β的浓度，并且通过Luminex Multiplex测定测试其他细胞因子和趋化因子的水平。与感染后第1天收集的BAL中的IFN-β浓度水平相比，VACVΔC7L感染增加了感染后第3天收集的BAL中的IFN-β浓度水平，然而WT VACV感染则未能诱导(图23A)。Luminex测定显示，与感染后第1天收集的BAL中的MCP-1(CCL-2)、IP-10(CXCL10)、MIG(CXCL9)和IFN-β的浓度相比，VACVΔC7L感染还增加了感染后第3天收集的BAL中的MCP-1(CCL-2)、IP-10(CXCL10)、MIG(CXCL9)和IFN-β的浓度。(图23B和23C)。这些结果指示，VACVΔC7L感染导致IFN-β以及促炎细胞因子和趋化因子释放进入BAL中，然而WTVACV感染则没有。
实施例24：在IFNβ/YFP报告小鼠中，VACVΔC7L感染诱导从II型肺泡上皮细胞(AECII)产生IFN-β。
为了测试鼻内感染VACVΔC7L后，哪些细胞群负责产生IFN-β，将WT小鼠和IFNB/黄色荧光蛋白(YFP)报告小鼠用VACVΔC7L以2x 107pfu感染。在Locksley博士的实验室中产生了IFNB/YFP敲入小鼠(其中YFP由通过内部核糖体进入位点与内源性IFNβmRNA相连的双顺反子mRNA表达)，并且所述小鼠为在单细胞水平上跟踪IFN-β产生细胞提供了工具(Scheu等人,2008)。感染后48h，收集感染小鼠的肺并且在1％低熔点琼脂的存在下在室温(RT)下用分散酶消化30min。产生单细胞悬浮液并且进行FACS分析。观察到大多数IFN-β/YFP+细胞位于CD45-细胞群中(图24)。其中，EpCAM+细胞群具有最高的IFN-β/YFP+细胞百分比。当排除CD31+细胞(内皮细胞)和Tla+细胞(I型肺泡上皮细胞；AECI)时，观察到II型肺泡上皮细胞(AECII)具有最高的IFN-β/YFP+细胞百分比(图24)。结果指示，鼻内感染VACVΔC7L后，AECII是促成IFN-β产生的最重要细胞类型。
实施例25：VACVΔC7L感染诱导从肺II型肺泡上皮细胞产生IFN-β、CCL4和CCL5。
为了测试肺AECII对WT VACV与VACVΔC7L感染的先天免疫应答，通过FACS对CD45-CD16-CD32-CD31-EpCAMhiCD104+细胞进行分选来分离谱系阴性上皮细胞祖细胞(LNEP)(图25A)。将这些细胞在角质形成细胞生长因子的存在下在基质胶包被的24孔板上培养4天。分化的细胞表达表面活性剂C，其是AECII的标记(图25B)。将细胞用WT VACV或VACVΔC7L病毒以10的MOI感染，并且在12h收集细胞用于RNA提取和定量实时PCR分析。与WTVACV相比，VACVΔC7L感染诱导了更高水平的Ifnb、Ccl4、Ccl5基因表达(图25C)。感染后24h收集被感染的AECII上清液，并且测试其IFN-β、CCL4和CCL5水平。AECII的VACVΔC7L感染诱导IFN-β、CCL4和CCL5分泌到上清液中，然而WT VACV感染则未能诱导(图25D)。这些结果指示，VACVΔC7L感染激活肺AECII的先天免疫传感机制，从而导致IFN-β、CCL4和CCL5的产生。
实施例26：鼻内施用IFN-β使小鼠免于致死性VACV感染。
为了测试肺支气管肺泡腔中的IFN-β是否足以保护小鼠免受WT VACV的致死性感染，将WT C57BL/6J小鼠用WT VACV以2x 106pfu鼻内感染，然后每只小鼠鼻内施用1μg重组IFN-β或施用PBS。监测小鼠的重量减轻和存活。发现所有未经IFN-β处理的WT VACV感染的小鼠均死亡，然而所有经IFN-β处理的小鼠仅短暂地重量减轻并且存活。这些结果指示，在肺AEC中，IFN-β处理足以限制VACV的致死性攻击。
实施例27：在B16-F10鼠黑素瘤细胞中，MVAΔC7L比MVA引起更强的先天免疫应答。
为了测试在鼠B16-F10黑素瘤细胞中MVAΔC7L是否比MVA诱导更强的先天免疫应答，将B16-F10细胞用MVAΔC7L或MVA以10的MOI感染。在感染后8和48h收集细胞。定量实时PCR分析显示，与MVA相比，MVAΔC7L诱导了更高水平的Ifnb、Ccl4、Ccl5和Cxcl10基因表达(图27A-27D)。这些结果指示，在肿瘤细胞中，MVAΔC7L比MVA具有更高的免疫刺激性。因此，这些结果显示，MVAΔC7L有用于诱导先天免疫应答的方法。
实施例28：在双侧B16-F10肿瘤植入模型中，瘤内(IT)注射MVAΔC7L比MVA更有效。
基于相对于MVA，MVAΔC7L诱导更高水平的I型IFN、促炎细胞因子和趋化因子的能力，在体内鼠肿瘤模型中评估了MVAΔC7L充当比MVA更强的免疫刺激剂的能力。使用了鼠双侧B16-F10肿瘤植入模型。简言之，将B16-F10黑素瘤细胞皮内植入C57B/6小鼠的左右侧腹(右侧腹5x 105，左侧腹1x 105)。肿瘤植入后9天，每两周一次将2x 107PFU的MVA或MVAΔC7L注射进右侧腹较大的肿瘤内(图28A)。初始注射的和未注射的肿瘤的体积在图28C和28D中示出。在用PBS处理的小鼠中，肿瘤生长迅速，这导致早期死亡(图28B)。与PBS相比，瘤内注射MVAΔC7L或MVA导致肿瘤生长延迟和存活提高(图28B)。在根除已注射的肿瘤并且延迟对侧未注射的肿瘤生长方面，瘤内注射MVAΔC7L比MVA更有效(图28C和28D)，这导致与MVA处理的小鼠相比，MVAΔC7L处理的小鼠的存活提高(图28B)。因此，这些结果显示，MVAΔC7L有用于治疗实体瘤的方法。
实施例29：与MVA相比，瘤内注射MVAΔC7L诱导更强的CD8+和CD4+免疫应答。
为了测试与MVA相比，在注射的和未注射的远端肿瘤中IT MVAΔC7L是否诱导更高水平的激活的CD8+和CD4+T细胞，诸位发明人在双侧B16-F10黑素瘤植入模型中进行了以下实验。肿瘤植入后，将较大的肿瘤用MVA或MVAΔC7L或PBS注射两次，间隔三天。在第二次注射后2天，收获注射的和未注射的远端肿瘤。分析了活的肿瘤浸润的淋巴细胞(TIL)。在注射的肿瘤中，IT MVA和MVAΔC7L均诱导了高水平的激活的颗粒酶+CD8+和CD4+T细胞(图29A)。另外，在注射的肿瘤的引流淋巴结中，与IT MVA处理的小鼠相比，IT MVAΔC7L引起了更高百分比的TRP2+CD8+T细胞(图29C)。在未注射的肿瘤中，与IT MVA相比，IT MVAΔC7L诱导了更高水平的颗粒酶+CD8+和CD4+T细胞(图29B)。在未注射的肿瘤的引流淋巴结中，与MVA处理的小鼠相比，MVAΔC7L处理的小鼠中也存在更高百分比的TRP2+CD8+T细胞(图29D)。这些结果指示，在注射的和未注射的肿瘤以及TDLN中，与MVA相比，IT MVAΔC7L均产生了更强的抗肿瘤CD8+和CD4+T细胞免疫应答。
实施例30：用于癌症免疫疗法的MVAΔC7L-hFlt3L重组病毒的产生。
使用pC7LhFlt3L-GFP载体将具有在牛痘合成早期和晚期启动子(PsE/L)控制下的人Flt3L(hFlt3L)和在牛痘P7.5启动子控制下的GFP的表达盒插入MVA的C7L基因座中。将表达盒两侧侧接C6R和C8R。表1提供了侧接C6R和C8R序列的示例性表达盒，其包含在牛痘合成早期和晚期启动子(PsE/L)的控制下的hFlt3L和在牛痘P7.5启动子控制下的GFP。将鸡胚成纤维细胞(CEF)用MVA以0.05的MOI感染1h，然后用上述质粒DNA转染(图30A)。在48h收集感染的细胞。将重组病毒(GFP插入C7基因座中)通过绿色荧光鉴定。在CEF上将阳性克隆噬斑纯化4-5次。进行PCR分析以确认重组病毒MVAΔC7L-hFlt3L具有GFP-hFlt3L盒的插入(图30B)。对插入的质粒DNA进行PCR扩增和测序，以验证插入物的序列。
使用多步生长测定测试了重组MVAΔC7L-hFlt3L病毒在BHK21细胞和CEF中的复制能力。简言之，将BHK21和CEF用MVAΔC7L-hFlt3L以0.05的MOI感染。在感染后1、24、48和72h收集细胞。在BHK21细胞上确定病毒滴度。在BHK21和CEF中，MVAΔC7L-hFlt3L均强劲复制(图30C)。
表1.插入以替换MVA基因组中的C7基因的侧接C6和C8序列的包含在牛痘p7.5启动子控制下的GFP和在牛痘合成早期和晚期启动子(PsE/L)控制下的hFlt3L基因的基因表达盒(SEQ ID NO:9)。
Figure BDA0002361606670000561
实施例31：通过重组MVAΔC7L-hFlt3L病毒表达转基因人Flt3L和GFP。
为了测试重组病毒MVAΔC7L-hFlt3L是否表达两个转基因hFlt3L和GFP，将BHK21、B16-F10鼠黑素瘤、SK-MEL28、SK-MEL31和SK-MEL146人黑素瘤细胞用MVAΔC7L(表达GFP)或MVAΔC7L-hFlt3L(表达GFP)以10的MOI感染。感染后24h收集细胞，并且通过FACS分析hFlt3L和GFP的表达。在感染的细胞上，MVAΔC7L-hFlt3L感染诱导了更高水平的GFP和hFlt3L表达(图31)。
实施例32：MC38鼠结肠腺癌细胞的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACV ΔC7L-hFlt3L感染诱导I型IFN和炎性细胞因子/趋化因子的产生。
为了确定在其他类型的实体瘤细胞中MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACVΔC7L-hFlt3L是否触发类似的应答，在MC38结肠腺癌细胞中测试了MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACVΔC7L-hFlt3L诱导I型IFN途径的能力。将MC38细胞用MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L以10的MOI感染，或用假感染对照感染。在感染后22h收集上清液。使用ELISA分析MC38细胞中IFN-β、IL-6、CCL4、CCL5和CXCL10的水平。实时PCR分析将评估MC38细胞中的Ifnb、1l6、Ccl4、Ccl5、Cxcl10基因表达水平。Western印迹分析将评估感染后22h在MC38细胞中IRF3的磷酸化水平。预期这些实验将显示本发明的治疗的功效不限于黑素瘤，并且本发明技术的组合物可以用作治疗实体瘤的免疫治疗剂。因此，此实施例将显示MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L有用于诱导先天免疫应答以治疗实体瘤的方法。
实施例33：MC38鼠结肠腺癌细胞的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACV ΔC7L-hFlt3L感染诱导细胞凋亡。
为了研究在MC38鼠结肠腺癌细胞中MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACVΔC7L-hFlt3L是否也触发细胞凋亡，将MC38细胞用MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACVΔC7L-hFlt3L以10的MOI感染，或用假感染对照感染。预期Western印迹分析将显示MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACVΔC7L-hFlt3L触发PARP从116kDa的全长蛋白质切割为89kDa的片段。还预期MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACVΔC7L-hFlt3L将在不同类型的癌细胞中触发细胞凋亡。预期这些实验将指示由本发明的病毒引起的免疫应答一直持续到细胞凋亡，从而导致癌细胞死亡，从而进一步将目前公开的治疗证实作为治疗黑素瘤、结肠癌、一般癌症和实体瘤的可行方法。因此，此实施例将显示MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L有用于治疗实体瘤的方法。
实施例34：在结肠癌的鼠模型中，MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACV ΔC7L-hFlt3L抑制肿瘤发生。
为了测试在其他实体瘤中MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACVΔC7L-hFlt3L是否能够抑制肿瘤生长，在鼠结肠癌植入模型中测试了MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACVΔC7L-hFlt3L的抗肿瘤作用。结肠癌是与黑素瘤不相关的肿瘤的代表。将2x 105个MC38结肠癌细胞皮内植入C57B/6小鼠的右侧腹中。允许肿瘤形成7天，然后将MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L(2x 107)或PBS对照瘤内注射到小鼠中。在注射前(第0天)和注射后长达45天测量肿瘤，并且根据以下公式计算肿瘤体积：l(长)x w(宽)x h(高)/2。预期用MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L处理的肿瘤明显小于PBS处理的肿瘤。此外，预期用MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L处理的小鼠展现出提高的存活，如通过用PBS或MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACVΔC7L-hFlt3L注射的荷瘤小鼠的Kaplan-Meier存活曲线所证明。共同地，这些结果将显示在结肠癌以及黑素瘤的背景下，MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACVΔC7L-hFlt3L维持抑制肿瘤发生和肿瘤生长的能力。因此，这些结果将证明MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACVΔC7L-hFlt3L在各种实体瘤中均有效地促进抗肿瘤作用，并且本发明技术的应用不限于黑素瘤，而是可以外推到其他各种来源的实体瘤。因此，此实施例将显示MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L有用于治疗实体瘤的方法。
实施例35：在单侧黑素瘤植入模型中，瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACV ΔC7L或VACVΔC7L-hFlt3L与腹膜内递送免疫检查点阻断抗体的组合。
本发明病毒的瘤内注射将用于增强当前免疫疗法(如免疫检查点(例如，抗CTLA-4抗体)的阻断)的治疗效果，将荷瘤小鼠用MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的瘤内注射与抗CTLA-4抗体的腹膜内递送的组合进行处理。简言之，将B16-F10黑素瘤细胞(2x 105)皮内植入WT C57B/6小鼠的右侧腹中。肿瘤植入后十天，将小鼠用以下组合处理：PBS+同种型对照，PBS+抗CTLA-4抗体，MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L+同种型对照和MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L+抗CTLA-4。预期与单独的免疫检查点阻断或者单独的MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L处理相比，用MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L和抗CTLA-4抗体处理将产生优越的治疗功效。因此，此实施例将显示包含MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L与免疫检查点阻断剂的组合的组合物有用于治疗实体瘤的方法。
实施例36：在双侧黑素瘤植入模型中，瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACV ΔC7L或VACVΔC7L-hFlt3L与腹膜内递送免疫检查点阻断的组合。
分析了在双侧B16-F10黑素瘤模型(其还模拟患有转移性疾病的个体)中，瘤内注射的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的治疗效果以及所述处理是否增强免疫检查点阻断疗法(如抗CTLA-4、抗PD-1或抗PD-L1抗体)。简言之，将B16-F10黑素瘤细胞皮内植入C57B/6小鼠的左右侧腹(右侧腹5x 105，左侧腹1x 105)。肿瘤植入后8天，将MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L(2x 107pfu的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L)或PBS瘤内注射进右侧腹较大的肿瘤中，每周两次。将四组小鼠用MVAΔC7L处理，将四组小鼠用MVAΔC7L-hFlt3L处理，将四组小鼠用VACVΔC7L处理，并且将四组小鼠用VACVΔC7L-hFlt3L处理，每组接受同种型对照或者抗CTLA-4或抗PD-1或抗PD-L1抗体的腹膜内递送。
预期与瘤内注射单独的检查点抑制剂或者单独的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L相比，MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的瘤内注射和检查点抑制剂(以抗CTLcomA-4、抗PD-1和抗PD-L1抗体为代表)的全身递送的组合将进一步延迟生长或根除未注射的肿瘤。
预期结果将显示MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的瘤内递送克服了在转移性B16黑素瘤模型中对免疫检查点阻断的治疗抗性，这很好地预示了将这种方法转移到人类疗法的有益结果。因此，此实施例将显示包含MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L与免疫检查点阻断剂的组合的组合物有用于治疗实体瘤的方法。
实施例37：在双侧MC38结肠腺癌植入模型中，瘤内注射MVAΔC7L、MVAΔC7L- hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L与腹膜内递送免疫检查点阻断的组合。
涉及瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的实验将显示在另一种双侧肿瘤植入模型(其模拟患有转移性疾病的受试者)中免疫检查点阻断疗法(如抗CTLA-4、抗或抗PD-L1)的治疗效果增强。简言之，将MC38结肠腺癌细胞皮内植入C57B/6小鼠的左右侧腹(右侧腹5x 105，左侧腹1x 105)。肿瘤植入后8天，将MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L(2x 107pfu的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L)或PBS瘤内注射进右侧腹较大的肿瘤中，每周两次。将三组小鼠用PBS处理，每组接受同种型对照或者抗CTLA-4或抗PD-L1抗体的腹膜内递送。对于MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACVΔC7L-hFlt3L中的每一种，将另外三组小鼠用MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L处理，每组接受同种型对照或者抗CTLA-4或抗PD-L1抗体的腹膜内递送。然后将每组分为也用MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L处理的亚组。也将提供仅用病毒处理的对照。
将监测和评价每组小鼠的注射的和未注射的肿瘤的肿瘤体积。此外，将监测每个处理组的存活。
预期MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的瘤内递送与检查点阻断(以抗CTLA-4抗体的腹膜内递送为代表)的组合或者MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的瘤内递送与抗PD-1/PD-L1的腹膜内递送的组合将导致根除未注射的远端肿瘤的效率高于MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L。因此，预期这些结果显示与单独的检查点阻断或单独的病毒相比，使用MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L和免疫检查点阻断的组合改善转移性实体瘤的治疗。更具体地说，预期注射的和未注射的肿瘤的大小均将减小，甚至根除至比任何一种类型的单一疗法所达到的程度更大的程度，并且预期结果将持续存在至少45天以上，从而验证了用于原发性和转移性实体瘤治疗的组合方法。因此，此实施例将显示包含MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L与免疫检查点阻断剂的组合的组合物有用于治疗实体瘤的方法。
实施例38：在双侧B16-F10植入模型中，瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、 VACVΔC7L或VACVΔC7L-hFlt3L与腹膜内递送免疫检查点阻断抗CTLA-4抗体的组合。
此实施例将评估MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L与免疫检查点阻断(以抗CTLA-4抗体为代表)(以1/10的剂量用于腹膜内递送)的共给予将在严格的双侧肿瘤植入模型中达到抗肿瘤作用。简言之，将B16-F10黑素瘤细胞皮内植入C57B/6小鼠的左右侧腹(右侧腹5x 105，左侧腹1x 105)。肿瘤植入后8天，将MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L(2x 107pfu的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L)或PBS瘤内注射进右侧腹较大的肿瘤中，每周两次。将MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L和VACVΔC7L-hFlt3L中的每一种的三组小鼠用MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L处理，每组接受：(i)腹膜内递送抗CTLA-4(100μg/小鼠)、(ii)瘤内递送同种型抗体(10μg/小鼠)或(iii)瘤内递送抗CTLA-4抗体(10μg/小鼠)。
将监测和评价注射的和未注射的肿瘤的肿瘤体积。诸位发明人预期MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L和检查点阻断(抗CTLA-4抗体，以10μg/小鼠)的瘤内共注射将与MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的瘤内注射和抗CTLA-4抗体(100μg/小鼠)的腹膜内递送的组合的治疗效果相当。预期MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L和大幅降低的剂量的免疫检查点阻断的共给予可以达到与MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的瘤内递送与较高剂量的抗CTLA-4抗体的全身递送的组合类似的全身抗肿瘤作用。因此，此实施例将显示包含MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L与免疫检查点阻断剂的组合的组合物有用于治疗实体瘤的方法。
实施例39：在双侧MC38肿瘤植入模型中，瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、 VACVΔC7L和VACVΔC7L-hFlt3L是有效的。
为了分析MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L在不同的实体瘤模型中的抗肿瘤功效，将5x 105，个MC38结肠癌细胞皮内植入C57B/6小鼠的右侧腹中，并且将1x 105个细胞皮内植入C57B/6小鼠的左侧腹中。允许肿瘤生长7-8天，然后将MVAΔC7L或MVAΔC7L-hFlt3L(2x 107pfu)或者PBS对照注射进较大的肿瘤中，每周两次。
预期瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L延长中值存活期。预期在双侧MC38肿瘤植入模型中，MVAΔC7L-hFlt3L或VACVΔC7L-hFlt3L将比MVAΔC7L或VACVΔC7L更有效。因此，预期包含MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的组合物将有用于治疗实体瘤的方法。
实施例40：在鼠三阴性乳腺癌4T1双侧植入模型中，瘤内注射MVAΔC7L、MVAΔC7L- hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L也有效。
除了B16-F10鼠黑素瘤和MC38结肠腺癌模型外，还研究了瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L在三阴性乳腺癌(TNBC)4T1双侧肿瘤植入模型的治疗中是否具有功效。简言之，将4T1鼠三阴性乳腺癌(TNBC)细胞皮内植入BALB/c小鼠的左右侧腹(右侧腹2.5x 105，左侧腹5x 104)。肿瘤植入后5天，为右侧腹较大的肿瘤注射MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L(2x 107pfu)，每周两次。每天监测小鼠，并且每周测量两次肿瘤大小。监测小鼠的存活。预期与PBS处理的肿瘤相比，瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L将导致注射的肿瘤的肿瘤体积减小。这些结果将显示在双侧4T1乳腺癌模型中，瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L有效延迟肿瘤生长并且延长被治疗小鼠的存活期。基于这些结果，预期在这种双侧4T1植入模型中，MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L与免疫检查点阻断(如抗CTLA-4或抗PD-1/PD-L1抗体)的组合将比单独的病毒疗法更有效。
实施例41：在鼠前列腺癌TRAMP-C2单侧肿瘤植入模型(其需要STING)中，瘤内注射 MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L是有效的。
研究了瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L在鼠前列腺腺癌TRAMP-C2单侧肿瘤植入模型的治疗中是否具有功效。简言之，将TRAMP-C2细胞皮内植入STINGGt/Gt小鼠和年龄匹配的WT C57B/6对照的剃毛的右侧腹中(在50μl PBS中1x 106个细胞/小鼠)。肿瘤植入后17天，为右侧腹的肿瘤(直径约3-4mm)注射PBS或者MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L(2x 107pfu)，每周两次。每天监测小鼠，并且每周测量两次肿瘤大小。监测小鼠的存活。预期与PBS处理的肿瘤相比，瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L导致WT小鼠的注射的肿瘤的肿瘤体积显著减小，但是这在STING缺陷型小鼠中效果较差。预期在WT和STINGGt/Gt小鼠中，MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L将均具有抗肿瘤作用。因此，预期包含MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的组合物将有用于治疗实体瘤的方法。
实施例42：在双侧B16-F10黑素瘤植入模型中，瘤内注射MVAΔC7L、MVAΔC7L- hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L也是有效的。
为了测试瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L在双侧B16-F10植入模型中是否发挥抗肿瘤作用，将MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L或者PBS注射进较大的肿瘤中，每周两次，并且监测肿瘤大小和存活。预期相对于PBS组，瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L将根除或延迟注射的和未注射的肿瘤的肿瘤生长，并且延长中值存活期。这些结果将显示，在双侧肿瘤植入模型中，瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L对抗肿瘤也是有效的。因此，预期包含MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的组合物将有用于治疗实体瘤的方法。
实施例43：在双侧B16-F10黑素瘤植入模型中，瘤内注射MVAΔC7L、MVAΔC7L- hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L与全身递送免疫检查点的组合具有协同抗肿瘤作 用。
此实施例将测试在双侧B16-F10黑素瘤植入模型中，MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的瘤内注射与免疫检查点阻断的全身递送的组合是否将比单独的病毒疗法导致更好地杀死肿瘤并且提高存活。肿瘤植入后8天，将MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L病毒注射进右侧腹较大的肿瘤中，每周两次。将四组小鼠用MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L处理，每组接受同种型对照或者抗CTLA-4或抗PD-1或抗PD-L1抗体的腹膜内递送。预期与PBS组相比，用MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L+同种型处理将显著延长存活期。预期与单独的瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L相比，MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的瘤内注射与抗CTLA-4、抗PD-1和抗PD-L1抗体的全身递送的组合在根除或延迟注射的和未注射的肿瘤的生长方面具有协同作用。因此，预期包含单独的或与免疫检查点阻断剂组合的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的组合物将有用于治疗实体瘤的方法。
实施例44：瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L 导致抗肿瘤CD8+T细胞免疫的产生，其在抗CTLA-4抗体的存在下增强。
通过使用酶联免疫斑点(ELISpot)检查了在单独地或在存在腹膜内递送抗CTLA-4抗体的情况下用瘤内注射MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L处理后，存活的小鼠是否对B16-F10和MC38结肠癌产生了抗肿瘤记忆T细胞免疫。简言之，从脾细胞中分离CD8+T细胞，并且在抗IFN-γ包被的BD ELISPOT板微孔中，将1x 105个细胞在37℃下培养过夜。将CD8+T细胞用γ辐射器辐照的B16-F10或MC38细胞刺激，并且用抗IFN-γ抗体检测细胞因子分泌。预期具有免疫原性的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L牛痘感染导致在B16-F10和MC38癌细胞中均存在的肿瘤抗原的有效交叉呈递，这导致异源肿瘤交叉保护的形成。因此，预期包含单独的或与免疫检查点阻断剂组合的MVAΔC7L、MVAΔC7L-hFlt3L、VACVΔC7L或VACVΔC7L-hFlt3L的组合物将有用于治疗实体瘤的方法。
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等效物
在本申请中描述的具体实施方案方面本发明技术并不受限，旨在将所述实施方案作为本发明技术单独方面的单一说明。对于本领域技术人员清楚的是，可以在不背离本发明技术的精神和范围的情况下，对本发明技术进行多种修改和改变。本领域技术人员根据前述描述将清楚，除了本文列举的方法和装置外，在本发明技术范围内的功能上等效的方法和装置。此类修改和改变旨在落于所附权利要求的范围内。本发明技术仅由所附权利要求的条款以及此类权利要求授权的等效物的全部范围来限定。应当理解，本发明技术不限于具体方法、试剂、化合物、组合物或生物系统，它们当然可以改变。还应当理解，本文所用的术语仅用于描述具体实施方案的目的，而不旨在是限制性的。
另外，在本公开文本的特征或方面按马库什群组(Markush group)来描述的情况下，本领域技术人员应认识到，本公开文本也从而按马库什群组的任何单独成员或成员亚组来描述。
本领域技术人员应理解，出于任何和所有目的，特别是就提供书面描述而言，本文公开的所有范围还涵盖任何和所有可能的子范围及其子范围的组合。任何所列范围都可以容易地识别为充分描述相同范围并且使得相同范围能分解为至少相等的二分之一、三分之一、四分之一、五分之一、十分之一等。作为非限制性例子，本文讨论的每个范围可以容易地分解为下三分之一、中三分之一和上三分之一等。同样本领域技术人员应理解，诸如“高达(upto)”、“至少(at least)”、“大于(greater than)”、“小于(less than)”等所有言辞都包括所述数字并且涉及随后可以分解为如上文所讨论的子范围的范围。最后，本领域技术人员应理解，范围包括每个单独的成员。因此，例如，具有1-3个细胞的组是指具有1、2或3个细胞的组。类似地，具有1-5个细胞的组是指具有1、2、3、4或5个细胞的组等等。
本文提到或引用的所有专利、专利申请、临时申请和出版物都通过引用以其整体而并入，包括所有图形和表格，并入程度至其与本说明书的明确教示一致。
其他实施方案在以下权利要求中提出。
序列表
<110> MEMORIAL SLOAN KETTERING CANCER CENTER
<120> 有用于癌症免疫疗法的牛痘病毒突变体
<130> 115872-0781
<140>
<141>
<150> 62/505,713
<151> 2017-05-12
<160> 6
<170> PatentIn版本3.5
<210> 1
<211> 194711
<212> DNA
<213> 牛痘病毒WR
<400> 1
atttaaaata taatattaat gtactaaaac ttatatatta ttaatttatc taactaaagt 60
tagtaaatta tatatataat tttataatta atttaatttt actaatttta tttagtgtct 120
agaaaaaaat gtgtgaccca tgactgtagg aaactctaga gtgtaagaaa gatcgatcgc 180
tttatagaga ccatcagaaa gaggtttaat atttttgtga gaccatcgaa gagagaaaga 240
gataaaactt ttttacgact ccatcagaaa gaggtttaat atttttgtga gaccatcgaa 300
gagagaaaga gataaaactt ttttacgact ccatcagaaa gaggtttaat atttttgtga 360
gaccatcgaa ggagaaagag ataaaacttt tttacgactc catcagaaag aggtttaata 420
tttttgtgag accatcgaag gagaaagaga taaaactttt ttacgactcc atcagaaaga 480
ggtttaatat ttttgtgaga ccatcgaaga gagaaagaga taaaactttt ttacgactcc 540
atcagaaaga ggtttaatat ttttgtgaga ccatcgaaga gagaaagaga taaaactttt 600
ttacgactcc atcagaaaga ggtttaatat ttttgtgaga ccatcgaagg agaaagagat 660
aaaacttttt tacgactcca tcagaaagag gtttaatatt tttgtgagac catcgaagag 720
agaaagagat aaaacttttt tacgactcca tcagaaagag gtttaatatt tttgtgagac 780
catcgaagag agaaagagat aaaacttttt tacgactcca tcagaaagag gtttaatatt 840
tttgtgagac catcgaagag agaaagagat aaaacttttt tacgactcca tcagaaagag 900
gtttaatatt tttgtgagac catcgaagag agaaagagat aaaacttttt tacgactcca 960
tcagaaagag gtttaatatt tttgtgagac catcgaagag agaaagagat aaaacttttt 1020
tacgactcca tcagaaagag gtttaatatt tttgtgagac catcgaagag agaaagagaa 1080
agagatagtt gatctagata tttttcttag tacaaaagtc aatgttttaa aatatatgga 1140
caagaatttg tctgtataaa aacttgtgtg aaattttgta ccaaagaaaa aatgtgagca 1200
gtatccccta catggatttt actagatcat ttatatacca aaaaatatta tacgatctac 1260
gttttattat atgattttaa cgtgtaaatt ataaacatta ttttatgata tacaattgtc 1320
tggtaaccta gatgggcata ggggatgttg ataagctcga cgagtatatg ttgttggacg 1380
ttattgttta agaaatagtt gatgcatcag aaagagaata aaaaatattt tagtgagacc 1440
atcgaagaga gaaagagata aaactttttt acgactccat cagaaagagg tttaatattt 1500
ttgtgagacc atcgaagaga gaaagagata aaactttttt acgactccat cagaaagagg 1560
tttaatattt ttgtgagacc atcgaagaga gaaagagata aaactttttt acgactccat 1620
cagaaagagg tttaatattt ttgtgagacc atcgaagaga gaaagagata aaactttttt 1680
acgactccat cagaaagagg tttaatattt ttgtgagacc atcgaagaga gaaagagata 1740
aaactttttt acgactccat cagaaagagg tttaatattt ttgtgagacc atcgaagaga 1800
gaaagagata aaactttttt acgactccat cagaaagagg tttaatattt ttgtgagacc 1860
atcgaagaga gaaagagata aaactttttt acgactccat cagaaagagg tttaatattt 1920
ttgtgagacc atcgaagaga gaaagagata aaactttttt acgactccat cagaaagagg 1980
tttaatattt ttgtgagacc atcgaagaga gaaagagata aaactttttt acgactccat 2040
cagaaagagg tttaatattt ttgtgagacc atcgaagaga gaaagagata aaactttttt 2100
acgactccat cagaaagagg tttaatattt ttgtgagacc atcgaagaga gaaagagata 2160
aaactttttt acgactccat cagaaagagg tttaatattt ttgtgagacc atcgaagaga 2220
gaaagagata aaactttttt acgactccat cagaaagagg tttaatattt ttgtgagacc 2280
atcgaagaga gaaagagata aaactttttt acgactccat cagaaagagg tttaatattt 2340
ttgtgagacc atcgaagaga gaaagagata aaactttttt acgactccat cagaaagagg 2400
tttaatattt ttgtgagacc atcgaagaga gaaagagata aaactttttt acgactccat 2460
cagaaagagg tttaatattt ttgtgagacc atcgaagaga gaaagagata aaactttttt 2520
acgactccat cagaaagagg tttaatattt ttgtgagacc atcgaagaga gaaagagata 2580
aaactttttt acgactccat cagaaagagg tttaatattt ttgtgagacc atcgaagaga 2640
gaaagagata aaactttttt acgactccat cagaaagagg tttaatattt ttgtgagacc 2700
atcgaagaga gaaagagaat aaaaatattt tatgactcca ttgaagagag aaagagaaaa 2760
tgagaatgag aataaaaata ttttagtgac accatcagaa agaggtttaa tatttttgtg 2820
agaccatcga agagagaaag agaataaaaa tattttatga ctccattgaa gagagaaaga 2880
gaaaatgaga atgagaataa aaatatttta gtgacaccat cagaaagagg tttaatattt 2940
tttatgagac catcaaagag agaaagagaa taaaaatatt tttgtaaaac tttttttatg 3000
agaccatcaa agagagaaag agaataaaaa tatttttgta aaactttttt tatgagacca 3060
tcaaagagag aaagagaata aaaatatttt tgtaaaactt tttttatgag accatcaaag 3120
agagaaagag aataaaaata tttttgtaaa acttttttta tgagaccatc aaagagagaa 3180
agagaataaa aatatttttg taaaactttt tttatgagac catcaaagag agaaagagaa 3240
taaaaatatt tttgtaaaac tttttttatg agaccatcaa agagagaaag agaataaaaa 3300
tatttttgta aaactttttt tatgagacca tcaaagagag aaagagaata aaaatatttt 3360
tgtaaaactt tttttatgag accatcagaa agaggtttaa tatttttgtg ataccctgaa 3420
aggaaatagg aataggaata ggaatagtgt cataatcgta tcacactatt gagacagaaa 3480
aagaagaagt cgcgagaggt aactttttgt gaatgtagtt aagaacattt ttgttttgca 3540
aaccggaata tagtgtccgg tacacttttt taattcgtgg tgtgcctgaa tcgttcgatt 3600
aaccctactc atccaatttc agatgaatag agttatcgat tcagacacac gctttgagtt 3660
ttgttgaatc gatgagtgaa gtatcatcgg ttgcaccttc agatgccgat ccgtcgacat 3720
acttaaatcc atccttgacc tcaagttcag atgattcctt gcacatgtct ccgatacgaa 3780
cgctaaactc tagattcttg acacattttg tatcgacgat cgttgaaccg atgatatctt 3840
cgtaactcac tttcttatga gagatgttag acccgagtac tggatgggtc ttgatgtcgc 3900
tgtctttctc ttcttcgcta catctgatgt cgatagacac ctcacagtct ttgatcatag 3960
ccagagcttc ttcatgagtg atcgcgggag agtccttacc ttgtcctggg gacacgctgg 4020
acaatctagc attcactgtg tttccatcag cggattctga gatggattta atctgaggac 4080
atttggtgaa tccaaagttc attctcagac ctccaccgat gatggagtaa taagtggtag 4140
gaggatctac atcctcgact gatgtggaat catcttctga ttccacctcg ggatctggat 4200
ctgactcgga ctctgtaatt tccgttacgg attggcaaat cttatcattg gtcggtgttt 4260
ggtcttgctt tgtgactttg ataataacat cgattcccat atgatgtttg ttttcttctt 4320
ccgtacacga ggaggaggat gaggatgatt gctgaagact ggcaggcaca tgcatgccag 4380
gacgatatat tgtttcatga ttgctattga ttgagtactg ttctttatga ttctacttcc 4440
ttaccgtgca ataaattaga atatattttc tacttttacg agaaattaat tattgtattt 4500
attatttatg ggtgaaaaac ttactataaa aagcgggtgg gtttggaatt agtgatcagt 4560
ttatgtatat cgcaactacc gggcatatgg ctatcgacat cgagaacatt acccacatga 4620
taagagattg tatcagtttc gtagtcttga gtattggtat tactatatag tatatagatg 4680
tcgacgctag atagacagtc tccgaatgcg gcatgatacc gtcatcattc tttgctttcg 4740
ttaactgttt ggaggaaaaa tttttgttat tgcatttaat ctcgaaattc agagtgcaca 4800
cctttctcct gtaaagaaac ctgaagttgc taccttatta aggacggaga agtattcctc 4860
acgaaatacg ggattacagt ctttatgatt catagtaata gttagttccg acgttgagat 4920
ggattcgctg agaccggtag tggtcgttaa ctggatacag attaatttcc acatcgatat 4980
agttaaaggt attactgggt acgggttcgc atttatctgc ggaagagacg gtgtgagaat 5040
atgttccgag accacacgga gaacagatga cgtctccgga tactccgtat cctattccac 5100
attttgtttg ggaaacacat gccttgcatc cggatgatcc tttgagaaga caataatatc 5160
cgggagagca ttcacagatt ctattgtgag tcgtgttaca cggtcgcgtc ttccgttaca 5220
acttagacaa gcgggtaaat gattattgcg agatgtgaag gtacccgaac cacacggcgt 5280
acattgtgtg ttagtcttgc tatcgcataa tctggaagcg tatgttcccg gacacaaatt 5340
atggcgtttg tattcgttgt ctttacactt tccatcggat ggtgcatgcg gtgctatatc 5400
tcttccgttt attattatac atgagagaaa caatatatac gagtataata cggacttcat 5460
gatttaataa tgtagtaatc gtcgtcttgt tcctgtttcc tacttctcca atcatataga 5520
tattttcttt ctatcatgga taatatttgt aatggttctt ttcgtacaac atactgttta 5580
gatgatattg cgcataattt ccggaggcaa atacgatagt ctagattgac cgatggtaga 5640
ctctaattta ttgagtgctt tgtcgacgag tttactttta cgctccatcg atagatggca 5700
ctgttctatg agatcgtcgt acatgggaaa tgaaatgtga ctgtctgaat gtatggcttt 5760
aagatagctg tgataccgta tacaggtcgg tgtcggagat tcgaatctct ttaaggcgac 5820
ttatgtcacg atgatggaat ctatcttatc gaatgatata tttttcataa atacactttt 5880
atagtcctcg tttaaacaga atttactatg tagttccgcg aatgactcgt cccttaatag 5940
gcagtaggct attatcttct ttacgtagta atcgtcgtag ggagagacat cttgtagaac 6000
aacgatttaa tcataggtag agatactttc agtctgtggt ggatgatgtc attcacaaca 6060
tccgccttgt atatgatgtt tctgttttca aacaccaagt cgaataccgt ctttagtcgg 6120
aaggttgatg tcgtatccga tgtatgaggc aacattgttg ttacaatttt gaaaggcggt 6180
attatagtat tcgtctttct gaatgtcgaa cctatctagt agataccgta gtatattgag 6240
agtgtatcct tgattatgtt ttatgaatag ataaagtaga tgttgtcctt cttccttttg 6300
ttcgtgccaa ttgagtaaca ttatgagaat atgacctgtt gcacaatcgt tccatgatgg 6360
gtgtacaatc aagattatta cgtatcctcg tatcggctcc tcgagataaa agagcataca 6420
ccacacgagg actatgtttg gtatactgtt gaaggtaagt gtgtaaccgc gttaatgttt 6480
gctccataat ctattatcgc gtagatgaat cgcttctcgg ctcgcatctt agtgtgactt 6540
aacttgtaat aattgctttt gtagaacgtg gatatgtgtt tacagtagta atgaagagaa 6600
gtgagttcat cctcgtcgga tcctttgtac agaacgtaat agtttaagct cccattgaat 6660
ttatatctaa gataacacag caatagatcg gatgatttac taaagtcatc aatggtgtcc 6720
gttagtatat caaagatctt gttatcgatt gatagtggtg tcctttttca tccttgctat 6780
caaagttacg catgccgtgg tgtaacaata tctttaatac agatggatta aatcgtgtat 6840
tcatcgtata gcaatgtaat ggagagttac ctcgtttatt cagatcgcag tgtttaataa 6900
ctagcttaaa cagatgagac gatgtatcca catcaaagaa cgtgaaatac atatgacaga 6960
cattgttgac agaaacgtga ccttcattct taccgtcgtc cataaatacg ttaggtatgt 7020
accacatact gtcgcgaacg atgcgtacaa tctcgtccat ctcataatga tttacttttt 7080
cataattaaa gatgtgaaag aaaaacagaa caatatattt ttttagtaat gtttatgcga 7140
gacatataaa ataaactccg tgtttatgat catttttaac agcaacacat tcaatattgt 7200
attgttattt ttatattatt tacacaatta acaatatatt attagtttat attactgaat 7260
taataatata aaattcccaa tcttgtcata aacacacact gagaaacagc ataaacacaa 7320
aatccatcaa aaatgtcgat gaaatatctg atgttgttgt tcgctgctat gataatcaga 7380
tcattcgccg atagtggtaa cgctatcgaa acgacatcgc cagaaattac aaacgctaca 7440
acagatattc cagctatcag attatgcggt ccagagggag atggatattg tttacacggt 7500
gactgtatcc acgctagaga tattgacggt atgtattgta gatgctctca tggttataca 7560
ggcattagat gtcagcatgt agtattagta gactatcaac gttcagaaaa cccaaacact 7620
acaacgtcat atatcccatc tcccggtatt atgcttgtat tagtaggcat tattattatt 7680
acgtgttgtc tattatctgt ttataggttc actcgacgaa ctaaactacc tatacaagat 7740
atggttgtgc cataattttt ataaattttt ttatgagtat ttttacaaaa aaaatgtata 7800
aagtgtatgt cttatgtata tttataaaaa tgctaagtat gcgatgtatc tatgttattt 7860
gtatttatct aaacaatacc tctacctcta gatattatac aaaaattttt tatttcggca 7920
tattaaagta aaatctagtt accttgaaaa tgaatacagt gggtggttcc gtatcaccag 7980
taagaacata atagtcgaat acagtatccg attgagattt tgcatacaat actagtctag 8040
aaagaaattt gtaatcatct tctgtgacgg gagtccatat atctgtatca tcgtctagtt 8100
tatcagtgtc ccatgctata ttcctgttat catcattagt taatgaaaat aactctcgtg 8160
cttcagaaaa gtcaaatatt gtatccatac atacatctcc aaaactatcg cttatacgtt 8220
tatctttaac gatacctata cctagatggt tatttactaa cagacatttt ccagatctat 8280
tgactataac tcctatagtt tccacatcaa ccaagtaatg atcatctatt gttatataac 8340
aataacataa ctcttttcca tttttatcag tatgtatatc tatatcaacg tcgtcgttgt 8400
agtgaatagt agtcattgat ctattatatg aaacggatat gtctagaacg gcaattgttt 8460
tacgtccagt taacactttc tttgatttaa agtctagagt ctttgcaaac ataatatcct 8520
tatccgactt tatatttcct gtagggtggt ataattttat tttgcctcca catatcggtg 8580
tttccaaata tattactaga caatattcca tatagttatt agttaagggt acccaattag 8640
aacacgtacg cttattatca tcatttggat cgtatttcat aaaagttatt gtactatcga 8700
tgtcaacaca ttctacattt tttaatcgtc tatatagtat ttttctgata ttttctataa 8760
tatcagaatt gtcttccatc ggaagttgta tactatcgga atcagttaca tgtttaaata 8820
attctctgat gtcattcctt atacaatcaa attcattatt aaacagttta atagtctgta 8880
gacctttatc gtcgtaaata tccattgtct tattagttac gcttattttt atgtgtttta 8940
cgttgcttta ttatatttta taagaatgat tgtttgacga atcacgagaa ctattaagac 9000
acattattag gtatatatta taaaaaagtt tttgattacg atgttataag aggaaagagg 9060
acacattaac atcatacatc aattaactac attcttataa catcgtaatc aaaagaattg 9120
caattttgat gtataacaac tgtcaatggg ttatggaatt gtatattaca tattatacgg 9180
tatgttggta acgacaaata ccgatcggta attgtctgcc ggtgtaatag aattatatat 9240
atctatctat tacaccggct gagtatgcat aataataagt tgtggtagta tgatctccat 9300
atttataatt taggactttg tattcagtat ttttggaatc ataaaaaata aaaaaaagtt 9360
ttactaattt aaaatttaaa aagtatttac atttttttca ctgtttagtc gcggatatgg 9420
aattcgatcc tgccaaaatc aatacatcat ctatagatca tgtaacaata ttacaataca 9480
tagatgaacc aaatgatata agactaacag tatgcattat ccgaaatatt aataacatta 9540
catattatat caatatcaca aaaataaata cacatttggc taatcaattt cgggcttgga 9600
aaaaacgtat cgccggaagg gactatatga ctaacttatc tagagataca ggaatacaac 9660
aatcaaaact tactgaaact atacgtaact gtcaaaaaaa tagaaacata tatggtctat 9720
atatacacta caatttagtt attaatgtgg ttattgattg gataaccgat gtgattgttc 9780
aatcaatatt aagagggttg gtaaattggt acatagctaa taatacctat acacccaata 9840
atacaacaac catttctgag ttggatatca tcaaaatact ggataaatac gaggacgtgt 9900
atagagtaag taaagaaaaa gaatgtggaa tttgctatga agttgtttac tcaaaacgat 9960
agatactttg gtttattgga ttcgtgtact catatatttt gcataacatg catcaatata 10020
tggcataaaa cacgaagaga aaccggtgcg tcggataatt gtcctatatg tcgtacccgt 10080
tttagaaaca taacaatgag caagttctat aagctagtta actaataaat aaaaagttta 10140
atttgttgac gacgtatgtc gttatttttc tcgtatgaaa gattaaattc aattcaattc 10200
gttgtttcta atataatctg ccgtattgga tggattctca agacaattgc atttagatta 10260
tattatcatg aataaaaata gtagcacgca ctacttcagc caaatattct tttttgaaac 10320
gccatctatc gtagtgagga cacaagtgaa cctataatta tcaaatttat tagtatcagt 10380
cacatgaagg actttctgta gagtgacgat tctaccatct atggtactaa cggtttcatc 10440
ctccttgata ccctcaccca aatgttctat aaatttagca tcctcgtccg atctcatatc 10500
ctttgccaac caatacatgt agctaaaatt aggcataaat ttcacacatc cagtgcaacg 10560
aaattctcca gaagatgtta cgatgtttag gttaggacat ttgatttcgt cggcattaac 10620
atatgggtga acacacccat acatgaaagc gatgagaaat aggattctca tcttgccaaa 10680
atatcactag aaaaaattta tttatcaatt ttaaaggtat aaaaaatact tattgttgct 10740
cgaatatttt gtatttgatg gtatacggaa gattagaaat gtaggtatta tcatcaactg 10800
attctatggt tttatgtatt ctatcatgtt tcactattgc gtcggaaata atatcatatg 10860
cttccacata tattttattt tgttttaact cataatactc acgtaattct ggattattgg 10920
catatctatg aataatttta gctccatgat cagtaaatat taatgagaac atagtattac 10980
cacctaccat tatttttttc atttcgttca attcttgatt gcaaagatct atataatcat 11040
tatagcgttg acttatggac tctggaatct tagacgatgt acagtcatct ataatcatgg 11100
catatttaat acattgtttt atagcatagt agttatctac gatgttagat atttctctca 11160
atgaatcaat cacacaatct aatgtaggtt tatgacataa tagcattttc agcagttcaa 11220
tgtttctaga ttcgttgatg gcaatggcta tacatgtata tccgttattt gatctaatgt 11280
tgacatctga accggattct agcagtaaag atactagaga ttgtttatta tatctaacag 11340
ccttgtgaag aagtgtttct cctcgtttgt caatcatgtt aatgtcttta agataaggta 11400
ggcaaatgtt tatagtacta agaattgggc aagcataaga catgtcacaa agaccctttt 11460
tgtatgtata agtgtaaaaa ttataacatt catagttgga tttacatagg tgtccaatcg 11520
ggatctctcc atcatcgaga taattgatgg catctccctt ccttttttag tagatatttc 11580
atcgtgtaag aatcaatatt aatatttcta aagtattcgt gtatagcctc tttatttacc 11640
acagttccat attccactag agggatatcg ccgaatgtca tatactcaat tagtatatgt 11700
tggaggacat ccgagttcat tgttttcaat atcaaaaaga tggtttcctt atcatttctc 11760
catagtggta caatactaca cattattccg tgcggctttc cattttccaa aaacaatttg 11820
accaaatcta aatctacatc tttattgtat ctataatcac tatttagata atcagccata 11880
attactcgag tgcaacatgt tagatcgtct atatatgaat aagcagtgtt atctattcct 11940
ttcattaaca atttaacgat gtctatatct atatgagatg acttaatata atattgaaga 12000
gctgtacaat agtttttatc tatagaagac ggcttgattc cgtgattaat tagacattta 12060
acaacttccg gacgcacata tgctctcgta tccgactttg aatacagatg agagatgata 12120
tacagatgca atacggtacc gcaatttcgt agttgataat catcatacgc gtatcagtac 12180
tcgtcctcat aaagaacact gcagccattt tctatgaaca aatcaataat tttaggaaca 12240
ggatcattgt cattacataa ttttctataa ctgaacgatg gttttcacat ttaacactca 12300
agtcaaatcc atgttctacc aacaccttta tcaagtcaac gtctacattt ttggatttca 12360
tatagctgaa tatattaaag tcatttatgt tgctaaatcc agtggcttct agtagagcca 12420
tcgctatatc ctttaacttt aacatgtcta ctatttgtgt attcttctaa tggggtagct 12480
gtctccaatt tttgcgtaat ggattagtgc cactgtctag tagtagtttg acgacctcga 12540
cattattaca atgctcatta aaaaggtatg cgtgtaaagc attattcttg aattggttcc 12600
tggtatcatt aggatctctg tctctcaaca tctgtttaag ttcatcgaga gccacctcct 12660
cattttccag atagtcaaac attttgactg aatgagctac tgtgaactct atacacccac 12720
acaactaatg tcattaaata ttattttttt gaatgtattt ataccatgtc aaaaacttgt 12780
acaattatta ataaaaataa tttagtgttt aaattttacc agttccagat tttacacctc 12840
cgttaacccc actttttaca ccactggacg atcctcctcc ccacattcca ccgccaccag 12900
atgtataagt tttagatcct ttattactac catcatgtcc atggataaag acactccaca 12960
tgccgccact actaccccct ttagaagaca tattaataag acttaaggac aagtttaaca 13020
ataaaattaa tcacgagtac cctactacca acctacacta ttatatgatt atagtttcta 13080
tttttacagt accttaacta aagtctctag tcacaagagc aatactacca acctacacta 13140
ttatatgatt atagtttcta tttttatagg aacgcgtacg agaaaatcaa atgtctaatt 13200
tctaacggta gtgttgataa acgattatcg tcaatggata cctcctctat catgtcgtct 13260
attttcttac tttgttctat taacttatta gcattatata ttatttgatt ataaaactta 13320
tattgcttat tagcccaatc tgtaaatatc ggattattaa catatcgttt ctttgtaggt 13380
ttatttaaca tgtacatcac tgtaagcatg tccgtaccat ttattttaat ttgacgcata 13440
tccgcaattt ctttttcgca gtcggttata aattctatat atgatggata catgctacat 13500
gtgtacttat aatcgactaa tatgaagtac ttgatacata ttttcagtaa cgatttatta 13560
ttaccaccta tgaataagta cctgtgatcg tctaggtaat caactgtttt cttaatacat 13620
tcgatggttg gtaatttact cagaataatt tccaatatct taatatataa ttctgctatt 13680
tctgggatat atttatctgc cagtataaca caaatagtaa tacatgtaaa cccatatttt 13740
gttattatat taatgtctgc gccattatct attaaccatt ctactaggct gacactatgc 13800
gacttaatac aatgataaag tatactacat ccatgtttat ctattttgtt tatatcatca 13860
atatacggct tacaaagttt tagtatcgat aacacatcca actcacgcat agagaaggta 13920
gggaataatg gcataatatt tattaggtta tcatcattgt cattatctac aactaagttt 13980
ccatttttta aaatatactc gacaacttta ggatctctat tgccaaattt ttgaaaatat 14040
ttatttatat gcttaaatct atataatgta gctccttcat caatcataca tttaataaca 14100
ttgatgtata ctgtatgata agatacatat tctaacaata gatcttgtat agaatctgta 14160
tatcttttaa gaattgtgga tattaggata ttattacgta aactattaca caattctaaa 14220
atataaaacg tatcacggtc gaataatagt tgatcaacta tataattatc gattttgtga 14280
tttttcttcc taaactgttt acgtaaatag ttagatagaa tattcattag ttcatgacca 14340
ctatagttac tatcgaataa cgcgtcaaat atttcccgtt taatatcgca tttgtcaaga 14400
taataataga gtgtggtatg ttcacgataa gtataataac gcatctcttt tttgtgtgaa 14460
attaaatagt ttatcacgtc caaagatgta gcataaccat cttgtgacct agtaataata 14520
taataataga gaactgtttt acccattcta tcatcataat cagtggtgta gtcgtaatcg 14580
taatcgtcta attcatcatc ccaattataa tattcaccag cacgtctaat ctgttctatt 14640
ttgatcttgt atccatactg tatgttgcta catgtaggta ttcctttatc caataatagt 14700
ttaaacacat ctacattggg atttgatgtt gtagcgtatt tctctacaat attaatacca 14760
tttttgatac tatttatttc tatacctttc gaaattagta atttcaataa gtctatatcg 14820
atgttatcag aacatagata ttcgaatata tcaaaatcat tgatattttt atagtcgact 14880
gacgacaata acaaaatcac aacatcgttt ttgatattat tatttttctt ggtaacgtat 14940
gcctttaatg gagtttcacc atcatactca tataatggat ttgcaccact ttctatcaat 15000
gattgtgcac tgctggcatc gatgttaaat gttttacaac tatcatagag tatcttatcg 15060
ttaaccatga ttggttgttg atgctatcgc attttttggt ttctttcatt tcagttatgt 15120
atggatttag cacgtttggg aagcatgagc tcatatgatt tcagtactgt agtgtcagta 15180
ctattagttt cgatcagatc aatgtctaga tctatagaat caaaacacga taggtcagaa 15240
gataatgaat atctgtacgc ttctttttgt actgtaactt ctggttttgt tagatggttg 15300
catcgtgctt taacatcaat ggtacaaatt ttatcctcgc tttgtgtatc atattcgtct 15360
ctagtataaa attctatatt cagattatca tgcgatgtgt atacgctaac ggtatcaata 15420
aacggagcac accatttagt cataacagta atccaaaatt ttttaaagta tatcttaacg 15480
aaagaagttg tgtcattgtc tacggtgtat ggtactagat cctcataagt gtatatatct 15540
agagtaatgt ttaatttatt aaatggttga taatatggat cctcatgaca atttccgaag 15600
atggaaatga gatatagaca tgcaataaat ctaatcgaag acatggttac tccttaaaaa 15660
aatacgaata atcaccttgg ctatttagta agtgtcattt aacactatac tcatattaat 15720
ccatggactc ataatctcta tacgggatta acggatgttc tatatacggg gatgagtagt 15780
tttcttcttt aactttatac tttttactaa tcatatttag actgatgtat gggtaatagt 15840
gtttaaagag ttcgttctca tcatcagaat aaatcaatat ctctgttttt ttgttataca 15900
gatgtattac agcctcatat attacgtaat agaacgtgtc atctacctta ttaactttca 15960
ccgcatagtt gtttgcaaat acggttaatc ctttgacctc gtcgatttcc gaccaatctg 16020
ggcgtataat gaatctaaac tttaatttct tgtaatcatt cgaaataatt tttagtttgc 16080
atccgtagtt atccccttta tgtaactgta aatttctcaa cgcgatatct ccattaataa 16140
tgatgtcgaa ttcgtgctgt atacccatac tgaatggatg aactaacgaa tatcaacggc 16200
gttaatagta atttactttt tcatctttac atattgggta ctagttttac tatcataagt 16260
ttataaattc cacaagctac tatggaataa gccaaccatc ttagtatacc acacatgtct 16320
taaagtttat taattaatta catgttgttt tatatatatc gctacgaatt taaagagaaa 16380
tcagtttagg aagaaaaaaa ttatctatct acatcatcac gtctctgtat tctacgatag 16440
agtgctactt taagatgaga catatccgtg tcatcaaaaa tatactccat taaaatgatt 16500
attccggcag cgaacttgat attggatata tcacaacctt tgttaatatc tacgacaata 16560
gacagcagtc ccatggttcc ataaacagtg agtttatctt tctttgaagc gatagtttgt 16620
agagatctta taaaaccgtc aaacgacatc gcatttatat ctttagctaa ttcatatatg 16680
ttaccatcgt aatatctaac cgcgtctatc ttaaacgttt ccatcgcttt aaagacgttt 16740
ccgatagatg gtctcatttc atcagtcata ctgagccaac aaatataatc gtgtataaca 16800
tctttgatag aatcagactc taaagaaaac gaatcggctt tattatacgc attcatgata 16860
aacttaatga aaaatgtttt tcgttgttta agttggatga atagtatgtc ttaataattg 16920
ttattatttc attaattaat atttagtaac gagtacactc tataaaaacg agaatgacat 16980
aactagttat caaagtgtct aggacgcgta attttcatat ggtatagatc ctgtaagcat 17040
tgtctgtatt ctggagctat tttctttatc gcattagtaa gttcagaata tgttataaat 17100
ttaaatcgaa taacgaacat gactttagta aagtcgtcta tattaactct tttattttct 17160
agccatcgta ataccatgtt taagatagta tattctctag ttactacgat ctcatcgttg 17220
tctagaatat cacatactga atctacatcc aattttagaa attggtctgt gttacatatc 17280
tcttctatat tattgttgat gtattgtcgt agaaaactat tacgtagacc attttcttta 17340
taaaacgaat atatagtact ccaattatct ttaccgatat atttgcacac ataatccatt 17400
ctctcaatca ctacatcttt aagattttcg ttgttaagat atttggctaa actatataat 17460
tctattagat catcaacaga atcagtatat atttttctag atccaaagac gaactctttg 17520
gcgtcctcta taatattccc agaaaagata ttttcgtgtt ttagtttatc gagatctgat 17580
ctgttcatat acgccatgat tgtacggtac gttatgataa ccgcataaaa taaaaatcca 17640
ttttcatttt taaccaatac tattcataat tgagattgat gtaatacttt gttactttga 17700
acgtaaagac agtacacgga tccgtatctc caacaagcac gtagtaatca aatttggtgt 17760
tgttaaactt cgcaatattc atcaatttag atagaaactt atactcatca tctgttttag 17820
gaatccatgt attattacca ctttccaact tatcattatc ccaggctatg tttcgtccat 17880
catcgttgcg cagagtgaat aattcttttg tattcggtag ttcaaatata tgatccatgc 17940
atagatcggc aaagctattg tagatgtgat ttttcctaaa tctaatataa aactcgttta 18000
ctagcaaaca ctttcctgat ttatcgacca agacacatat ggtttctaaa tctatcaagt 18060
ggtggggatc catagttatg acgcagtaac atagattatt acattcttga ctgtcgctaa 18120
tatctaaata tttattgtta tcgtattgga ttctgcatat agatggcttg tatgtcaaag 18180
atatagaaca cataaccaat ttatagtcgc gctttacatt ctcgaatcta aagttaagag 18240
atttagaaaa cattatatcc tcggatgatg ttatcactgt ttctggagta ggatatatta 18300
aagtctttac agatttcgtc cgattcaaat aaatcactaa ataatatccc acattatcat 18360
ctgttagagt agtatcatta aatctattat attttatgaa agatatatca ctgctcacct 18420
ctatatttcg tacattttta aactgtttgt ataatatctc tctgatacaa tcagatatat 18480
ctattgtgtc ggtagacgat accgttacat ttgaattaat ggtgttccat tttacaactt 18540
ttaacaagtt gaccaattca tttctaatag tatcaaactc tccatgatta aatattttaa 18600
tagtatccat tttatatcac tacggacaca aagtagctga cataaaccat tgtataattt 18660
ttatgtttta tgtttattag cgtacacatt ttggaagttc cggcttccat gtatttcctg 18720
gagagcaagt agatgatgag gaaccagata gtttatatcc gtacttgcac ttaaagtcta 18780
cattgtcgtt gtatgagtat gatcttttaa acccgctaga caagtatccg tttgatattg 18840
taggatgtgg acatttaaca atctgacacg tgggtggatc ggaccattct cctcctgaac 18900
acaggacacc agagttacca atcaacgaat atccactatt gcaactataa gttacaacgc 18960
tcccatcggt ataaaaatcc tcgtatccgt tatgtcttcc gttggatata gatggagggg 19020
attggcattt aacagattca caaataggtg cctcgggatt ccataccata gatccagtag 19080
atcctaattc acaatacgat ttagattcac cgatcaaatg atatccgcta ttacaagagt 19140
acgttatact agagccaaag tctactccac caatatcaag ttggccatta tcgatatctc 19200
gaggcgatgg gcatctccgt ttaatacatt gattaaagag tgtccatcca gtacctgtac 19260
atttagcata tataggtccc attttttgct ttctgtatcc aggtagacat agatattcta 19320
tagtgtctcc tatgttgtaa ttagcattag catcagtctc cacactattc ttaaatttca 19380
tattaatggg tcgtgacgga atagtacagc atgatagaac gcatcctatt cccaacaatg 19440
tcaggaacgt cacgctctcc accttcatat ttatttatcc gtaaaaatgt tatcctggac 19500
atcgtacaaa taataaaaag cccatatatg ttcgctattg tagaaattgt ttttcacagt 19560
tgctcaaaaa cgatggcagt gacttatgag ttacgttaca ctttggagtc tcatctttag 19620
taaacatatc ataatattcg atattacgag ttgacatatc gaacaaattc caagtatttg 19680
attttggata atattcgtat tttgcatctg ctataattaa gatataatca ccgcaagaac 19740
acacgaacat ctttcctaca tggttaaagt acatgtataa ttctatccat ttgtcttcct 19800
taactatata tttgtataga taattacgag tctcgtgagt aattccagta attacataga 19860
tgtcgccgtc gtactctaca gcataaacta tactatgatg tctaggcatg ggagactttt 19920
ttatccaacg atttttagtg aaacattcca catcgtttaa tactacatat ttttcatacg 19980
tggtataaac tccacccatt acatatatat catcgtttac gaataccgac gcgcctgaat 20040
atctaggagt aattaagttt ggaagtctta tccatttcga agtgccgtgt ttcaaatatt 20100
ctgccacacc cgttgaaata gaaaattcta atcctcctat tacatataac tttccatcgt 20160
taacacaagt actaacttct gattttaacg acgacatatt agtaaccgtt ttccattttt 20220
tcgtttcaag atctacccgc gatacggaat aaacatgtct attgttaatc atgccgccaa 20280
taatgtatag acaattatgt aaaacatttg cattatagaa ttgtctatct gtattaccga 20340
ctatcgtcca atattctgtt ctaggagagt aatgggttat tgtggatata taatcagagt 20400
ttttaatgac tactatatta tgttttatac catttcgtgt cactggcttt gtagatttgg 20460
atatagttaa tcccaacaat gatatagcat tgcgcatagt attagtcata aacttgggat 20520
gtaaaatgtt gatgatatct acatcgtttg gatttttatg tatccacttt aataatatca 20580
tagctgtaac atcctcatga tttacgttaa cgttttcgtg ggataagata gttgtcagtt 20640
catcctttga taattttcca aattctggat cggatgtcac cgcagtaata ttgttgatta 20700
tttctgacat cgacgcatta tatagttttt taattccata tcttttagaa aagttaaaca 20760
tccttataca atttgtggaa ttaatattat gaatcatagt ttttacacat agatctacta 20820
caggcggaac atcaattatt atggcagcaa ctagtatcat ttctacattg tttatggtga 20880
tgtttatctt cttccagcgt atatagtcta atagcgattc aaacgcgtga tagtttatac 20940
cattcaatat aatcgcttca tcctttagat ggtgatcctg aattcgttta aaaaaattat 21000
acggagatgc cgtaataatt tccttattca cttgtataat ttccccattg atagaaaata 21060
tcacgctttc cattcttgaa gtactataag taattatagt ataatgtaaa ggtttatata 21120
ttcaatattt tttataaaaa aatcattttg acattaattc ctttttaaat ttccgtctat 21180
catctataga aacgtattct atgaatttat aaaatgcttt tacgtgtcct atcgtaggcg 21240
atagaaccgc taaaaagcct atcgaatttc tacaaaagaa tctgttatat ggtataggga 21300
gagtataaaa cattaaatgt ccgtacttat taaagtattc agtagccaat cctaactctt 21360
tcgaatactt attaatggct cttgttctgt acgaatctat ttttttgaac aacggaccta 21420
gtggtatatc ttgttctatg tatctaaaat aatgtctgac tagatccgtt agtttaatat 21480
cctcagtcat cttgtctaga atggcaaatc taactgcggg tttaggcttt agtttagttt 21540
ttatatctac atctatgtct ttatctaaca ccaaaaatat aatagctaat attttattac 21600
aatcatccgg atattcttct acgatctcac taactaatgt ttctttggtt atactagtat 21660
agtcactatc ggacaaataa agaaaatcag atgatcgatg aataatacat ttaaattcat 21720
catctgtaag atttttgaga tgtctcatta aaatattatt agggtcagta ctcattatca 21780
ttcggcagct attacttatt ttatttttct gtattttatt atttttcacc atatagatca 21840
atcattagat catcaaaata tgtttcaatc atcctaaaga gtatggtgaa tgactcttcc 21900
catctaattt ctgaacgttc accaatgtct ctagccactt tggcactaat agcgatcatt 21960
cgcttagcgt cttctatatt attaactggt tgattcaatc tatctagcaa tggaccgtcg 22020
gacagcgtca ttctcatgtt cttaatcaat gtacatacat cgccgtcatc taccaattca 22080
tccaacaaca taagcttttt aaaatcatca ttataatagg tttgatcgtt gtcatttctc 22140
caaagaatat atctaataag tagagtcctc atgcttagta atttaactat tttagttaac 22200
aactattttt tatgttaaat caattagtac accgctatgt ttaatactta ttcatatttt 22260
agtttttagg attgagaatc aatacaaaaa attaatgcat cattaatttt agaaatactt 22320
agtttccacg tagttaatga aacatttgaa ctcatcgtac aggacgttct cgtacaggac 22380
gtaactataa accggtttat atttgttcaa gatagataca aatccgataa ctttttttac 22440
gaattctacg ggatccactt taaaagtgtc ataccgggtt ctttttattc ttttaaacag 22500
atcaatggtg tgatgttgat taggtctttt acgaatttga tatagaatag cgttcacata 22560
tcctccataa tggtcaatcg ccatttgttc gtatgtcata aattctttaa ttatatgaca 22620
ctgtgtatta tttagttcat ccttgttcat cattaggaat ctatccaaaa tggcaattat 22680
actagaacta taggtgcgtt gtatacacat attgatgtgt ctgtttatac aatccatgat 22740
atttggatcc atgctactac cttcgggtaa aattgtagca tcatatacca tttctagtac 22800
tttaggttca ttattatcca ttgcagagga cgtcatgatc gaatcctaaa aaaatatatt 22860
atttttatgt tattttgtta aaaataatca tcgaatactt cgtaagatac tccttcatga 22920
acataatcag ttacaaaacg tttatatgaa gtaaagtatc tacgattttt acaaaagtcc 22980
ggatgcataa gtacaaagta cgcgataaac ggaataataa tagatttatc tagtctatct 23040
ttttctatag ctttcatagt tagatacatg gtctcagaag taggattatg taacatcagc 23100
ttcgataaaa tgactgggtt atttagtctt acacattcgc tcatacatgt atgaccgtta 23160
actacaaagt ctacactaaa atgattgaac aatagatagt ctaccattgt ttcgtattca 23220
gatagtacag cgtagtacat agcatcttca caaattatat cattgtctaa tagatatttg 23280
acgcatctta tggatcccac ttcaacagcc atcttaaaat cggtagaatc atattgcttt 23340
cctttatcat taataatttc taaaacatca tctctatcat aaaagataca aatattaact 23400
gtttgatccg taataacatt gctagtcgat agcaatttgt taataagatg cgctgggctc 23460
aatgtcttaa taagaagtgt aagaggacta tctccgaatt tgttttgttt attaacatcc 23520
gttgatggaa gtaaaagatc tataatgtct acattcttga ctgttttaga gcatacaata 23580
tggagaggtg tatttccatc atgatctggt tttgagggac taattcctag tttcatcatc 23640
catgagattg tagaagcttt tggattgtct gacataagat gtctatgaat atgatttttg 23700
ccaaatttat ccactatcct ggcttcgaat ccgatggaca ttattttttt aaacactctt 23760
tctgaaggat ctgtacacgc caacaacgga ccacatcctt cttcatcaac cgagttgtta 23820
atcttggctc catactgtac caataaattt attctctcta tgacttcatc atctgttccc 23880
gagagataat atagaggtgt tttattatgt ttatcacacg cgtttggatc tgcgccgtgc 23940
gtcagcagca tcgcgactat tctattatta ttaattttag aagctatatg caatggataa 24000
tttccatcat catccgtctc atttggagag tatcctctat gaagaagttc ttcgacaaat 24060
cgttcatcta gtcctttaat tccacaatac gcatgtagaa tgtgataatt atttccagaa 24120
ggttcgatag cttgtagcat attcctaaat acatctaaat ttttactatt atatttggca 24180
taaagagata gataatactc ggccgacata atgttgtcca ttgtagtata aaaattaata 24240
tttctatttc tatttctgta tatttgcaac aatttactct ctataacaaa tatcataact 24300
tagttctttt atgtcaagaa ggcactggtt tagttcatct ataaatgtca cgccataact 24360
accacgcatg ctatactcag aattatgata aagatattta tccttggggt gtaggtaatg 24420
gggattaatc tttgttggat cagtctctaa gttaacacat gtcacacatg atccatttat 24480
agttatatca cacgatgatg atttatgaat tgattccgga agatcgctat cgtattttgt 24540
ggttccacaa ttcatttcca tacatgttat tgtcacacta atattatgat gaactttatc 24600
tagccgctga gtggtaaaca acagaacaga tagtttatta tctttaccaa caccctcagc 24660
cgctgccaca aatctctgat ccgtatccat gatggtcatg tttatttcta gtccgtatcc 24720
agtcaacact atgttagcat ttctgtcgat atagctttca ctcatatgac actcaccaat 24780
aatagtagaa ttaatgtcgt aatttacacc aatagtgagt tcggcggcaa agtaccaata 24840
ccggtaatct tgtcgaggag gacatatagt attcttgtat tctaccgaat acccgagaga 24900
tgcgatacaa aagagtaaga ctaatttgta aaccatctta ctcaaaatat gtaacaatag 24960
tacgatgcaa tgagtaagac aataggaaat ctatcttata tacacataat tattctatca 25020
attttaccaa ttagttagtg taatgttaac aaaaatgtgg gagaatctaa ttagtttttc 25080
tttacacaat tgacgtacat gagtctgagt tccttgtttt tgctaattat ttcatccaat 25140
ttattattct tgactatatc gagatctttt gtataggagt cagacttgta ttcaacatgc 25200
ttttctataa tcattttagc tatttcggca tcatccaata gtacattttc cagattagca 25260
gaatagatat taatgtcgta tttgaacaga gcctgtaaca tctcaatgtc tttattatct 25320
atagccaatt taatgtccgg aatgaagaga agggaattat tggtgtttgt cgacgtcata 25380
tagtcgagca agagaatcat catatccacg tgtccatttt ttatagtgat gtgaatacaa 25440
ctaaggagaa tagccagatc aaaagtagat ggtatctctg aaagaaagta ggaaacaata 25500
cttacatcat taagcatgac ggcatgataa aatgaagttt tccatccagt tttcccatag 25560
aacatcagtc tccaattttt cttaacaaac agttttaccg tttgcatgtt accactatca 25620
accgcataat acaatgcggt gtttcccttg tcatcaaatt gtgaatcatc cagtccactg 25680
aatagcaaaa tctttactat tttggtatct tccaatgtgg ctgcctgatg taatggaaat 25740
tcattctcta gaagattttt caatgctcca gcgttcaaca acgtacatac tagacgcacg 25800
ttattatcag ctattgcata atacaaggca ctatgtccat ggacatccgc cttaaatgca 25860
tctttgctag agagaaagct tttcagctgc ttagacttcc aagtattaat tcgtgacaga 25920
tccatgtctg aaacgagacg ctaattagtg tatatttttt cattttttat aattttgtca 25980
tattgcacca gaattaataa tatctctaat agatctgatt agtagataca tggctatcgc 26040
aaaacaacat atacacattt aataaaaata atatttatta agaaaattca gatttcacgt 26100
acccatcaat ataaataaaa taatgattcc ttacaccgta cccatattaa ggagattcca 26160
ccttacccat aaacaatata aatccagtaa tatcatgtct gatgatgaac acaaatggtg 26220
tattaaattc cagtttttca ggagatgatc tcgccgtagc taccataata gtagatgcct 26280
ctgctacagt tccttgttcg tcgacatcta tctttgcatt ctgaaacatt ttataaatat 26340
ataatgggtc cctagtcata tgtttaaacg acgcattatc tggattaaac atactaggag 26400
ccatcatttc ggctatcgac ttaatatccc tcttattttc gatagaaaat ttagggagtt 26460
taagattgta cactttattc cctaattgaa acgaccaata gtctaatttt gcagccgtaa 26520
tagaatctgt gaaatgggtc atattatcac ctattgccag gtacatacta atattagcat 26580
ccttatacgg aaggcgtacc atatcatatt cttcgtcatc gattgtgatt gtatttcctt 26640
gcaatttagt aactacgttc atcatgggaa ccgttttcgt accgtactta ttagtaaaac 26700
tagcattgcg tgttttagtg atatcaaacg gatattgcca tataccttta aaatatatag 26760
tattaatgat tgcccataga gtattattgt cgagcatatt agaatctact acattagaca 26820
taccggatct acgttctact atagaattaa ttttattaac cgcatctcgt ctaaagttta 26880
atctatatag gccgaatcta tgatattgtt gataatacga cggtttaatg cacacagtat 26940
tatctacgaa actttgataa gttagatcag tgtacgtata tttagatgtt ttcagcttag 27000
ctaatcctga tattaattct gtaaatgctg gacccagatc tctttttctc aaatccatag 27060
tcttcaataa ttctattcta gtattacctg atgcaggcaa tagcgacata aacatagaaa 27120
acgaataacc aaacggtgag aagacaatat tatcatcttg aatattttta tacgctacta 27180
taccggcatt ggtaaatcct tgcagacgat aggtagacac tgaacacgtt aacgatagta 27240
tcaataacgc aatcatgatt ttatggtatt aataattaac cttattttta tgttcggtat 27300
aaaaattatt gatgtctaca catccttttg taattgacat ctatatatcc ttttgtataa 27360
tcaactctaa tcactttaac ttttacagtt ttccctacca gtttatccct atattcaaca 27420
tatctatcca tatgcatctt aacactctct gccaagatag cttcaaagtg aggatagtca 27480
aaaagataaa tatatagagc ataatccttc tcgtatactc tgccctttat tacatcaccc 27540
gcattgggca acgaataaca aaatgcaagc atcttgttaa cgggctcgta aattgggata 27600
aaaattatgt ttttatatct attttattca agagaatatt caggaatttc tttttccggt 27660
tgtatctcat cgcagtatat atcatttgta cattgtttca tattttttaa tagtctacac 27720
cttttagtag gactagtatc gtacaattca tagctgtatt ttgaattcca atcacgcata 27780
aaaatatctt ccaattgttg acgaagacct aatccatcat ccggtgtaat attaatagat 27840
gctccacatg tatccgtaaa gtaatttcct gtccaatttg aggtacctat atacgccgtt 27900
ttatcggtta ccatatattt ggcatggttt accctagaat acggaatggg aggatcagca 27960
tctggtacaa taaatagctt tacttctata tttatgtttt tagattttag catagcgata 28020
gatcttaaaa agtttctcat gataaacgaa gatcgttgcc agcaactaat caatagctta 28080
actgacactt gtctgtctat agcggctctt cttaattcat cttctatata aggccaaaac 28140
aaaatattgc ctgccttcga ataaataata gggataaagt tcataacaga tacataaacg 28200
aatttactcg catttctgat acatgacaat aaagcggtta aatcattggt tctttccata 28260
gtacatagtt gttgcggtgc agaagcaata aatacagagt gtggaacgcc gcttacgtta 28320
atactaagag gatgatctgt attataatac gacggataaa agtttttcca attatatggt 28380
agattgttaa ctccaagata ccagtatacc tcaaaaattt gagtgagatc cgctgccaag 28440
ttcctattat tgaagatcgc aatacccaat tctttgacct gagttagtga tctccaatcc 28500
atgttagcgc ttcctaaata aatatgtgta ttatcagata tccaaaattt tgtatgaaga 28560
actcctccta ggatatttgt aatatctatg tatcgtactt caactccggc catttgtagt 28620
ctttcaacat cctttaatgg tttgttagat ttattgacgg ctactctaac tcgtactcct 28680
cttttgggta attgtacaat cttgtttaat attatcgtgc cgaaattcgt acccacttca 28740
tccgataaac tccaataaaa agatgatata tctagtgttt ttgtggtatt ggatagaatt 28800
tccctccaca tgttaaatgt agacaaatat actttatcaa attgcatacc tataggaata 28860
gtctctgtaa tcactgcgat tgtattatcc ggattcattt tatttgttaa aagaataatc 28920
ctatatcact tcactctatt aaaaatccaa gtttctattt ctttcatgac tgatttttta 28980
acttcatccg tttccttatg aagatgatgt ttggcacctt cataaatttt tatttctcta 29040
ttacaatttg catgttgcat gaaataatat gcacctaaaa catcgctaat cttattgttt 29100
gttccctgga gtatgagagt cggggggtgt taatcttgga aattattttt ctaaccttgt 29160
tggtagcctt caagacctga ctagcaaatc cagccttaat tttttcatga ttgattaatg 29220
ggtcgtattg gtatttataa actttatcca tatctctaga tactgattct ggacatagct 29280
ttccgactgg cgcatttagt gtgatggttc ccataagttt ggcagctagc agattcagtt 29340
ttgaaacagc atctgcatta actagaggag acattagaat cattgctgta aacaagtttg 29400
gattatcgta agaggctagc tcccatggaa tgacccaata agtagattta atagttacca 29460
cgtgctgtac caaagtcatc aatcatcatt ttttcaccat tacttcttcc atgtccaata 29520
tgatcatgtg agaatactaa aattcctaac gatgatatgt tttcagctag ttcgtcataa 29580
cgtccagaat gtttaccagc tccatgactt atgaatacta atgccttagg atatgtaata 29640
ggtttccaat atatgtaatc attgtccaga ttgaacatac agtttgcact catgattcac 29700
gttatataac tatcaatatt aacagttcgt ttgatgatca tattattttt atgttttatt 29760
gataattgta aaaacataca attaaatcaa tatagaggaa ggagacggct actgtctttt 29820
gtgagatagt catggcgact aaattagatt atgaggatgc tgttttttac tttgtggatg 29880
atgataaaat atgtagtcgc gactccatca tcgatctaat agatgaatat attacgtgga 29940
gaaatcatgt tatagtgttt aacaaagata ttaccagttg tggaagactg tacaaggaat 30000
tgatgaagtt cgatgatgtc gctatacggt actatggtat tgataaaatt aatgagattg 30060
tcgaagctat gagcgaagga gaccactaca tcaattttac aaaagtccat gatcaggaaa 30120
gtttattcgc taccatagga atatgtgcta aaatcactga acattgggga tacaaaaaga 30180
tttcagaatc tagattccaa tcattgggaa acattacaga tctgatgacc gacgataata 30240
taaacatctt gatacttttt ctagaaaaaa aattgaattg atgatatagg ggtcttcata 30300
acgcataatt attacgttag cattctatat ccgtgttaaa aaaaattatc ctatcatgta 30360
tttgagagtt ttatatgtag caaacatgat agctgtgatg ccaataagct ttagatattc 30420
acgcgtgcta gtgttaggga tggtattatc tggtggtgaa atgtccgtta tataatctac 30480
aaaataatca tcgcatatag tatgcgatag tagagtaaac atttttatcg tttctactgg 30540
gttcatacat cgtctaccca attcggttat aaatgaaatt gtcgccaatc ttacacccaa 30600
ccccttgtta tccattagta tagtattaac ttcgttattt atgtcataaa ctgtaaatga 30660
ttttgtagat gccatatcat acatgatatt catgtcccta ttataatcat tactaacttt 30720
atcacaatat atgttgataa tatctatata tgatctagtc tttgtgggca actgtctata 30780
caagtcgtct aaacgttgtt tactcatata gtatcgaaca gccatcatta catggtcccg 30840
ttccgttgat agataatcga gtatgttagt ggacttgtca aatctatata ccatattttc 30900
tggaagtgga tatacatagt cgtgatcaac attattgcta gcctcatctt ctatatcctg 30960
tactatacca ttatctatat catctacata atctacgata ttattacaca taaacatcga 31020
caacatacta ttgtttatta tctaagtcct gttgatccaa acccttgatc tcctctattt 31080
gtactatcta gagattgtac ttcttccagt tctggataat atatacgttg atagattagc 31140
tgagctattc tatctccagt atttacatta aacgtacatt ttccattatt aataagaatg 31200
actcctatgt ttcccctata atcttcgtct attacaccgc ctcctatatc aatgcctttt 31260
agggacagac cagacctagg agctattcta ccatagcaga acttaggcat ggacatacta 31320
atatctgtct taattaactg tcgttctcct ggagggatag tataatcgta agcgctatat 31380
aaatcatatc cggcggcgta aggtgattgc ctagtaggag atttagctct gttagtttcc 31440
ttaacaaatc taactggtga gttaatattc atgttgaaca taaaactaat attttatttc 31500
aaaattattt accatcccat atattccatg aataagtgtg atgattgtac acttctatag 31560
tatctatata cgattcacga taaaatcctc ctatcaatag cagtttatta tccactatga 31620
tcaattctgg attatccctc ggataaatag gatcatctat cagagtccat gtattgctgg 31680
attcacaata aaattccgca tttctaccaa ccaagaataa ccttctaccg aacactaacg 31740
cgcatgattt ataatgagga taataagtgg atggtccaaa ctgccactga tcatgattgg 31800
gtagcaaata ttctgtagtt gtatcagttt cagaatgtcc tcccattacg tatataacat 31860
tgtttatgga tgccactgct ggattacatc taggtttcag aagactcggc atattaaccc 31920
aagcagcatc cccgtggaac caacgctcaa cagatgtggg atttggtaga cctcctacta 31980
cgtataattt attgttagcg ggtatcccgc tagcatacag tctggggcta ttcatcggag 32040
gaattggaat ccaattgttt gatatataat ttaccgctat agcattgtta tgtatttcat 32100
tgttcatcca tccaccgatg agatatacta cttctccaac atgagtactt gtacacatat 32160
ggaatatatc tataatttga tccatgttca taggatactc tatgaatgga tacttgtatg 32220
atttgcgtgg ttgtttatca caatgaaata ttttggtaca gtctagtatc cattttacat 32280
tatttatacc tctgggagaa agataatttg acctgattac atttttgata aggagtagca 32340
gatttcctaa tttatttctt cgctttatat accacttaat gacaaaatca actacataat 32400
cctcatctgg aacatttagt tcatcgcttt ctagaataag tttcatagat agataatcaa 32460
aattgtctat gatgtcatct tccagttcca aaaagtgttt ggcaataaag tttttagtat 32520
gacataagag attggatagt ccgtattcta tacccatcat gtaacactcg acacaatatt 32580
cctttctaaa atctcgtaag ataaagttta tacaagtgta gatgataaat tctacagagg 32640
ttaatataga agcacgtaat aaattgacga cgttatgact atctatatat acctttccag 32700
tatacgagta aataactata gaagttaaac tgtgaatgtc aaggtctaga caaacccttg 32760
taactggatc tttatttttc gtgtattttt gacgtaaatg tgtgcgaaag taaggagata 32820
actttttcaa tatcgtagaa ttgactatta tattgccacc tatagcatca ataattgttt 32880
tgaatttctt agtcatagac aatgctaata tattcttaca gtacacagta ttaacaaata 32940
tcggcattta tgtttcttta aaagtcaaca tctaaagaaa aatgattatc ttcttgagac 33000
ataactccca ttttttggta ttcacccaca cgtttttcga aaaaattagt ttttccttcc 33060
aatgatatat tttccatgaa atcaaacgga ttggtaacat tataaatttt tttaaatccc 33120
aattcagaaa tcaatctatc cgcgacgaat tctatatatg ttttcatcat ttcacaattc 33180
attcctataa gtttaactgg aagagccgca gtaagaaatt cttgttcaat ggataccgca 33240
tctgttataa tagatctaac ggtttcttca ctcggtggat gcaataaatg tttaaacatc 33300
aaacatgcga aatcgcagtg cagaccctcg tctctactaa ttagttcgtt ggaaaacgtg 33360
agtccgggca ttaggccacg ctttttaagc caaaatatgg aagcgaatga tccagaaaag 33420
aagattcctt ctactgcagc aaaggcaata agtctctctc cataaccggc gctgtcatgt 33480
atccactttt gagcccaatc ggccttcttt tttacacaag gcatcgtttc tatggcatta 33540
aagagatagt ttttttcatt actatcttta acataagtat cgatcaaaag actatacatt 33600
tccgaatgaa tgttttcaat ggccatctga aatccgtaga aacatctagc ctcggtaatc 33660
tgtacttctg tacaaaatcg ttccgccaaa ttttcattca ctattccgtc actggctgca 33720
aaaaacgcca atacatgttt tataaaatat ttttcgtctg gtgttagttt attccaatca 33780
ttgatatctt tagatatatc tacttcttcc actgtccaaa atgatgcctc tgccttttta 33840
tacatgttcc agatgtcata atattggatt gggaaaataa caaatctatt tggatttggt 33900
gcaaggatgg gttccataac taaattaaca ataacaataa attttttttc agttatctat 33960
atgcctgtac ttggatcttt tgtacatcga tatcgccgca atcactacaa taattacaag 34020
tattattgat agcattgtta ttagtactat cataattaaa ttatcgacat tcatgggtgc 34080
tgaataatcg ttattatcat cattatcatt ttgtaattgt gacatcatac tagataaatc 34140
gtttgcgaga ttgttgtggg aagcgggcat ggaggatgaa ttatcgttat tattatttaa 34200
cgcctcccat tcggattcac aaatgttacg cacattcaac attttatgga aactataatt 34260
ttgtgaaaac agataacaag aaaactcgtc atcgttcaaa tttttaacga tagtaaaccg 34320
attaaacgtc gagctaattt ctaacgctag cgactctgtt ggatatgggt ttccagatat 34380
atatcttttc agttccccta cgtatctata atcatctgta ggaaatggaa gatatttcca 34440
tttatctact gttcctaata tcatatgtgg tggtgtagta gaaccattaa gcgcgaaaga 34500
tgttatttcg catcgtattt taacttcgca ataatttctg gttagataac gcactctacc 34560
agtcaagtca atgatattag cctttacaga tatattcata gtagttgtaa cgatgactcc 34620
atcttttaga tgcgatactc ctttgtatgt accagaatct tcgtaccgca aactcgatat 34680
atttaaacaa gttaatgaga tattaacgcg ttttatgaat gatgatatat aaccagaagt 34740
tttatcctcg gtggctagcg ctataacctt atcattataa taccaactag tgtgattaat 34800
atgtgacacg ttagtgtggg tacaaatatg tacattatcg tctacgtcgt attcgataca 34860
tccgcataca gccaacaaat ataaaatgac aaatactcta acgccgttcg tacccatctt 34920
gatgcggttt aataaatgtt ttgatttcaa tttattgtaa aaaaagattc ggttttatac 34980
tgttcgatat tctcattgct tatattttca tctatcatct ccacacagtc aaatccgtgg 35040
ttagcatgca cctcatcaac cggtaaaaga ctatcggact cttctatcat tataactcta 35100
gaatatttaa tttggtcatt attaatcaag tcaattatct tatttttaac aaacgtgagt 35160
attttactca ttttttataa aaacttttag aaatatacag actctatcgt gtgtctatat 35220
cttcttttta tatccaatgt atttatgtct gatttttctt catttatcat atataatggt 35280
ccaaattcta cacgtgcttc ggattcatcc agatcattaa ggttcttata attgtaacat 35340
ccttctcttc cctcttctac atcttccttc ttattcttat tcttagcgtc acagaatcta 35400
ccacagcagg atcccatgac gagcgtcata ttaaactaat ccattttcaa ttataatata 35460
cgattagtaa tgaccattaa aataaaaaat attcttcata accggcaaga aagtgaaaag 35520
ttcacattga aactatgtca gtagtataca tcatgaaatg atgatatata tatactctat 35580
tttggtggag gattatatga tataattcgt ggataatcat tcttaagaca catttcttca 35640
ttcgtaaatc ttttcacgtt aaatgagtgt ccatattttg caatttcttc atatgatggc 35700
ggtgtacgtg gacgaagctg ctcctgttct tgttgtagtc gccgactgtc gtgtttgcgt 35760
ttagatccct ccattatcgc gattgcgtag atggagtact attatatacc ttgtaattaa 35820
atttttttat taattaaacg tataaaaacg ttccgtatct gtatttaaga gccagatttc 35880
gtctaataga acaaatagct acagtaaaaa taactagaat aattgctaca cccactagaa 35940
accacggatc gtaatacggc aatcggtttt cgataatagg tggaacgtat attttattta 36000
aggacttaac aattgtctgt aaaccacaat ttgcttccgc ggatcctgta ttaactatct 36060
gtaaaagcat atgttgaccg ggcggagccg aacattctcc gatatctaat ttctgtatat 36120
ctataatatt attaacctcc gcatacgcat tacagttctt ttctagcttg gataccgcac 36180
taggtacatc gtctagatct attcctattt cttcagcgat agctcttcta tccttttccg 36240
gaagcaatga aatcacttca ataaatgatt caaccatgag tgtgaaacta agtcgagaat 36300
tactcatgca tttgttagtt attcggagcg cgcaattttt aaactgtcct ataacctctc 36360
ctatatgaat agcacaagtg acattagtag ggatagaatg ttgagctaat ttttgtaaat 36420
aactatctat aaaaagatta tacaaagttt taaactcttt agtttccgcc atttatccag 36480
tctgagaaaa tgtctctcat aataaatttt tccaagaaac taattgggtg aagaatggaa 36540
acctttaatc tatatttatc acagtctgtt ttggtacaca tgatgaattc ttctaatgct 36600
gtactaaatt cgatatcttt ttcgatttct ggatatgttt ttaataaagt atgaacaaag 36660
aaatggaaat cgtaatacca gttatgttca actttgaaat tgttttttat tttcttgtta 36720
atgattccag ccacttggga aaagtcaaag tcgtttaatg ccgatttaat acgttcatta 36780
aaaacaaact ttttatcctt tagatgaatt attattggtt cattggaatc aaaaagtaag 36840
atattatcgg gtttaagatc tgcgtgtaaa aagttgtcgc aacagggtag ttcgtagatt 36900
ttaatgtata acagagccat ctgtaaaaag ataaacttta tgtattgtac caaagattta 36960
aatcctaatt tgatagctaa ctcggtatct actttatctg ccgaatacag tgctagggga 37020
aaaattataa tatttcctct ttcgtattcg tagttagttc tcttttcatg ttcgaaaaag 37080
tgaaacatgc ggttaaaata gtttataaca ttaatattac tgttaataac tgccggataa 37140
aagtgggata gtaatttcac gaatttgata ctgtcctttc tctcgttaaa cgcctttaaa 37200
aaaactttag aagaatatct caatgagagt tcctgaccat ccatagtttg tatcaataat 37260
agcaacatat gaagaacccg tttatacaga gtatgtaaaa atgttaattt atagtttaat 37320
cccatggccc acgcacacac gattaatttt ttttcatctc cctttagatt gttgtataga 37380
aatttgggta ctgtgaactc cgccgtagtt tccatgggac tatataattt tgtggcctcg 37440
aatacaaatt ttactacata gttatctatc ttaaagacta taccatatcc tcctgtagat 37500
atgtgataaa aatcgtcgtt tataggataa aatcgtttat ccttttgttg gaaaaaggat 37560
gaattaatgt aatcattctc ttctatcttt agtagtgttt ccttattaaa attcttaaaa 37620
taatttaaca atctaactga cggagcccaa ttttggtgta aatctaattg ggacattatg 37680
ttgttaaaat acaaacagtc tcctaatata acagtatctg ataatctatg gggagacatc 37740
cattgatatt caggggatga atcattggca acacccattt attgtacaaa aagccccaat 37800
ttacaaacga aagtccaggt ttgatagaga caaacaatta actattttgt ctctgttttt 37860
aatttctttg gtaatgaaat tattcacaat atcagtatct tctttatcta ccagagattt 37920
tactaacttg ataaccttgg ctgtctcatt caatagggta gtaatatttg tatgtgtgat 37980
attgatatct ttttgaattg tttcttttag aagtgattct ttgatggtgc cagcatacga 38040
attacaataa tgcagaaact cagttaacat gcaggaatta tagtaagcca attccaattg 38100
ttgcctgtat tgtattagag tattaatatg cgcaatggtg tccttgcgtt tctctgatag 38160
aatgcgagca gcgattttgg cgttatcatt tgacgatatt tctggaatga cgaatcctgt 38220
ttctactaac tttttggtag gacaaagtga aacaatcaag aagatagctt ctcctcctat 38280
ttgtggaaga aattgaactc ctctagatga tctactgacg atagtatctc cttgacagat 38340
attggaccga attacagaag tacctggaat gtaaagccct gaaaccccct cattttttaa 38400
gcagattgtt gccgtaaatc ctgcactgtg accaagatag agagctcctt tggtgaatcc 38460
atctctatgt ttcagtttaa ccaagaaaca gtcagctggt ctaaaatttc catctctatc 38520
taatacagca tctaacttga tgtcaggaac tatgaccggt ttaatgttat atgtaacatt 38580
gagtaaatcc ttaagttcat aatcatcact gtcatcagtt atgtacgatc caaacaatgt 38640
ttctactggc atagtggata cgaagatgct atccatcaga atgtttccct gattagtatt 38700
ttctatatag ctattcttct ttaaacgatt ttccaaatca gtaactatgt tcattttttt 38760
aggagtagga cgcctagcca gtatggaaga ggattttcta gatcctctct tcaacatctt 38820
tgatctcgat ggaatgcaaa accccatagt gaaacaacca acgataaaaa taatattgtt 38880
tttcactttt tataatttta ccatctgact catggattca ttaatatctt tataagagct 38940
actaacgtat aattctttat aactgaactg agatatatac accggatcta tggtttccat 39000
aattgagtaa atgaatgctc ggcaataact aatggcaaat gtatagaaca acgaaattat 39060
actagagttg ttaaagttaa tattttctat gagctgttcc aataaattat ttgttgtaac 39120
tgcgttcaag tcataaatca tcttgatact atccagtaaa ccgtgtttaa gttctggaat 39180
attatcatcc cattgtaaag cccctaattc gactatcgaa tatcctgctc tgatagcagt 39240
ttcaatatcg acggacgtca atactgtaat aaaggtggta gtattgtcat catcgtgata 39300
aactacggga atatggtcgt tagtaggtac ggtgacttta cacaacgcga tatataactt 39360
tccttttgta ccatttttaa cgtagttggg acgtcctgca gggtattgtt ttgaagaaat 39420
gatatcgaga acagatttga tacgatattt gttggattcc tgattattca ctataatata 39480
atctagacag atagatgatt cgataaatag agaaggtata tcgttggtag gataatacat 39540
ccccattcca gtattctcgg atactctatt gatgacacta gttaagaaca tgtcttctat 39600
tctagaaaac gaaaacatcc tacatggact cattaaaact tctaacgctc ctgattgtgt 39660
ctcgaatgcc tcgtacaagg atttcaagga tgccatagat tctttgacca acgatttaga 39720
attgcgttta gcatctgatt tttttattaa atcgaatggt cggctctctg gtttgctacc 39780
ccaatgataa caatagtctt gtaaagataa accgcaagaa aatttatacg catccatcca 39840
aataacccta gcaccatcgg atgatattaa tgtattatta tagattttcc atccacaatt 39900
attgggccag tatactgtta gcaacggtat atcgaataga ttactcatgt aacctactag 39960
aatgatagtt cgtgtactag tcataatatc tttaatccaa tctaagaaat ttaaaattag 40020
attttttaca ctgttaaagt taacaaaggt attacccgga tacgtggata tcatatatgg 40080
cattggtcca ttatcagtaa tagctccata aactgatacg gcgatggttt ttatatgtgt 40140
ttgatctaac gaggaagaaa ttcgcgccca caattcatct ctagatatgt atttaatatc 40200
aaacggtaac acatcaattt cgggacgcgt atatgtttct aaatttttaa tccaaatata 40260
atgatgacct atatgcccta ttatcatact gtcaactata gtacacctag agaacttacg 40320
atacatctgt ttcctataat cgttaaattt tacaaatcta taacatgcta aaccttttga 40380
cgacagccat tcattaattt ctgatatgga atctgtattc tcgataccgt attgttctaa 40440
agccagtgct atatctccct gttcgtggga acgctttcgt ataatatcga tcaacggata 40500
atctgaagtt tttggagaat aatatgactc atgatctatt tcgtccataa acaatctaga 40560
cataggaatt ggaggcgatg atcttaattt tgtgcaatga gtcgtcaatc ctataacttc 40620
taatcttgta atattcatca tcgacataat actatctatg ttatcatcgt atattagtat 40680
accacggcct tcttcatttc gtgccaaaat aatatacagt cttaaataat tacgcaatat 40740
ctcaatagtt tcataattgt tagctgtttt catcaagatt tgtaccctgt ttaacatgat 40800
ggcgttctat acgtctctat tttctttttt ttaaattttt aacgatttac tgtggctaga 40860
tacccaatct ctctcaaata tttttttagc ctcgcttaca agctgtttat ctatactatt 40920
aaaactgacg aatccgtgat tttggtaatg ggttccgtcg aaatttgccg aagtgatatg 40980
aacatattcg tcgtcgacta tcaacaattt tgtattattc tgaatagtga aaaccttcac 41040
agatagatca ttttgaacac acaacgcgtc tagacttctg gcggttgcca tagaatatac 41100
gtcgttctta tcccaattac caactagaag tctgatctta actcctctat taatggctgc 41160
ttctataatg gagttgtaaa tgtcgggcca atagtagcta ttaccgtcga cacgtgtagt 41220
gggaactatg gccaaatgtt caatatctat actagtctta gccgacttga gtttatcaat 41280
aactacatcg gtatctagat ctctagaata tcccaatagg tgttccggag aatcagtaaa 41340
gaacactcca cctataggat tcttaatatg atacgcagtg ctaactggca aacaacaagc 41400
cgcagagcat aaattcaacc atgaattttt tgcgctatta aaggctttaa aagtatcaaa 41460
tcttctacga agatctgtgg ccagcggggg ataatcagaa tatacaccta acgttttaat 41520
cgtatgtata gatcctccag taaatgacgc gtttcctaca taacatcttt catcatctga 41580
cacccaaaaa caaccgagta gtagtcccac attatttttt ttatctatat taacggttat 41640
aaaatttata tccgggcagt gactttgtag ctctcccaga tttcttttcc ctcgttcatc 41700
tagcaaaact attattttaa tccctttttc agatgcctct tttagtttat caaaaataag 41760
cgctccccta gtcgtactca gaggattaca acaaaaagat gctatgtata tatatttctt 41820
agctagagtg ataatttcgt taaaacattc aaatgttgtt aaatgatcgg atctaaaatc 41880
catattttct ggtagtgttt ctaccagcct acattttgct cccgcaggta ccgatgcaaa 41940
tggccacatt tagttaacat aaaaacttat acatcctgtt ctatcaacga ttctagaata 42000
tcatcggcta tatcgctaaa attttcatca aagtcgacat cacaacctaa ctcagtcaat 42060
atattaagaa gttccatgat gtcatcttcg tctatttcta tatccgtatc cattgtagat 42120
tgttgaccga ttatcgagtt taaatcatta ctaatactca atccttcaga atacaatctg 42180
tgtttcattg taaatttata ggcggtgtat ttaagttggt agattttcaa ttatgtatca 42240
atatagcaac agtagttctt gctcctcctt gattctagca tcctcttcat tattttcttc 42300
tacgtacata agcatgtcca atacgttaga caacacaccg acgatggcgg ccgccacaga 42360
cacgaatatg actagaccga tgaccattta aaaacccctc tctagctttc acttaaactg 42420
tatcgattat tcttttagaa catgtataat ataaaaacat tattctattt cgaatttagg 42480
cttccaaaaa tttttcatcc gtaaaccgat aataatatat atagacttgt taatagtcgg 42540
aataaataga ttaatgctta aactatcatc atctccacga ttagagatac aatatttaca 42600
ttttttttgc tgtttcgaaa ctttatcaat acacgttaat acaaacccag gaaggagata 42660
ttgaaactga ggctgttgaa aatgaaacgg tgaatacaat aattcagata atgtaaaatc 42720
atgattccgt attctgatga tattagaact gctaatggat gtcgatggta tgtatctagg 42780
agtatctatt ttaacaaagc atcgatttgc taatatacaa ttatcctttt gattaattgt 42840
tattttattc atattcttaa aaggtttcat atttatcaat tcttctacat taaaaatttc 42900
catttttaat ttatgtagcc cccgcaatac tcctcattac gtttcatttt ttgtctataa 42960
tatccatttt gttcatctcg gtacatagat tatccaattg agaagcgcat ttagtagttt 43020
tgtacatttt aagtttattg acgaatcgtc gaaaactagt tatagttaac attttattat 43080
ttgataccct gatattaata cccctgccgt tactattatt tataactgat gtaatccacg 43140
taacattaga attaattatc gatagtaatg catcgacgct tccaaaattg tctattataa 43200
actcaccgat aattttttta ttgcatgttt tcatattcat taggattatc aaatctttaa 43260
tcttactacg attgtatgcg ttgatattgc aagacgtcat tctaaaagac ggaggatctc 43320
catcaaatgc cagacaatca cgtacaaagt acatggaaat aggttttgtt ctattgcgca 43380
tcatagattt atatagaaca cccgtagaaa tactaatttg ttttactcta taaaatacta 43440
atgcatctat ttcatcgttt tgtataacgt ctttccaagt gtcaaattcc aaattttttt 43500
cattgatagt accaaattct tctatctctt taactacttg catagatagg taattacagt 43560
gatgcctaca tgccgttttt tgaaactgaa tagatgcgtc tagaagcgat gctacgctag 43620
tcacaatcac cactttcata tttagaatat atgtatgtaa aaatatagta gaatttcatt 43680
ttgttttttt ctatgctata aatgaattct cattttgcat ctgctcatac tccgttttat 43740
atcaatacca aagaaggaag atatctggtt ctaaaagccg ttaaagtatg cgatgttaga 43800
actgtagaat gcgaaggaag taaagcttcc tgcgtactca aagtagataa accctcatcg 43860
cccgcgtgtg agagaagacc ttcgtccccg tccagatgcg agagaatgaa taaccctgga 43920
aaacaagttc cgtttatgag gacggacatg ctacaaaata tgttcgcggc taatcgcgac 43980
aacgtggcgt cgagactttt gaactaaaat acaattatat ccttttcgat attaataaat 44040
ccgtgtcgtc caggtttttt atctctttca gtatgtgaat agataggtat tttatctcta 44100
ttcatcatcg aatttaagag atccgataaa cattgtttgt attctccaga tgtcagcatc 44160
tgatacaaca atatatgtgc acataaacct ctggcactta tttcatgtac cttcccctta 44220
tcactaagga gaatagtatt tgagaaatat gtatacatga tattatcatg aattagatat 44280
acagaatttg taacactctc gaaatcacac gatgtgtcgg cgttaagatc taatatatca 44340
ctcgataaca cattttcatc tagatacact agacattttt taaagctaaa atagtcttta 44400
gtagtgacag taactatgcg attattttca tcgatgatac atttcatcgg catattatta 44460
cgcttaccat caaagactat accatgtgta tatctaacgt attctagcat ggttgccata 44520
cgcgcattaa acttttcagg atctttggat agatcttcca atctatctat ttgagaaaac 44580
atttttatca tgttcaatag ttgaaacgtc ggatccacta tatagatatt atctataaag 44640
attttaggaa ctacgttcat ggtatcctgg cgaatattaa aactatcaat gatatgatta 44700
tcgttttcat cttttatcac catatagttt ctaagatatg ggattttact taatataata 44760
ttatttcccg tgataaattt tattagaaag gccaaatcta taagaaaagt tctagaatta 44820
gtctgaagaa tatctatatc gccgtaccgt atatttggat taattagata tagagaatat 44880
gatccgtaac atatacaact tttattatgg cgtctaagat attcttccat caacttatta 44940
acatttttga ctagggaaga tacattatga cgtcccatta cttttgcctt gtctattact 45000
gcgacgttca tagaatttag catatctctt gccaattctt ccattgatgt tacattataa 45060
gaaattttag atgaaattac atttggagct ttaatagtaa gaactcctaa tatgtccgtg 45120
tatgtggtca ctaatacaga ttgtagttct ataatcgtaa ataatttacc tatattatat 45180
gtttgagtct gtttagaaaa gtagctaagt atacgatctt ttatttctga tgcagatgta 45240
ttaacatcgg aaaaaaatct ttttttattc ttttttacta aagatacaaa tatgtctttg 45300
ttaaaaacag ttattttttg aatatttcta gcttgtaatt ttaacatatg atattcgttc 45360
acactaggta ctctgcctaa ataggtttct ataatcttta atgtaatatt aggaagagta 45420
ttctgatcag gattcctatt cattttgagg atttaaaact ctgattattg tctaatatgg 45480
tctctacgca aactttttca cagagcgata gagtttttga taactcgttt ttcttaagaa 45540
atataaaact actgtctcca gagctcgctc tatcttttat tttatttaat tcgatacaaa 45600
ctcctgatac tggttcagaa agtaattcat taattttcag tcctttatag aagatattta 45660
atatagataa tacaaaattt tcagttcttg atatcgatct gattgatcct agaactagat 45720
atattaataa cgtgctcatt aggcagttta tggcagcttg ataattagat atagtatatt 45780
ccagttcata tttattagat accgcattgc ccagattttg atattctatg aattcctctg 45840
aaaataaatc caaaataact aaacattcta ttttttgtgg attagtgtac tctcttccct 45900
ctatcatgtt cactactggt gtccacgatg ataaatatct agagggaata taatatagtc 45960
cataggatgc caatctagca atgtcgaata actgtaattt gattcttcgt tcttcattat 46020
gaattgattc ttgaggtata aacctaacac aaattatatt attagacttt tcgtatgtaa 46080
tgtctttcat gttataagtt tttaatcctg gaatagaatc tattttaatg aggcttttaa 46140
acgcagagtt ctccaacgag tcaaagcata atactctgtt gtttttctta tatacgatgt 46200
tacgattttc ttctttgaat ggaataggtt tttgaattag tttataatta caacataata 46260
gataaggaag tgtgcaaata gtacgcggaa aaaacataat agctcccctg ttttcatcca 46320
tggttttaag taaatgatca ctggcttctt tagtcaatgg atattcgaac attaaccgtt 46380
tcatcatcat tggacagaat ccatatttct taatgtaaag agtgatcaaa tcattgtgtt 46440
tattgtacca tcttgttgta aatgtgtatt cggttatcgg atctgctcct ttttctatta 46500
aagtatcgat gtcgatctcg tctaagaatt caactatatc gacatatttc atttgtatac 46560
acataaccat tactaacgta gaatgtatag gaagagatgt aacgggaaca gggtttgttg 46620
attcgcaaac tattctaata cataattctt ctgttaatac gtcttgcacg taatctatta 46680
tagatgccaa gatatctata taattatttt gtaagatgat gttaactatg tgatctatat 46740
aagtagtgta ataattcatg tatttcgata tatgttccaa ctctgtcttt gtgatgtcta 46800
gtttcgtaat atctatagca tcctcaaaaa atatattcgc atatattccc aagtcttcag 46860
ttctatcttc taaaaaatct tcaacgtatg gaatataata atctatttta cctcttctga 46920
tatcattaat gatatagttt ttgacactat cttctgtcaa ttgattctta ttcactatat 46980
ctaagaaacg gatagcgtcc ctaggacgaa ctactgccat taatatctct attatagctt 47040
ctggacataa ttcatctatt ataccagaat taatgggaac tattccgtat ctatctaaca 47100
tagttttaag aaagtcagaa tctaagacct gatgttcata tattggttca tacatgaaat 47160
gatctctatt gatgatagtg actatttcat tctctgaaaa ttggtaactc attctatata 47220
tgctttcctt gttgatgaag gatagaatat actcaataga atttgtacca acaaactgtt 47280
ctcttatgaa tcgtatatca tcatctgaaa taatcatgta aggcatacat ttaacaatta 47340
gagacttgtc tcctgttatc aatatactat tcttgtgata atttatgtgt gaggcaaatt 47400
tgtccacgtt ctttaatttt gttatagtag atatcaaatc caatggagct acagttcttg 47460
gcttaaacag atatagtttt tctggaacga attctacaac attattataa aggactttgg 47520
gtagataagt gggatgaaat cctattttaa ttaatgcgat agccttgtcc tcgtgcagat 47580
atccaaacgc ttttgtgata gtatggcatt cattgtctag aaacgctcta cgaatatctg 47640
tgacagatat catctttaga gaatatacta gtcgcgttaa tagtactaca atttgtattt 47700
tttaatctat ctcaataaaa aaattaatat gtatgattca atgtataact aaactactaa 47760
ctgttattga taactagaat cagaatctaa tgatgacgta accaagaagt ttatctactg 47820
ccaatttagc tgcattattt ttagcatctc gtttagattt tccatctgcc ttatcgaata 47880
ctcttccgtc gatgtctaca caggcataaa atgtaggaga gttactaggc cccactgatt 47940
caatacgaaa agaccaatct ctcctagtaa tttggcagta ctcattaata acggtgacag 48000
ggttagcacc tttccaatca ataatttttt tagccggaat aacatcatca aaagacttat 48060
gatcctctct cattgatttt tcgcgggata catcatctat tatgacgtca gccatagcat 48120
cagcatccgg cttatccgcc tccgttgtca taaaccaacg aggaggaata tcgtcggagc 48180
tgtacaccat agcactacgt tgaagatcgt acagagcttt attaacttct cgcttctcca 48240
tattaagttg tctagttagt tgtgcagcag tagctccttc gattccaatg gttttaatag 48300
cctcacacac aatctctgcg ttagaacgct cgtcgatata gattttagac atttttagag 48360
agaactaacg caatcagtaa taaaactaat ttattttatc atttttttta ttcatcatcc 48420
tctggtggtt cgtcgtttct atcgaatgta gctctgatta acccgtcatc tataggtgat 48480
gctggttctg gagattctgg aggagatgga ttattatctg gaagaatctc tgttatttcc 48540
ttgttttcat gtatcgattg cgttgtaaca ttaagattgc gaaatgctct aaatttggga 48600
ggcttaaagt gttgtttgca atctctacac gcgtgtctaa ctagtggagg ttcgtcagcg 48660
gctctagttt gaatcatcat cggcgtagta ttcctacttt tacagttagg acacggtgta 48720
ttgtatttct cgtcgagaac gttaaaataa tcgttgtaac tcacatcctt tattttatct 48780
atattgtatt ctactccttt cttaatgcat tttataccga ataagagata gcgaaggaat 48840
tctttttcgg tgccgctagt acccttaatc atatcacata gtgttttata ttccaaattt 48900
gtggcaatag acggtttatt tctatacgat agtttgtttc tggaatcctt tgagtattct 48960
ataccaatat tattctttga ttcgaattta gtttcttcga tattagattt tgtattacct 49020
atattcttga tgtagtactt tgatgatttt tccatggccc attctattaa gtcttccaag 49080
ttggcatcat ccacatattg tgatagtaat tctcggatat cagtagcggt taccgccatt 49140
gatgtttgtt cattggatga gtaactacta atgtatacat tttccattta taacacttat 49200
gtattaactt tgttcattta tattttttca ttattatgtt gatattaaca aaagtgaata 49260
tatatatgtt aataattgta ttgtggttat acggctacaa ttttataatt agtgaaagtc 49320
agtgtccgat gatcaatgac gatagcttta ctctgaaaag aaagtatcaa atcgatagtg 49380
cggagtcaac aataaaaatg gataagaaga ggacaaagtt tcagaataga gccaaaatgg 49440
taaaagaaat aaatcagaca ataagagcag cacaaactca ttacgagaca ttgaaactag 49500
gatacataaa atttaagaga atgattagga ctactactct agaagatata gcaccatcta 49560
ttccaaataa tcagaaaact tataaactat tctcggacat ttcagccatc ggcaaagcat 49620
cacggaatcc aagtaagatg gtatatgctc tgctgcttta catgtttccc aatttgtttg 49680
gagatgatca tagattcatt cgttatagaa tgcatccaat gagtaaaatc aaacacaaga 49740
tcttctctcc tttcaaactt aatcttatta gaatattagt ggaagaaaga ttctataata 49800
atgaatgcag atctaataaa tggagaataa ttggaacaca agttgataaa atgttgatag 49860
ctgaatctga taaatataca atagatgcaa ggtataacct aaaacccatg tatagaatca 49920
agggaaaatc tgaagaagat accctcttta tcaaacagat ggtagaacaa tgtgtgacat 49980
cccaggaatt ggtggaaaaa gtgttgaaga tactgtttag agatttgttc aagagtggag 50040
aatacaaagc gtacagatac gatgatgatg tagaaaatgg atttattgga ttggatacac 50100
taaaattaaa cattgttcat gatatagttg aaccatgtat gcctgttcgt aggccagtgg 50160
ctaagatact gtgtaaagaa atggtaaata aatactttga gaatccgcta catattattg 50220
gtaaaaatct tcaagagtgc attgactttg ttagtgaata ggcatttcat ctttctccaa 50280
tactaattca aattgttaaa ttaataatgg atagtataaa tagttattag tgataaaata 50340
gtaaaaataa ttattagaat aagagtgtag tatcatagat aactctcttc tataaaaatg 50400
gattttattc gtagaaagta tcttatatac acagtagaaa ataatataga ttttttaaag 50460
gatgatacat taagtaaagt aaacaatttt accctcaatc atgtactagc tctcaagtat 50520
ctagttagca attttcctca acatgttatt actaaggatg tattagctaa taccaatttt 50580
tttgttttca tacatatggt acgatgttgt aaagtgtacg aagcggtttt acgacacgca 50640
tttgatgcac ccacgttgta cgttaaagca ttgactaaga attatttatc gtttagtaac 50700
acaatacaat cgtacaagga aaccgtgcat aaactaacac aagatgaaaa atttttagag 50760
gttgccaaat acatggacga attaggagaa cttataggcg taaattatga cttagttctt 50820
aatccattat ttcacggagg ggaacccatc aaagatatgg aaatcatttt tttaaaactg 50880
tttaagaaaa cagacttcaa agttgttaaa aaattaagtg ttataagatt acttatttgg 50940
gcttacctaa gcaagaaaga tacaggcata gagtttgcgg ataatgatag acaagatata 51000
tatactctat ttcaacaaac tggtagaatc gtccatagca atctaacaga aacgtttaga 51060
gattatatct ttcccggaga taagactagc tattgggtgt ggttaaacga aagtatagct 51120
aatgatgcgg atattgttct taatagacac gccattacca tgtatgataa aattcttagt 51180
tatatatact ctgagataaa acaaggacgc gttaataaaa acatgcttaa gttagtttat 51240
atctttgagc ctgaaaaaga tatcagagaa cttctgctag aaatcatata tgatattcct 51300
ggagatatcc tatctattat tgatgcaaaa aacgacgatt ggaaaaaata ttttattagt 51360
ttttataaag ctaattttat taacggtaat acatttatta gtgatagaac gtttaacgag 51420
gacttattca gagttgttgt tcaaatagat cccgaatatt tcgataatga acgaattatg 51480
tctttattct ctacgagtgc tgcggacatt aaacgatttg atgagttaga tattaataac 51540
agttatatat ctaatataat ttatgaggtg aacgatatca cattagatac aatggatgat 51600
atgaagaagt gtcaaatctt taacgaggat acgtcgtatt atgttaagga atacaataca 51660
tacctgtttt tgcacgagtc ggatcccatg gtcatagaga acggaatact aaagaaactg 51720
tcatctataa aatccaagag tagacggctg aacttgttta gcaaaaacat tttaaaatat 51780
tatttagacg gacaattggc tcgtctaggt cttgtgttag atgattataa aggagacttg 51840
ttagttaaaa tgataaacca tcttaagtct gtggaggatg tatccgcatt cgttcgattt 51900
tctacagata aaaaccctag tattcttcca tcgctaatca aaactatttt agctagttat 51960
aatatttcca tcatcgtctt atttcaaagg tttttaagag ataatctata tcatgtagaa 52020
gaattcttgg ataaaagcat ccatctaacc aagacggata agaaatatat acttcaattg 52080
ataagacacg gtagatcata gaacagacca aatatattat taataatttg tatatacata 52140
gatataatta tcacatatta aaaattcaca catttttgat aaatgggaac tgctgcaaca 52200
attcagactc ccaccaaatt aatgaataaa gaaaatgcag aaatgatttt ggaaaaaatt 52260
gttgatcata tagttatgta tattagtgac gaatcaagtg attcagaaaa taatcctgaa 52320
tatattgatt ttcgtaacag atacgaagac tatagatctc tcattataaa aagtgatcac 52380
gagtttgtaa agctatgtaa aaatcatgca gagaaaagtt ctccagaaac gcaacaaatg 52440
attatcaaac acatatacga acaatatctt attccagtat ctgaagtact attaaaacct 52500
ataatgtcca tgggtgacat aattacatat aacggatgta aagacaatga atggatgcta 52560
gaacaactct ctaccctaaa ctttaacaat ctccgcacat ggaactcatg tagcataggc 52620
aatgtaacgc gtctgtttta tacatttttt agttatctga tgaaagataa actaaatata 52680
taagtataat cccattctaa tactttaacc tgatgtatta gcatcttatt agaatattaa 52740
cctaactaaa agacataaca taaaaactca ttacatagtt gataaaaagc ggtaggatat 52800
aaatattatg gctgccaccg ttccgcgttt tgacgacgtg tacaaaaatg cacaaagaag 52860
aattctagat caagaaacat tttttagtag aggtctaagt agaccgttaa tgaaaaacac 52920
atatctattt gataattacg cgtatggatg gataccagaa actgcaattt ggagtagtag 52980
atacgcaaac ttagatgcaa gtgactatta tcccatttcg ttgggattac ttaaaaagtt 53040
cgagtttctc atgtctctat ataaaggtcc tattccagta tacgaagaaa aagtaaatac 53100
tgaattcatt gctaatggat cgttctctgg tagatacgta tcatatcttc gaaagttttc 53160
tgctcttcca acaaacgagt ttattagttt tttgttactg acttccattc caatctataa 53220
tatcttgttc tggtttaaaa atactcagtt tgatattact aaacacacat tattcagata 53280
cgtctataca gataatgcca aacacctggc gttggctagg tatatgcatc aaacaggaga 53340
ctataagcct ttgtttagtc gtctcaaaga gaattatata tttaccggtc ccgttccaat 53400
aggtatcaaa gatataaatc accctaatct tagtagagca agaagtccat ccgattatga 53460
gacattagct aatattagta ctatattgta ctttaccaag tatgatccgg tattaatgtt 53520
tttattgttt tacgtacctg ggtattcaat tactacaaaa attactccag ccgtagaata 53580
tctaatggat aaactgaatc taacaaagag cgacgtacaa ctgttgtaaa ttattttatg 53640
cttcgtaaaa tgtaggtttt gaaccaaaca ttctttcaaa gaatgagatg cataaaactt 53700
tattatccaa tagattgact atttcggacg tcaatcgttt aaagtaaact tcgtaaaata 53760
ttctttgatc actgccgagt ttaaaacttc tatcgataat tgtttcatat gttttaatat 53820
ttacaagttt tttggtccat ggtacattag ccggacaaat atatgcaaaa taatatcgtt 53880
ctccaagttc tatagtttct ggattatttt tattatattc agtaaccaaa tacatattag 53940
ggttatctgc ggatttataa tttgagtgat gcattcgact caacataaat aattctagag 54000
gagacgatct actatcaaat tcggatcgta aatctgtttc taaagaacgg agaatatcta 54060
tacatacctg attagaattc atccgtcctt cagacaacat ctcagacagt ctggtcttgt 54120
atgtcttaat catattctta tgaaacttgg aaacatctct tctagtttca ctagtacctt 54180
tattaattct ctcaggtaca gattttgaat tcgacgatgc cgagtatttc atcgttgtat 54240
atttcttctt cgattgcata atcagattct tatataccgc ctcaaactct attttaaaat 54300
tattaaacaa tactctatta ttaatcagtc gttctaactc ctttgctatt tctatggact 54360
tatctacatc ttgactgtct atctctgtaa acacggagtc ggtatctcca tacacgctac 54420
gaaaacgaaa tctgtaatct ataggcaacg atgttttcac aatcggatta atatctctat 54480
cgtccatata aaatggatta cttaatggat tggcaaaccg taacataccg ttagataact 54540
ctgctccatt tagtaccgat tctagataca agatcattct acgtcctatg gatgtgcaac 54600
tcttagccga agcgtatgag tatagagcac tatttctaaa tcccatcaga ccatatactg 54660
agttggctac tatcttgtac gtatattgca tggaatcata gatggccttt tcagttgaac 54720
tggtagcctg ttttaacatc tttttatatc tggctctctc tgccaaaaat gttcttaata 54780
gtctaggaat ggttccttct atcgatctat cgaaaattgc tatttcagag atgaggttcg 54840
gtagtctagg ttcacaatga accgtaatat atctaggagg tggatatttc tgaagcaaga 54900
gctgattatt tatttcttct tccaatctat tggtactaac aacgacaccg actaatgttt 54960
ccggagatag atttccaaag atacacacat taggatacag actgttataa tcaaagatta 55020
atacattatt actaaacatt ttttgttttg gagcaaatac cttaccgcct tcataaggaa 55080
acttttgttt tgtttctgat ctaactaaga tagttttagt ttccaacaat agctttaaca 55140
gtggaccctt gatgactgta ctcgctctat attcgaatac catggattga ggaagcacat 55200
atgttgacgc acccgcgtct gtttttgttt ctactccata atactcccac aaatactgac 55260
acaaacaagc atcatgaata cagtatctag ccatatctaa agctatgttt agattataat 55320
ccttatacat ctgagctaaa tcaacgtcat cctttccgaa agataattta tatgtatcat 55380
taggtaaagt aggacataat agtacgactt taaatccatt ttcccaaata tctttacgaa 55440
ttactttaca tataatatcc tcatcaacag tcacataatt acctgtggtt aaaacctttg 55500
caaatgcagc ggctttgcct ttcgcgtccg tagtatcgtc accgatgaac gtcatttctc 55560
taactcctct atttaatact ttacccatgc aactgaacgc gttcttggat atagaatcca 55620
atttgtacga atccaatttt tcagattttt gaatgaatga atatagatcg aaaaatatag 55680
ttccattatt gttattaacg tgaaacgtag tattggccat gccgcctact cccttatgac 55740
tagactgatt tctctcataa atacagagat gtacagcttc ctttttgtcc ggagatctaa 55800
agataatctt ctctcctgtt aataactcta gacgattagt aatatatctc agatcaaagt 55860
tatgtccgtt aaaggtaacg acatagtcga acgttagttc caacaattgt ttagctattc 55920
gtaacaaaac tatttcagaa cataaaacta gttctcgttc gtaatccatt tccattagtg 55980
actgtatcct caaacatcct ctatcgacgg cttcttgtat ttcctgttcc gttaacatct 56040
cttcattaat gagcgtaaac aataatcgtt taccacttaa atcgatataa cagtaacttg 56100
tatgcgagat tgggttaata aatacagaag gaaacttctt atcgaagtga cactctatat 56160
ctagaaataa gtacgatctt gggatatcga atctaggtat ttttttagcg aaacagttac 56220
gtggatcgtc acaatgataa catccattgt taatctttgt caaatattgc tcgtccaacg 56280
agtaacatcc gtctggagat atcccgttag aaatataaaa ccaactaata ttgagaaatt 56340
catccatggt ggcattttgt atgctgcgtt tctttggctc ttctatcaac cacatatctg 56400
cgacggagca ttttctatct ttaatatcta gattataact tattgtctcg tcaatgtcta 56460
tagttctcat ctttcccaac ggcctcgcat taaatggagg aggagacaat gactgatata 56520
tttcgtccgt cactacgtaa taaaagtaat gaggaaatcg tataaatacg gtctcaccat 56580
ttcgacatct ggatttcaga tataaaaatc tgttttcacc gtgactttca aaccaattaa 56640
tgcaccgaac atccatttat agaatttaga aatatatttt catttaaatg aatcccaaac 56700
attggggaag agccgtatgg accattattt ttatagtact ttcgcaagcg ggtttagacg 56760
gcaacataga agcgtgtaaa cgaaaactat atactatagt tagcactctt ccatgtcctg 56820
catgtagacg gcacgcgact atcgctatag aggacaataa tgtcatgtct agcgatgatc 56880
tgaattatat ttattatttt ttcatcagat tatttaacaa tttggcatct gatcccaaat 56940
acgcgatcga tgtgacaaag gttaaccctt tataaactta acccattata aaacttatga 57000
ttagtcacga ctgaaataac cgcgtgatta ttttttggta taattctaca cggcatggtt 57060
tctgtgacta tgaattcaac ccccgttaca ttagtgaaat ctttaacaaa cagcaagggt 57120
tcgtcaaaga cataaaactc attgtttaca atcgaaatag accccctatc acacttaaaa 57180
taaaaaatat ccttatcctt taccaccaaa taaaattctg attggtcaat gtgaatgtat 57240
tcacttaaca gttccacaaa tttatttatt aactccgagg cacatacatc gtcggtattt 57300
tttatggcaa actttactct tccagcatcc gtttctaaaa aaatattaac gagttccatt 57360
tatatcatcc aatattattg aaatgacgtt gatggacaaa tgatacaaat aagaaggtac 57420
ggtacctttg tccaccatct cctccaattc atgctctatt ttgtcattaa ctttaatgta 57480
tgaaaacagt acgccacatg cttccatgac agtgtgtaac actttggata caaaatgttt 57540
gacattagta taattgttca agactgtcaa tctataatag atagtagcta taatatattc 57600
tatgatggta ttgaagaaga tgacaacctt ggcatattga tcatttaaca cagacatggt 57660
atcaacagat agcttgaatg aaagagaatc agtaattgga ataagcgtct tctcgatgga 57720
gtgtccgtat accaacatgt ctgatatttt gatgtattcc attaaattat ttagtttttt 57780
ctttttattc tcgttaaaca gcatttctgt caacggaccc caacatcgtt gaccgattaa 57840
gttttgattg atttttccgt gtaaggcgta tctagtcaga tcgtatagcc tatccaataa 57900
tccatcgtct gtgtgtagat cacatcgtac actttttaat tctctataga agagcgacag 57960
acatctggag caattacaga cagcaatttc tttattctct acagatgtaa gatacttgaa 58020
gacattccta tgatgatgca gaattttgga taacacggta ttgatggtat ctgttaccat 58080
aattcctttg atggctgata gtgtcagagc acaagatttc caatctttga caatttttag 58140
caccattatc tttgttttga tatctatatc agacagcatg gtgcgtctga caacacaagg 58200
attaagacgg aaagatgaaa tgattctctc aacatcttca atggatacct tgctattttt 58260
tctggcatta tctatatgtg cgagaatatc ctctagagaa tcagtatcct ttttgatgat 58320
agtggatctc aatgacatgg gacgtctaaa ccttcttatt ctatcaccag attgcatggt 58380
gatttgtctt ctttctttta tcataatgta atctctaaat tcatcggcaa attgtctata 58440
tctaaaatca taatatgaga tgtttacctc tacaaatatc tgttcgtcca atgttagagt 58500
atttacatca gttttgtatt ccaaattaaa catggcaacg gatttaattt tatattcctc 58560
tattaagtcc tcgtcgataa taacagaatg tagataatca tttaatccat cgtacatggt 58620
tggaagatgc tcgttgacaa aatctttaat tgtcttgatg aaggtgggac tatatctaac 58680
atcttgatta ataaaattta taacattgtc cataggatac tttgtaacta gttttataca 58740
catctcttca tcggtaagtt tagacagaat atcgtgaaca ggtggtatat tatattcatc 58800
agatatacga agaacaatgt ccaaatctat attgtttaat atattatata gatgtagtgt 58860
agctcctaca ggaatatctt taactaagtc aatgatttca tcaaccgtta gatctatttt 58920
aaagttaatc atataggcat tgatttttaa aaggtatgta gccttgacta cattctcatt 58980
aattaaccat tccaagtcac tgtgtgtaag aagattatat tctatcataa gcttgactac 59040
atttggtccc gataccatta aagaattctt atgatataag gaaacagatt ttaggtactc 59100
atctactcta caagaatttt ggagagcctt aacgatatca gtgacgttta ttatttcagg 59160
aggaaaaaac ctaacattga gaatatcgga attaatagct tccagataca gtgattttgg 59220
caatagtccg tgtaatccat aatccagtaa cacgagctgg tgcttgctag acaccttttc 59280
aatgtttaat ttttttgaaa taagctttga taaagccttc ctcgcaaatt ccggatacat 59340
gaacatgtcg gcgacatgat taagtattgt tttttcatta tttttatatt ttctcaacaa 59400
gttctcaata ccccaataga tgatagaata tcacccaatg cgtccatgtt gtctatttcc 59460
aacaggtcgc tatatccacc aatagaagtt ttcccaaaaa agattctagg aacagttcta 59520
ccaccagtaa tttgttcaaa atagtcacgc aattcatttt cgggtttaaa ttctttaata 59580
tcgacaattt catacgctcc tcttttgaaa ctaaacttat ttagaatatc cagtgcattt 59640
ctacaaaaag gacatgtata cttgacaaaa attgtcactt tgttattggc caacctttgt 59700
tgtacaaatt cctcggccat tttaatattt aagtgatata aaactatctc gacttattta 59760
actctttagt cgagatatat ggacgcagat agctatatga tagccaacta cagaaggcaa 59820
acgctataaa aaacataatt acgacgagca tatttataaa tatttttatt cagcattact 59880
tgatatagta atattaggca cagtcaaaca ttcaaccact ctcgatacat taactctctc 59940
attttcttta acaaattctg caatatcttc gtaaaaagat tcttgaaact ttttagaata 60000
tctatcgact ctagatgaaa tagcgttcgt caacatacta tgttttgtat acataaaggc 60060
gcccatttta acagtttcta gtgacaaaat gctagcgatc ctaggatcct ttagaatcac 60120
atagattgac gattcgtctc tcttagtaac tctagtaaaa taatcataca atctagtacg 60180
cgaaataata ttatccttga cttgaggaga tctaaacaat ctagttttga gaacatcgat 60240
aagttcatcg ggaatgacat acatactatc tttaatagaa ctcttttcat ccagttgaat 60300
ggattcgtcc ttaaccaact gattaatgag atcttctatt ttatcatttt ccagatgata 60360
tgtatgtcca ttaaagttaa attgtgtagc gcttcttttt agtctagcag ccaatacttt 60420
aacatcacta atatcgatat acaaaggaga tgatttatct atggtattaa gaattcgttt 60480
ttcgacatct gtcaaaacca attccttttt gcctgtatca tccagttttc catcctttgt 60540
aaagaaatta ttttctacta gactattaat aagactgata aggattcctc cataattgca 60600
caatccaaac tttttcacaa aactagactt tacaagatct acaggaatgc gtacttcagg 60660
tttcttagct tgtgattttt tcttttgtgg acattttctt gtgaccaact catctaccat 60720
ttcattgatt ttagcagtga aataagcttt caatgcacgg gcactgatac tattgaaaac 60780
gagttgatct tcaaattccg ccatttaagt tcaccaaaca acttttaaat acaaatatat 60840
caatagtagt agaataagaa ctataaaaaa aataataatt aaccaatacc aaccccaaca 60900
accggtatta ttagttgatg tgactgtttt ctcatcactt agaacagatt taacaatttc 60960
tataaagtct gtcaaatcat cttccggaga ccccataaat acaccaaata tagcggcgta 61020
caacttatcc atttatacat tgaatattgg cttttcttta tcgctatctt catcatattc 61080
atcatcaata tcaacaagtc ccagattacg agccagatct tcttctacat tttcagtcat 61140
tgatacacgt tcactatctc cagagagtcc gataacgtta gccaccactt ctctatcaat 61200
gattagtttc ttgagtgcga atgtaatttt tgtttccgtt ccggatctat agaaaactac 61260
aggtgtgata attgccttgg ccaattgtct ttctctttta ctgagtgatt ctagttcacc 61320
ttctatagat ctgagaatgg atgattctcc agtcgaaaca tattctacca tggctccgtt 61380
taatttgttg atgaagatgg attcatcctt aaatgttttc tctgtaatag tttccaccga 61440
aagactatgc aaagaatttg gaatgcgttc cttgtgctta atgtttccat agacggcttc 61500
tagaagttga tacaacatag gactagccgc ggtaactttt atttttagaa agtatccatc 61560
gcttctatct tgtttagatt tatttttata aagtttagtc tctccttcca acataataaa 61620
agtggaagtc atttgactag ataaactatc agtaagtttt atagagatag acgaacaatt 61680
agcgtattga gaagcattta gtgtaacgta ttcgatacat tttgcattag atttactaat 61740
cgattttgca tactctataa cacccgcaca agtctgtaga gaatcgctag atgcagtagg 61800
tcttggtgaa gtttcaactc tcttcttgat taccttactc atgattaaac ctaaataatt 61860
gtactttgta atataatgat atatattttc actttatctc atttgagaat aaaaatgttt 61920
ttgtttaacc actgcatgat gtacagattt cggaatcaca aaccaccggt ggttttattt 61980
tatccttgtc caatgtgaat tgaatgggag cggatgcggg tttcgtacgt agatagtaca 62040
ttcccgtttt tagaccgaga ctccatccgt aaaaatgcat actcgttagt ttggaataac 62100
tcggatctgc tatatggata ttcatagatt gactttgatc gatgaaggct cccctgtctg 62160
cagccatttt tatgatcgtc ttttgtggaa tttcccaaat agttttataa actcgcttaa 62220
tatcttctgg aaggtttgta ttctgaatgg atccaccatc tgccataatc ctattcttga 62280
tctcatcatt ccataatttt ctctcggtta aaactctaag gagatgcgga ttaactactt 62340
gaaattctcc agacaatact ctccgagtgt aaatattact ggtatacggt tccaccgact 62400
cattatttcc caaaatttga gcagttgatg cagtcggcat aggtgccacc aataaactat 62460
ttctaagacc gtatgttctg attttatctt ttagaggttc ccaattccaa agatccgacg 62520
gtacaacatt ccaaagatca tattgtagaa taccgttact ggcgtacgat cctacatatg 62580
tatcgtatgg tccttccttc tcagctagtt cacaactcgc ctctaatgca ccgtaataaa 62640
tggtttcgaa gatcttctta tttagatctt gtgcttccag gctatcaaat ggataattta 62700
agagaataaa cgcgtccgct aatccttgaa caccaatacc gataggtcta tgtctcttat 62760
tagagatttc agcttctgga ataggataat aattaatatc tataatttta ttgagatttc 62820
tgacaattac tttgaccaca tccttcagtt tgagaaaatc aaatcgccca tctattacaa 62880
acatgttcaa ggcaacagat gccagattac aaacggctac ctcattagca tccgcatatt 62940
gtattatctc agtgcaaaga ttactacact tgatagttcc taaattttgt tgattactct 63000
ttttgttaca cgcatcctta taaagaatga atggagtacc agtttcaatc tgagattcta 63060
taatcgcttt ccagacgact cgagccttta ttatagattt gtatctcctt tctctttcgt 63120
atagtgtata caatcgttcg aactcgtctc cccaaacatt gtccaatcca ggacattcat 63180
ccggacacat caacgaccac tctccgtcat ccttcactcg tttcataaag agatcaggaa 63240
tccaaagagc tataaataga tctctggttc tatgttcctc gtttcctgta ttctttttaa 63300
gatcgaggaa cgccataata tcagaatgcc acggttccaa gtatatggcc ataactccag 63360
gccgtttgtt tcctccctga tctatgtatc tagcggtgtt attataaact ctcaacattg 63420
gaataatacc gtttgatata ccattggtac cggagatata gcttccactg gcacgaatat 63480
tactaattga tagacctatt ccccctgcca ttttagagat taatgcgcat cgttttaacg 63540
tgtcatagat accctctatg ctatcatcga tcatgttaag tagaaaacag ctagacattt 63600
ggtgacgact agttcccgca ttaaataagg taggagaagc gtgcgtaaac catttttcag 63660
aaagtagatt gtacgtctca atagctgagt ctatatccca ttgatgaatt cctactgcga 63720
cacgcattaa catgtgctga ggtctttcaa cgatcttgtt gtttattttc aacaagtagg 63780
atttttccaa agttttaaaa ccaaaatagt tgtatgaaaa gtctcgttcg taaataataa 63840
ccgagttgag tttatcctta tatttgttaa ctatatccat ggtgatactt gaaataatcg 63900
gagaatgttt cccattttta ggattaacat agttgaataa atcctccatc acttcactaa 63960
atagtttttt tgtttccttg tgtagatttg atacggctat tctggcggct agaatggcat 64020
aatccggatg ttgtgtagta caagtggctg ctatttcggc tgccagagtg tccaattcta 64080
ccgttgttac tccattatat attccttgaa taaccttcat agctatttta ataggatcta 64140
tatgatccgt gtttaagcca taacataatt ttctaatacg agacgtgatt ttatcaaaca 64200
tgacattttc cttgtatcca tttcgtttaa tgacaaacat ttttgttggt gtaataaaaa 64260
aattatttaa cttttcatta atagggattt gacgtacgta gcgtacaaaa tgattgttcc 64320
tggtatatag ataaagagtc ctatatattt gaaaatcgtt acggctcgat taaactttaa 64380
tgattgcata gtgaatatat cattaggatt taactccttg actatcaggg cggcaccaga 64440
aattaccatc aaaagcatta atacagttat gcctatcgca gttagaacgg ttatagcatc 64500
caccatttat atctaaaaat tagatcaaag aatatgtgac aaagtcctag ttgtatattg 64560
agaattgaca aaacaatgtt tcttacatat ttttttttta ttagtaaccg acttaatagt 64620
aggaactgga aaactagact tgattattct ataagtatag atacccttcc aaataatatt 64680
ctctttgata aaagttccag aaaatgtaga attttttaaa aagttatctt ttgctattac 64740
caagattgtg tttagacgct tattattaat atgagtgatg aaatccacac cgcctctaga 64800
tatcgccttt atttccacat tagatggtaa atccaatagt gaaactatct ttttaggaat 64860
gtatggactc gcgtttagag gagtgaacgt cttgggcgtc ggaaaggatg attcgtcaaa 64920
cgaataaaca atttcacaaa tggatgttaa tgtattagta ggaaattttt tgacgctagt 64980
ggaattgaaa attctaatgg atgatgttct acctatttca tccgataaca tgttaatttc 65040
cgacaccaac ggttttaata tttcgatgat atacggtagt ctctctttcg gacttatata 65100
gcttattcca caatacgagt cattatatac tccaaaaaac aaaataacta gtataaaatc 65160
tgtatcgaat gggaaaaacg aaattatcga cataggtata gaatccggaa cattgaacgt 65220
attaatactt aattcttttt ctgtggtaag taccgatagg ttattgacat tgtatggttt 65280
taaatattct ataacttgag acttgataga tattagtgat gaattgaaaa ttatttttat 65340
caccacgtgt gtttcaggat catcgtcgac gcccgtcaac caaccgaacg gagtaaaata 65400
aatatcatta atatatgctc tagatattag tatttttatc aatcctttga ttatcatctt 65460
ctcgtaggcg aatgattcca tgatcaagag tgatttaaga acatcctccg gagtattaat 65520
gggcttagta aacagtccat cgttgcaata ataaaagtta tccaagttaa aggatattat 65580
gcattcgttt aaagatatca cctcatctga cggagacaat tttttggtag gttttagaga 65640
ctttgaagct acttgtttaa caaagttatt catcgtcgtt tactattcta tttaattttg 65700
tagttaattt atcacatatc acattaattg actttttggt ccatttttcc atacgtttat 65760
attcttttaa tcctgcgtta tccgtttccg ttatatccag tgatagatcg tgcaggttaa 65820
atagaatgct cttaaataat gtcatttttt tatccgctaa aaatttaaag aatgtataaa 65880
cttttttcaa agatttaaaa cttttaggtg gtgtcctagt acacaatatc ataaacaaac 65940
taataaacat cccgcattca gattccaaca gctgattaac ttccacatta atacagccta 66000
ttttcgctcc aaatgtacat tcgaaaaatc tgaataaaac atcaatgtcg caatttgtat 66060
tatccaatac agaatgtttg tgattcgtgt taaaaccatc ggagaaggaa tagaaataaa 66120
aattattata gtggtggaat tcagttggaa tattgcctcc ggagtcataa aaggatacta 66180
aacattgttt tttatcataa attacacatt tccaatgaga caaataacaa aatccaaaca 66240
ttacaaatct agaggtagaa cttttaattt tgtctttaag tatatacgat aagatatgtt 66300
tattcataaa cgcgtcaaat ttttcatgaa tcgctaagga gtttaagaat ctcatgtcaa 66360
attgtcctat ataatccact tcggatccat aagcaaactg agagactaag ttcttaatac 66420
ttcgattgct catccaggct cctctctcag gctctatttt catcttgacg acctttggat 66480
tttcaccagt atgtattcct ttacgtgata aatcatcgat tttcaaatcc atttgtgaga 66540
agtctatcgc cttagatact ttttcccgta gtcgaggttt aaagaaatac gctaacggta 66600
tactagtagg taactcaaaa acatcatata tagaatggta acgcgtcttt aactcgtcgg 66660
ttaactcttt cttttgatcg agttcgtcgc tactattggg tctgctcagg tgccccgact 66720
ctactagttc caacatcata ccgataggaa tacaagacac tttgccggcg gttgtagatt 66780
tatcatattt ttccactaca tatccgttac aatttgttaa aaatttagat acatctatat 66840
tgctacataa tccagctagt gaatatatat gacataataa attggtaaat cctagttctg 66900
gtattttact aattactaaa tctgtatatc tttccattta tcatggaaaa gaatttacca 66960
gatatcttct tttttccaaa ctgcgttaat gtattctctt acaaatattc acaagatgaa 67020
ttcagtaata tgagtaaaac ggaacgtgat agtttctcat tggccgtgtt tccagttata 67080
aaacatagat ggcataacgc acacgttgta aaacataaag gaatatacaa agttagtaca 67140
gaagcacgtg gaaaaaaagt atctcctcca tcactaggaa aacccgcaca cataaaccta 67200
accgcgaagc aatatatata cagtgaacac acaataagct ttgaatgtta tagttttcta 67260
aaatgtataa caaatacaga aatcaattcg ttcgatgagt atatattaag aggactatta 67320
gaagctggta atagtttaca gatattttcc aattccgtag gtaaacgaac agatactata 67380
ggtgtactag ggaataagta tccatttagc aaaattccat tggcctcatt aactcctaaa 67440
gcacaacgag agatattttc agcgtggatt tctcatagac ctgtagtttt aactggagga 67500
actggagtgg gtaagacgtc acaggtaccc aagttattgc tttggtttaa ttatttattt 67560
ggtggattct ctactctaga taaaatcact aactttcacg aaagaccagt cattctatct 67620
cttcctagga tagctttagt tagattgcat agcaatacca ttttaaaatc attgggattt 67680
aaggtactag atggatctcc tatttcttta cggtacggat ctataccgga agaattaata 67740
aacaaacaac caaaaaaata tggaattgta ttttctaccc ataagttatc tctaacaaaa 67800
ctatttagtt atggcactct tattatagac gaagttcatg agcatgatca aataggagat 67860
attattatag cagtagcgag aaagcatcat acgaaaatag attctatgtt tttaatgact 67920
gccacgttag aggatgaccg agaacggcta aaagtatttt tacctaatcc cgcatttata 67980
catattcctg gagatacact gtttaaaatt agcgaggtat ttattcataa taagataaat 68040
ccatcttcca gaatggcata catagaagaa gaaaagagaa atttagttac tgctatacag 68100
atgtatactc ctcctgatgg atcatccggt atagtctttg tggcatccgt tgcacagtgt 68160
cacgaatata aatcatattt agaaaaaaga ttaccgtatg atatgtatat tattcatggt 68220
aaggtcttag atatagacga aatattagaa aaagtgtatt catcacctaa tgtatcgata 68280
attatttcta ctccttattt ggaatccagc gttactatac gcaatgttac acacatttat 68340
gatatgggta aagtttttgt ccccgctcct tttggaggat cgcaagaatt tatttctaaa 68400
tctatgagag atcaacgaaa aggaagagta ggaagagtta atcctggtac atacgtctat 68460
ttctatgatc tgtcttatat gaagtctata cagcgaatag attcagaatt tctacataat 68520
tatatattgt acgctaataa gtttaatcta acactccccg aagatttgtt tataatccct 68580
acaaatttgg atattctatg gcgtacaaag gaatatatag actcgttcga tattagtaca 68640
gaaacatgga ataaattatt atccaattat tatatgaaga tgatagagta tgctaaactt 68700
tatgtactaa gtcctattct cgctgaggag ttggataact ttgagaggac gggagaatta 68760
actagtattg tacgagaagc cattttatct ctaaatttac gaattaagat tttaaatttt 68820
aaacataaag atgatgatac gtatatacac ttttgtaaaa tattattcgg tgtctataac 68880
ggaacaaacg ctactatata ttatcataga cctctaacgg gatatatgaa tatgatttca 68940
gatactatat ttgttcctgt agataataac taaaaatcaa actctaatga ccacatcttt 69000
ttttagagat gaaaaatttt ctacatctcc ttttgtagac acgactaaac attttgcaaa 69060
aaaaagttta ttagtgttta gataatcgta tacttcatca gtgtagatag taaatgtgaa 69120
caaataaaag gtattcttac tcaatagatt ggtaaattcc atagaatata ttaatccttt 69180
cttcttgaga tcccacatca tttcaaccag agacgtttta tccaatgatt tacctcgtac 69240
tataccacat acaaaactag attttgcagt gacgtcgtac ctggtattcc taccaaacaa 69300
aattttactt ttagttcttt tagaaaattc taaggtagaa tctctatttg ccaatatgtc 69360
atctatggaa ttaccactag caaaaaatga tagaaatata tattgataca tcgcagctgg 69420
ttttgatcta ctatacttta aaaacgaatc agattccata attgcctgta tatcatcagc 69480
tgaaaaacta tgttttacac gtattccttc ggcatttctt tttaatgata tatcttgttt 69540
agacaatgat aaagttatca tgtccatgag agacgcgtct ccgtatcgta taaatatttc 69600
attagatgtt agacgcttca ttaggggtat acttctataa ggtttcttaa tcagtccatc 69660
attggttgcg tcaagaacta ctatcggatg ttgttgggta tctctagtgt tacacatggc 69720
cttactaaag tttgggtaaa taactatgat atctctatta attatagatg catatatttc 69780
attcgtcaag gatattagta tcgacttgct atcgtcatta atacgtgtaa tgtaatcata 69840
taaatcatgc gatagccaag gaaaattcaa atagatgttc atcatataat cgtcgctata 69900
attcatatta atacgttgac attgactaat ttgtaatata gcctcgccac gaagaaagct 69960
ctcgtattca gtttcatcga taaaggatac cgttaaatat aactggttgc cgatagtctc 70020
atagtctatt aagtggtaag tttcgtacaa atacagaatc cctaaaatat tatctaatgt 70080
tggattaatc tttaccataa ctgtataaaa tggagacgga gtcataacta ttttaccgtt 70140
tgtacttact ggaatagacg aaggaataat ctccggacat gctggtaaag acccaaatgt 70200
ctgtttgaag aaatccaatg ttccaggtcc taatctctta acaaaaatta cgatattcga 70260
tcccgatatc ctttgcattc tatttaccag catatcacga actatattaa gattatctat 70320
catgtctatt ctcccaccgt tatataaatc gcctccgcta agaaacgtta gtatatccat 70380
acaatggaat acttcatttc taaaatagta ttcgttttct aattctttaa tgtgaaatcg 70440
tatactagaa agggaaaaat tatctttgag ttttccgtta gaaaagaacc acgaaactaa 70500
tgttctgatt gcgtccgatt ccgttgctga attaatggat ttacaccaaa aactcatata 70560
acttctagat gtagaagcat tcgctaaaaa attagtagaa tcaaaggata taagtagatg 70620
ttccaacaag tgagcaattc ccaagatttc atctatatca ttctcgaatc cgaaattaga 70680
aattcccaag tagatatcct ttttcatccg atcgttgatg aaaatacgaa ctttattcgg 70740
taagacaatc atttactaag gagtaaaata ggaagtaatg ttcgtatgtc gttatcatcg 70800
tataaattaa aggtgtgttt tttaccatta agtgacatta taattttacc aatattggaa 70860
ttataatata ggtgtatttg cgcactcgcg acggttgatg catcggtaaa tatagctgta 70920
tctaatgttc tagtcggtat ttcatcattt cgctgtctaa taatagcgtt ttctctatct 70980
gtttccatta cagctgcctg aagtttattg gtcggataat atgtaaaata ataagaaata 71040
catacgaata acaaaaataa aataagatat aataaagatg ccatttagag atctaatttt 71100
gttcaacttg tccaaattcc tacttacaga agatgaggaa tcgttggaga tagtgtcttc 71160
cttatgtaga ggatttgaaa tatcttatga tgacttgata acttactttc cagataggaa 71220
ataccataaa tatatttcta aagtatttga acatgtagat ttatcggagg aattaagtat 71280
ggaattccat gatacaactt tgcgagattt agtctatctt agattgtaca agtattccaa 71340
gtgtatacgg ccgtgttata aattaggaga taatctaaaa ggcatagttg ttataaagga 71400
caggaatatt tatattaggg aagcaaatga tgacttgata gaatatctcc tcaaggaata 71460
cactcctcag atttatacat attctaatga gcgcgtcccc ataactggtt caaaattaat 71520
tctttgtgga ttttctcaag ttacatttat ggcgtataca acgtcgcata taacaacaaa 71580
taaaaaggta gatgttctcg tttccaaaaa atgtatagat gaactagtcg atccaataaa 71640
ttatcaaata cttcaaaatt tatttgataa aggaagcgga acaataaaca aaatactcag 71700
gaagatattt tattcggtaa caggtggcca aactccatag gtagcttttt ctatttcgga 71760
ttttagaatt tccaaattca ccagcgattt atctgttttg gtgaaatcca aggatttatt 71820
aatgtccaca aatgccattt gttttgtctg tggattgtat ttgaaaatgg aaacgatgta 71880
gttagataga tgcgctgcga agtttcctat tagggttccg cgcttcacgt cacccagcat 71940
acttgaatca ccatccttta aaaaaaatga taagatatca acatggagta tatcatactc 72000
ggattttaat tcttctactg catcactgac attttcacaa atactacaat acggtttacc 72060
gaaaataatc agtacgttct tcatttatgg gtatcaaaaa cttaaaatcg ttactgctgg 72120
aaaataaatc actgacgata ttagatgata atttatacaa agtatacaat ggaatatttg 72180
tggatacaat gagtatttat atagccgtcg ccaattgtgt cagaaactta gaagagttaa 72240
ctacggtatt cataaaatac gtaaacggat gggtaaaaaa gggagggcat gtaacccttt 72300
ttatcgatag aggaagtata aaaattaaac aagacgttag agacaagaga cgtaaatatt 72360
ctaaattaac caaggacaga aaaatgctag aattagaaaa gtgtacatcc gaaatacaaa 72420
atgttaccgg atttatggaa gaagaaataa aggcagaaat gcaattaaaa atcgataaac 72480
tcacatttca aatatattta tctgattctg ataacataaa aatatcattg aatgagatac 72540
taacacattt caacaataat gagaatgtta cattatttta ttgtgatgaa cgagacgcag 72600
aattcgttat gtgtctcgag gctaaaacac atttctctac cacaggagaa tggccgttga 72660
taataagtac cgatcaggat actatgctat ttgcatctgc tgataatcat cctaagatga 72720
taaaaaactt aactcaactg tttaaatatg ttccatctgc agaggataac tatttagcaa 72780
aattaacggc gttagtgaat ggatgtgatt tctttcctgg actctatggg gcatctataa 72840
cacccaacaa cttaaacaaa atacaattgt ttagtgattt tacaatcgat aatatagtca 72900
ctagtttggc aattaaaaat tattatagaa agactaactc taccgtagac gtgcgtaata 72960
ttgttacgtt tataaacgat tacgctaatt tagacgatgt ctactcgtat attcctcctt 73020
gtcaatgcac tgttcaagaa tttatatttt ccgcattaga tgaaaaatgg aatgaattta 73080
aatcatctta tttagaaagc gtgccgttac cctgccaatt aatgtatgcg ttagaaccac 73140
gcaaggagat tgatgtttca gaagttaaaa ctttatcatc ttatatagat ttcgaaaata 73200
ctaaatcaga tatcgatgtt ataaaatcta tatcctcgat cttcggatat tctaacgaaa 73260
actgtaacac gatagtattc ggcatctata aggataattt actactgagt ataaatagtt 73320
cattttactt taacgatagt ctgttaataa ccaatactaa aagtgataat ataataaata 73380
taggttacta gattaaaaat ggtgttccaa ctcgtgtgct ctacgtgcgg caaagatatt 73440
tctcacgaac gatataaatt gattatacga aaaaaatcat taaaggatgt actcgtcagt 73500
gtaaagaacg aatgttgtag gttaaaatta tctacacaaa tagaacctca acgtaactta 73560
acagtgcaac ctctattgga tataaactaa tatggatccg gttaatttta tcaagacata 73620
tgcgcctaga ggttctatta tttttattaa ttataccatg tcattaacaa gtcatttgaa 73680
tccatcgata gaaaaacatg tgggtattta ttatggtacg ttattatcgg aacacttggt 73740
agttgaatca acatatagaa aaggagttcg aatagtccca ttggatagtt tttttgaagg 73800
atatcttagt gcaaaagtat acatgttaga gaatattcaa gttatgaaaa tagcagctga 73860
tacgtcatta actttattgg gtattccgta tggatttggt catgatagaa tgtattgttt 73920
taaattggta gctgactgtt ataaaaatgc cggtattgat acatcgtcta aacgaatatt 73980
aggtaaagat atttttctga gccaaaactt cacagacgat aatagatgga taaagatata 74040
tgattctaat aatttaacat tttggcaaat tgattacctt aaagggtgag ttaatatgca 74100
taactactcc tccgttgttt tttccctcgt tctttttctt aacgttgttt gccatcactc 74160
tcataatgta aagatattct aaaatggtaa acttttgcat atcggacgca gaaattggta 74220
taaatgttgt aattgtatta tttcccgtca atggactagt cacagctcca tcagttttat 74280
atcctttaga gtatttctca ctcgtgtcta acattctaga gcattccatg atctgtttat 74340
cgttgatatt ggccggaaag atagattttt tattttttat tatattacta ttggcaattg 74400
tagatataac ttctggtaaa tatttttcta ccttttcaat ctcttctatt ttcaagccgg 74460
ctatatattc tgctatattg ttgctagtat caataccttt tctggctaag aagtcatatg 74520
tggtattcac tatatcagtt ttaactggta gttccattag cctttccact tctgcagaat 74580
aatcagaaat tggttcttta ccagaaaatc cagctactat aataggctca ccgatgatca 74640
ttggcaaaat cctatattgt accagattaa tgagagcata tttcatttcc aataattctg 74700
ctagttcttg agacattgat ttatttgatg aatctagttg gttctctaga tactctacca 74760
tttctgccgc atacaataac ttgttagata aaatcagggt tatcaaagtg tttagcgtgg 74820
ctagaatagt gggcttgcat gtattaaaga atgcggtagt atgagtaaac cgttttaacg 74880
aattatatag tctccagaaa tctgtggcgt tacatacatg agccgaatga catcgaagat 74940
tgtccaatat ttttaatagc tgctctttgt ccattatttc tatatttgac tcgcaacaat 75000
tgtagatacc attaatcacc gattcctttt tcgatgccgg acaatagcac aattgtttag 75060
ctttggactc tatgtattca gaattaatag atatatctct taatacagat tgcactatac 75120
attttgaaac tatgtcaaaa attgtagaac gacgctgttc tgcagccatt taactttaaa 75180
taatttacaa aaatttaaaa tgagcatccg tataaaaatc gataaactgc gccaaattgt 75240
ggcatatttt tcagagttca gtgaagaagt atctataaat gtagactcga cggatgagtt 75300
aatgtatatt tttgccgcct tgggcggatc tgtaaacatt tgggccatta tacctctcag 75360
tgcatcagtg ttctaccgcg gagccgaaaa tattgtgttt aatcttcctg tgtccaaggt 75420
aaaatcgtgt ttgtgtagtt ttcacaatga tgccatcata gatatagaac ctgatctgga 75480
aaataatcta gtaaaacttt ctagttatca tgtagtaagt gtcgattgta ataaggaact 75540
gatgcctatt aggacagata ctactatttg tctaagtata gatcaaaaga aatcttacgt 75600
gtttaatttt cacaagtatg aagaaaaatg ttgtggtaga accgtcattc atttagaatg 75660
gttgttgggc tttatcaagt gtattagtca gcatcagcat ttggctatta tgtttaaaga 75720
tgacaatatt attatgaaga ctcctggtaa tactgatgca ttttccaggg aatattctat 75780
gactgaatgt tctcaagaac tacaaaagtt ttctttcaaa atagctatct cgtctctcaa 75840
caaactacga ggattcaaaa agagagtcaa tgtttttgaa actagaatcg taatggataa 75900
tgacgataac attttaggaa tgttgttttc ggatagagtt caatccttta agatcaacat 75960
ctttatggcg tttttagatt aatactttca atgagataaa tatgggtggc ggagtaagtg 76020
ttgagctccc taaacgggat ccgcctccgg gagtacccac tgatgagatg ttattaaacg 76080
tggataaaat gcatgacgtg atagctcccg ctaagctttt agaatatgtg catataggac 76140
cactagcaaa agataaagag gataaagtaa agaaaagata tccagagttt agattagtca 76200
acacaggacc cggtggtctt tcggcattgt taagacaatc gtataatgga accgcaccca 76260
attgctgtcg cacttttaat cgtactcatt attggaagaa ggatggaaag atatcagata 76320
agtatgaaga gggtgcagta ttagaatcgt gttggccaga cgttcacgac accggaaaat 76380
gcgatgttga tttattcgac tggtgtcagg gggatacgtt cgatagaaac atatgccatc 76440
agtggatcgg ttcagccttt aataggagta atagaactgt agagggtcaa caatcgttaa 76500
taaatctgta taataagatg caaacattat gtagtaaaga tgctagtgta ccaatatgtg 76560
aatcattttt gcatcattta cgcgcacaca atacagaaga tagcaaagag atgatcgatt 76620
atattctaag acaacagtct gcggacttta aacagaaata tatgagatgt agttatccca 76680
ctagagataa gttagaagag tcattaaaat atgcggaacc tcgagaatgt tgggatccag 76740
agtgttcgaa tgccaatgtt aatttcttgc taacacgtaa ttataataat ttaggacttt 76800
gcaatattgt acgatgtaat actagcgtga acaacttaca gatggataaa acttcctcat 76860
taagattgtc atgtggatta agcaatagtg atagattttc tactgttccc gtcaatagag 76920
caaaagtagt tcaacataat attaaacact cgttcgacct aaaattgcat ttgatcagtt 76980
tattatctct cttggtaata tggatactaa ttgtagctat ttaaatgggt gccgcggcaa 77040
gcatacagac gacggtgaat acactcagcg aacgtatctc gtctaaatta gaacaagaag 77100
cgaatgctag tgctcaaaca aaatgtgata tagaaatcgg aaatttttat atccgacaaa 77160
accatggatg taacctcact gttaaaaata tgtgctctgc ggacgcggat gctcagttgg 77220
atgctgtgtt atcagccgct acagaaacat atagtggatt aacaccggaa caaaaagcat 77280
acgtgccagc tatgtttact gctgcgttaa acattcagac gagtgtaaac actgttgtta 77340
gagattttga aaattatgtg aaacagactt gtaattctag cgcggtcgtc gataacaaat 77400
taaagataca aaacgtaatc atagatgaat gttacggagc cccaggatct ccaacaaatt 77460
tggaatttat taatacagga tctagcaaag gaaattgtgc cattaaggcg ttgatgcaat 77520
tgacgactaa ggccactact caaatagcac ctaaacaagt tgctggtaca ggagttcagt 77580
tttatatgat tgttatcggt gttataatat tggcagcgtt gtttatgtac tatgccaagc 77640
gtatgttgtt cacatccacc aatgataaaa tcaaacttat tttagccaat aaggaaaacg 77700
tccattggac tacttacatg gacacattct ttagaacttc tccgatggtt attgctacca 77760
cggatatgca aaactgaaaa tatattgata atattttaat agattaacat ggaagttatc 77820
actgatcgtc tagacgatat agtgaaacaa aatatagcgg atgaaaaatt tgtagatttt 77880
gttatacacg gtctagagca tcaatgtcct gctatacttc gaccattaat taggttgttt 77940
attgatatac tattatttgt tatagtaatt tatattttta cggtacgtct agtaagtaga 78000
aattatcaaa tgttgttggc gttggtggcg ctagtcatca cattaactat tttttattac 78060
tttatactat aatagtacta gactgacttc taacaaacat ctcacctgcc ataaataaat 78120
gcttgatatt aaagtcttct atttctaaca ctattccatc tgtggaaaat aatactctga 78180
cattatcgct aattgacaca tcggtgagtg atatgcctat aaagtaataa tcttctttgg 78240
gcacatatac cagtgtacca ggttctaaca acctatttac tggtgctcct atagcatact 78300
ttttctttac cttgagaata tccatcgttt gcttggtcaa tagcgatatg tgatttttta 78360
tcaaccactc gaaaaagtaa ttggagtgtt catatcctct acgggctatt gtctcatggc 78420
cgtgtatgaa atttaagtaa cacgactgtg gtagatttgt tctatagagc cggttgccgc 78480
aaatagatag aactaccaat atgtctgtac aaatgttaaa cattaattga ttaacagaaa 78540
aaacaatgtt cgttctggga atagaaacca gatcaaaaca aaattcgtta gaatatatgc 78600
cacgtttata cattgaatat aaaataacta cagtttgaaa aataacagta tcatttaaac 78660
atttaacttg cggggttaat ctcacaactt tactgttttt gaactgttca aaatatagca 78720
tagatccgtg agaaatacgt ttagccgcct ttaatagagg aaatcccacc gcctttctgg 78780
atctcaccaa cgacgatagt tctgaccagc aactcatttc ttcatcatcc acctgtttta 78840
acatataata ggcaggagat agatatccgt cattgcaata ttccttctcg taggcacaca 78900
atctaatatt gataaaatct ccattctctt ctctgcattt attatcttgt ttcggtggct 78960
gattaggctg tagtcttggt ttaggctttg gtatatcgtt gttgaatcta ttttggtcat 79020
taaatctttc atttcttcct ggtatatttt tatcacctcg tttggttgga tttttgtcta 79080
tattatcgtt tgtaacatcg gtacgggtat tcatttatca caaaaaaaac ttctctaaat 79140
gagtctactg ctagaaaacc tcatcgaaga agataccata ttttttgcag gaagtatatc 79200
tgagtatgat gatttacaaa tggttattgc cggcgcaaaa tccaaatttc caagatctat 79260
gctttctatt tttaatatag tacctagaac gatgtcaaaa tatgagttgg agttgattca 79320
taacgaaaat atcacaggag caatgtttac cacaatgtat aatataagaa acaatttggg 79380
tctaggagat gataaactaa ctattgaagc cattgaaaac tatttcttgg atcctaacaa 79440
tgaagttatg cctcttatta ttaataatac ggatatgact gccgtcattc ctaaaaaaag 79500
tggtaggaga aagaataaga acatggttat cttccgtcaa ggatcatcac ctatcttgtg 79560
tattttcgaa actcgtaaaa agattaatat ttataaagaa aatatggaat ccgcgtcgac 79620
tgagtataca cctatcggag acaacaaggc tttgatatct aaatatgcgg gaattaatat 79680
cctaaatgtg tattctcctt ccacatccat aagattgaat gccatttacg gattcaccaa 79740
taaaaataaa ctagagaaac ttagtactaa taaggaacta gaatcgtata gttctagccc 79800
tcttcaagaa cccattaggt taaatgattt tctgggacta ttggaatgtg ttaaaaagaa 79860
tattcctcta acagatattc cgacaaagga ttgattacta taaatggaga atgttcctaa 79920
tgtatacttt aatcctgtgt ttatagagcc cacgtttaaa cattctttat taagtgttta 79980
taaacacaga ttaatagttt tatttgaagt attcgttgta ttcattctaa tatatgtatt 80040
ttttagatct gaattaaata tgttcttcat gcctaaacga aaaatacccg atcctattga 80100
tagattacga cgtgctaatc tagcgtgtga agacgataaa ttaatgatct atggattacc 80160
atggatgaca actcaaacat ctgcgttatc aataaatagt aaaccgatag tgtataaaga 80220
ttgtgcaaag cttttgcgat caataaatgg atcacaacca gtatctctta acgatgttct 80280
tcgcagatga tgattcattt tttaagtatt tggctagtca agatgatgaa tcttcattat 80340
ctgatatatt gcaaatcact caatatctag actttctgtt attattattg atccaatcaa 80400
aaaataaatt agaagccgtg ggtcattgtt atgaatctct ttcagaggaa tacagacaat 80460
tgacaaaatt cacagacttt caagatttta aaaaactgtt taacaaggtc cctattgtta 80520
cagatggaag ggtcaaactt aataaaggat atttgttcga ctttgtgatt agtttgatgc 80580
gattcaaaaa agaatcctct ctagctacca ccgcaataga tcctgttaga tacatagatc 80640
ctcgtcgcaa tatcgcattt tctaacgtga tggatatatt aaagtcgaat aaagtgaaca 80700
ataattaatt ctttattgtc atcatgaacg gcggacatat tcagttgata atcggcccca 80760
tgttttcagg taaaagtaca gaattaatta gacgagttag acgttatcaa atagctcaat 80820
ataaatgcgt gactataaaa tattctaacg ataatagata cggaacggga ctatggacgc 80880
atgataagaa taattttgaa gcattggaag caactaaact atgtgatgtc ttggaatcaa 80940
ttacagattt ctccgtgata ggtatcgatg aaggacagtt ctttccagac attgttgaat 81000
tctgtgagcg tatggcaaac gaaggaaaaa tagttatagt agccgcactc gatgggacat 81060
ttcaacgtaa accgtttaat aatattttga atcttattcc attatctgaa atggtggtaa 81120
aactaactgc tgtgtgtatg aaatgcttta aggaggcttc cttttctaaa cgattgggtg 81180
aggaaaccga gatagaaata ataggaggta atgatatgta tcaatcggtg tgtagaaagt 81240
gttacatcga ctcataatat tatatttttt atctaaaaaa ctaaaaataa acattgatta 81300
aattttaata taatacttaa aaatggatgt tgtgtcgtta gataaaccgt ttatgtattt 81360
tgaggaaatt gataatgagt tagattacga accagaaagt gcaaatgagg tcgcaaaaaa 81420
actgccgtat caaggacagt taaaactatt actaggagaa ttattttttc ttagtaagtt 81480
acagcgacac ggtatattag atggtgccac cgtagtgtat ataggatctg ctcccggtac 81540
acatatacgt tatttgagag atcatttcta taatttagga gtgatcatca aatggatgct 81600
aattgacggc cgccatcatg atcctatttt aaatggattg cgtgatgtga ctctagtgac 81660
tcggttcgtt gatgaggaat atctacgatc catcaaaaaa caactgcatc cttctaagat 81720
tattttaatt tctgatgtga gatccaaacg aggaggaaat gaacctagta cggcggattt 81780
actaagtaat tacgctctac aaaatgtcat gattagtatt ttaaaccccg tggcgtctag 81840
tcttaaatgg agatgcccgt ttccagatca atggatcaag gacttttata tcccacacgg 81900
taataaaatg ttacaacctt ttgctccttc atattcagct gaaatgagat tattaagtat 81960
ttataccggt gagaacatga gactgactcg agttaccaaa tcagacgctg taaattatga 82020
aaaaaagatg tactacctta ataagatcgt ccgtaacaaa gtagttgtta actttgatta 82080
tcctaatcag gaatatgact attttcacat gtactttatg ctgaggaccg tgtactgcaa 82140
taaaacattt cctactacta aagcaaaggt actatttcta caacaatcta tatttcgttt 82200
cttaaatatt ccaacaacat caactgaaaa agttagtcat gaaccaatac aacgtaaaat 82260
atctagcaaa aattctatgt ctaaaaacag aaatagcaag agatccgtac gcagtaataa 82320
atagaaacgt actactgaga tatactaccg atatagagta taatgattta gttactttaa 82380
taaccgttag acataaaatt gattctatga aaactgtgtt tcaggtattt aacgaatcat 82440
ccataaatta tactccggtt gatgatgatt atggagaacc aatcattata acatcgtatc 82500
ttcaaaaagg tcataacaag tttcctgtaa attttctata catagatgtg gtaatatctg 82560
acttatttcc tagctttgtt agactagata ctacagaaac taatatagtt aatagtgtac 82620
tacaaacagg cgatggtaaa aagactcttc gtcttcccaa aatgttagag acggaaatag 82680
ttgtcaagat tctctatcgc cctaatatac cattaaaaat tgttagattt ttccgcaata 82740
acatggtaac tggagtagag atagccgata gatctgttat ttcagtcgct gattaatcaa 82800
ttagtagaga tgagataaga acattataat aatcaataat atatcttata tctcgtttag 82860
aaaaatgcta atattaaaat agctaacgct agtaatccaa tcggaagcca tttgatatct 82920
ataatagggt atctaatttc ctgattcaga tagcggacag ctatattctc ggtagctact 82980
cgtttggaat cacaaacatt atttacatct aatttactat ctgtaatgga aacgtttccc 83040
aatgaaatgg tacaatccga tacattgcat tttgttatat ttttttttaa agaggctggt 83100
aacaacgcat cgcttcgttt acatggctcg taccaacaat aatagggtaa tcttgtatct 83160
attcctatcc gtactatgct tttatcagga taaatacatt tacatcgtat atcgtctttg 83220
ttagcatcac agaatgcata aatttgttcg tccgtcatga taaaaattta aagtgtaaat 83280
ataactatta tttttatagt tgtaataaaa agggaaattt gattgtatac cttcggttct 83340
ttaaaagaaa ctgacttgat aaaaatggct gtaatctcta aggttacgta tagtctatat 83400
gatcaaaaag agattaatgc tacagatatt atcattagtc atgttaaaaa tgacgacgat 83460
atcggtaccg ttaaagatgg tagactaggt gctatggatg gggcattatg taagacttgt 83520
gggaaaacgg aattggaatg tttcggtcac tggggtaaag taagtattta taaaactcat 83580
atagttaagc ctgaatttat ttcagaaatt attcgtttac tgaatcatat atgtattcac 83640
tgcggattat tgcgttcacg agaaccgtat tccgacgata ttaacctaaa agagttatcg 83700
ggacacgctc ttaggagatt aaaggataaa atattatcca agaaaaagtc atgttggaac 83760
agtgaatgta tgcaaccgta tcaaaaaatt actttttcaa agaaaaaggt ttgtttcgtc 83820
aacaagttgg atgatattaa cgttcctaat tctctcatct atcaaaagtt aatttctatt 83880
catgaaaagt tttggccatt attagaaatt catcaatatc cagctaactt attttataca 83940
gactactttc ccatccctcc gttgattatt agaccggcta ttagtttttg gatagatagt 84000
atacccaaag aaaccaatga attaacttac ttattaggta tgatcgttaa gaattgtaac 84060
ttgaatgctg atgaacaggt tatccagaag gcggtaatag aatacgatga tattaaaatt 84120
atttctaata acacttccag tatcaattta tcatatatta catccggcaa aaataatatg 84180
attagaagtt atatcgtcgc ccgacgaaaa gatcagacgg ctagatctgt aattggtccc 84240
agtacatcta tcaccgttaa tgaggtagga atgcccgcat atattagaaa tacacttaca 84300
gaaaagatat ttgttaatgc ctttacagtg gataaagtta aacaactatt agcatcaaac 84360
caagttaaat tttactttaa taaacgatta aaccaattaa caagaatacg ccaaggaaag 84420
tttatcaaaa ataaaataca tttattgcct ggtgattggg tagaagtagc tgttcaagaa 84480
tatacaagta ttatttttgg aagacagccg tctctacata gatacaacgt catcgcttca 84540
tctatcagag ctaccgaagg agatactatc aaaatatctc ccggaattgc caactctcaa 84600
aatgctgatt tcgacggaga tgaagaatgg atgatattag aacaaaatcc taaagctgta 84660
attgaacaaa gtattcttat gtatccgacg acgttactca aacacgatat tcatggagcc 84720
cccgtttatg gatctattca agatgaaatc gtagcagcgt attcattgtt taggatacaa 84780
gatctttgtt tagatgaagt attgaacatc ttggggaaat atggaagaga gttcgatcct 84840
aaaggtaaat gtaaattcag cggtaaagat atctatactt acttgatagg tgaaaagatt 84900
aattatccgg gtctcttaaa ggatggtgaa attattgcaa acgacgtaga tagtaatttt 84960
gttgtggcta tgaggcatct gtcattggct ggactcttat ccgatcataa gtcgaacgtg 85020
gaaggtatca actttattat caagtcatct tatgttttta agagatatct atctatttac 85080
ggttttgggg tgacattcaa agatctgaga ccaaattcga cgttcactaa taaattggag 85140
gccatcaacg tagaaaaaat agaacttatc aaagaagcat acgccaaata tctcaacgat 85200
gtaagagacg ggaaaatagt tccattatct aaagctttag aggcggacta tgtggaatcc 85260
atgttatcca acttgacaaa tcttaatatc cgagagatag aagaacatat gagacaaacg 85320
ctgatagatg atccagataa taacctcctg aaaatggcca aagcgggtta taaagtaaat 85380
cctacagaac taatgtatat tctaggtacg tatggacaac aaaggattga tggtgaacca 85440
gcagagactc gagtattggg tagagtctta ccttactatc ttccagactc taaggatcca 85500
gaaggaagag gttacattct taattcttta acaaaaggat taacaggttc tcaatattac 85560
ttttcgatgc tggttgcaag atctcaatct actgatatcg tctgtgaaac atcacgtacc 85620
ggaacactgg ctagaaaaat cattaaaaag atggaggata tggtggtcga cggatacgga 85680
caagtagtta taggtaatac gctcatcaag tacgccgcca attataccaa aattctaggc 85740
tcagtatgta aacctgtaga tcttatctat ccagatgagt ccatgacttg gtatttggaa 85800
attagtgctc tgtggaataa aataaaacag ggattcgttt actctcagaa acagaaactt 85860
gcaaagaaga cattggcgcc gtttaatttc ctagtattcg tcaaacccac cactgaggat 85920
aatgctatta aggttaagga tctgtacgat atgattcata acgtcattga tgatgtgaga 85980
gagaaatact tctttacggt atctaatata gattttatgg agtatatatt cttgacgcat 86040
cttaatcctt ctagaattag aattacaaaa gaaacggcta tcactatctt tgaaaagttc 86100
tatgaaaaac tcaattatac tctaggtggt ggaactccta ttggaattat ttctgcacag 86160
gtattgtctg agaagtttac acaacaagcc ctgtccagtt ttcacactac tgaaaaaagt 86220
ggtgccgtca aacaaaaact tggtttcaac gagtttaata acttgactaa tttgagtaag 86280
aataagaccg aaattatcac tctggtatcc gatgatatct ctaaacttca atctgttaag 86340
attaatttcg aatttgtatg tttgggagaa ttaaatccag acatcactct tcgaaaagaa 86400
acagataggt atgtagtaga tataatagtc aatagattat acatcaagag agcagaaatt 86460
accgaattag tcgtcgaata tatgattgaa cgattcatct cctttagcgt cattgtaaag 86520
gaatggggta tggaaacatt cattgaggac gaggataata ttagatttac tgtctatcta 86580
aatttcgttg aaccagagga attgaatctt agtaagttta tgatggttct tccgggggca 86640
gccaacaagg gaaagattag taaattcaag attcctatct ctgattatac gggttatgac 86700
gacttcaatc aaacaaaaaa gctcaataag atgactgtag aactcatgaa tctaaaagaa 86760
ttaggttctt tcgatttgga aaacgtcaac gtgtatcctg gagtatggaa tacatacgat 86820
atcttcggta tcgaggccgc tcgtgaatac ttgtgcgaag ccatgttaaa cacctatgga 86880
gaagggttcg attatctgta tcagccttgt gatcttctcg ctagtttact atgtgctagt 86940
tacgaaccag aatcagtgaa taaattcaag ttcggcgcag ctagtactct taagagagct 87000
acgttcggag acaataaagc attgttaaac gcggctcttc ataaaaagtc agaacctatt 87060
aacgataata gtagctgcca cttttttagc aaggtcccta atataggaac tggatattac 87120
aaatacttta tcgacttggg tcttctcatg agaatggaaa ggaaactatc tgataagata 87180
tcttctcaaa agatcaagga aatggaagaa acagaagact tttaattctt atcaataaca 87240
tatttttcta tgatctgtct tttaaacgat ggattttcca caaatgcgcc tctcaagtcc 87300
ctcatagaat gatacacgta taaaaaatat agcataggca atgactcctt atttttagac 87360
attagatatg ccaaaatcat agccccgctt ctatttactc ccgcagcaca atgaaccaac 87420
acgggctcgt ttcgttgatc acatttagat aaaaaggcgg ttacgtcgtc aaaatattta 87480
ctaatatcgg tagttgtatc atctaccaac ggtatatgaa taatattaat attagagtta 87540
ggtaatgtat atttatccat cgtcaaattt aaaacatatt tgaacttaac ttcagatgat 87600
ggtgcatcca tagcattttt ataatttccc aaatacacat tattggttac ccttgtcatt 87660
atagtgggag atttggctct gtgcatatct ccagttgaac gtagtagtaa gtatttatac 87720
aaacttttct tatccattta taacgtacaa atggataaaa ctactttatc ggtaaacgcg 87780
tgtaatttag aatacgttag agaaaaggct atagtaggcg tacaagcagc caaaacatca 87840
acacttatat tctttgttat tatattggca attagtgcgc tattactctg gtttcagacg 87900
tctgataatc cagtctttaa tgaattaacg agatatatgc gaattaaaaa tacggttaac 87960
gattggaaat cattaacgga tagcaaaaca aaattagaaa gtgatagagg tagacttcta 88020
gccgctggta aggatgatat attcgaattc aaatgtgtgg atttcggcgc ctattttata 88080
gctatgcgat tggataagaa aacatatctg ccgcaagcta ttaggcgagg tactggagac 88140
gcgtggatgg ttaaaaaggc ggcaaaggtc gatccatctg ctcaacaatt ttgtcagtat 88200
ttgataaaac acaagtctaa taatgttatt acttgtggta atgagatgtt aaatgaatta 88260
ggttatagcg gttattttat gtcaccgcat tggtgttccg attttagtaa tatggaatag 88320
tgttagataa atgcggtaac gaatgttcct gtaaggaacc ataacagttt agatttaacg 88380
ttaaagatga gcataaacat aataaacaaa attacaatca aacctataac attaatatca 88440
aacaatccaa aaaatgaaat cagtggagta gtaaacgcgt acataactcc tggataacgt 88500
ttagtagctg ccgttcctat tctagaccaa aaattcggtt tcatgttttc gaaacggtgt 88560
tctgcaacaa gtcggggatc gtgttctaca tatttggcgg cattatccag tatctgccta 88620
ttgatcttca tttcgttttc aattctggct atttcaaaat aaaatcccga tgatagacct 88680
ccagacttta taatttcatc tacgatgttc agcgccgtag taactctaat aatataggct 88740
gataagctaa catcataccc tcctgtatat gtgaatatgg catgattttt gtccattaca 88800
agctcggttt taactttatt gcctgtaata atttctctca tctgtaggat atctattttt 88860
ttgtcatgca ttgccttcaa gacgggacga agaaacgtaa tatcctcaat aacgttatcg 88920
ttttctacaa taactacata ttctaccttt ttattttcta actcggtaaa aaaattagaa 88980
tcccataggg ctaaatgtct agcgatattt cttttcgttt cctctgtaca catagtgtta 89040
caaaaccctg aaaagaagtg agtatacttg tcatcatttc taatgtttcc tccagtccac 89100
tgtataaacg cataatcctt gtaatgatct ggatcatcct tgactaccac aacatttctt 89160
ttttctggca taacttcgtt gtcctttaca tcatcgaact tctgatcatt aatatgctca 89220
tgaacattag gaaatgtttc tgatggaagt ctatcaataa ctggcacaac aataacagga 89280
gttttcgccg ccgccattta gttattgaaa ttaatcatat acaactcttt aatacgagtt 89340
atattttcgt ctatccattg tttcacattt acatatttcg acaaaaagat ataaaatgcg 89400
tattccaatg cttctctgtt taatgaatta ctaaaatata caaacacgtc actgtctggc 89460
aataaatgat atcttagaat attgtaacaa tttattttgt attgcacatg ttcgtgatct 89520
atgagttctt cttcgaatgg cataggatct ccgaatctga aaacgtataa ataggagtta 89580
gaataataat atttgagagt attggtaata tataaactct ttagcggtat aattagtttt 89640
tttctctcaa tttctatttt tagatgtgat ggaaaaatga ctaattttgt agcattagta 89700
tcatgaactc taatcaaaat cttaatatct tcgtcacacg ttagctcttt gaagttttta 89760
agagatgcat cagttggttc gaccgatgga gtaggtgcaa caattttttg ttcgatgtat 89820
gtatgtactg gagccattgt tttaactata atggtgcttg tatcgaaaaa ctttaatgca 89880
gatagcggaa gctcttcgcc gcgactttct acatcgtaat tgggttctaa cgccgatctc 89940
tgaatggata ctagttttct aagttctaat gtgattctct gaaaatgtaa atccaattcc 90000
tccggcatta tagatgtgta tacatcggta aataaaacta tagtatccaa cgatcccttc 90060
tcgcaaattc tagtcttaac caaaaaatcg tatataacca cggagatggc gtatttaaga 90120
gtggattctt ctaccgtttt gttcttggat gtcatatagg aaactataaa gtccgcacta 90180
ctgttaagaa tgattactaa cgcaactata tagttcaaat taagcatttt ggaaacataa 90240
aataactctg tagacgatac ttgactttcg aataagtttg cagacaaacg aagaaagaac 90300
agacctctct taatttcaga agaaaacttt ttttcgtatt cctgacgtct agagtttata 90360
tcaataagaa agttaagaat tagtcggtta atgttgtatt tcattaccca agtttgagat 90420
ttcataatat tatcaaaaga catgataata ttaaagataa agcgctgact atgaacgaaa 90480
tagctatatg gttcgctcaa aaatatagtc ttgttaaacg tggaaacgat aactgtattt 90540
ttaatcacgt cagcggcatc taaattaaat ataggtatat ttattccaca cactctacaa 90600
tatgccacac catcttcata ataaataaat tcgttagcaa aattattaat tttagtgaaa 90660
tagttagcgt caactttcat agcttccttc aatctaattt gatgctcaca cggtgcgaat 90720
tccactctaa catccctttt ccatgcctca ggttcatcga tctctataat atctagtttt 90780
ttgcgtttca caaacacagg ctcgtctctc gcgatgagat ctgtatagta actatgtaaa 90840
tgataactag atagaaagat gtagctatat agatgacgat cctttaagag aggtataata 90900
actttacccc aatcagatag actgttgtta tggtcttcgg aaaaagaatt tttataaatt 90960
tttccagtat tttccaaata tacgtactta acatctaaaa aatccttaat gataatagga 91020
atggataatc cgtctatttt ataaagaaat acatatcgca cattatactt ttttttggaa 91080
atgggaatac cgatgtgtct acataaatat gcaaagtcta aatatttttt agagaatctt 91140
aattggtcca aattcttttc caagtacggt aatagatttt tcatattgaa cggtatcttc 91200
ttaatctctg gttctagttc cgcattaaat gatgaaacta agtcactatt tttataacta 91260
acgattacat cacctctaac atcatcattt accagaatac tgatcttctt ttgtcgtaaa 91320
tacatgtcta atgtgttaaa aaaaagatca tacaagttat acgtcatttc atctgtggta 91380
ttcttgtcat tgaaggataa actcgtacta atctcttctt taacagcctg ttcaaattta 91440
tatcctatat acgaaaaaat agcaaccagt gtttgatcat ccgcgtcaat attctgttct 91500
atcgtagtgt ataacaatcg tatatcttct tctgtgatag tcgatacgtt ataaaggttg 91560
ataacgaaaa tatttttatt tcgtgaaata aagtcatcgt aggattttgg acttatattc 91620
gcgtctagta gatatgcttt tatttttgga atgatctcaa ttagaatagt ctctttagag 91680
tccatttaaa gttacaaaca actaggaaat tggtttatga tgtataattt ttttagtttt 91740
tatagattct ttattctata cttaaaaaat gaaaataaat acaaaggttc ttgagggttg 91800
tgttaaattg aaagcgagaa ataatcataa attatttcat tatcgcgata tccgttaagt 91860
ttgtatcgta atggcgtggt caattacaaa taaagcggat actagtagct tcacaaagat 91920
ggctgaaatc agagctcatc taaaaaatag cgctgaaaat aaagataaaa acgaggatat 91980
tttcccggaa gatgtaataa ttccatctac taagcccaaa accaaacgag ccactactcc 92040
tcgtaaacca gcggctacta aaagatcaac caaaaaggag gaagtggaag aagaagtagt 92100
tatagaggaa tatcatcaaa caactgaaaa aaattctcca tctcctggag tcagcgacat 92160
tgtagaaagc gtggccgctg tagagctcga tgatagcgac ggggatgatg aacctatggt 92220
acaagttgaa gctggtaaag taaatcatag tgctagaagc gatctctctg acctaaaggt 92280
ggctaccgac aatatcgtta aagatcttaa gaaaattatt actagaatct ctgcagtatc 92340
gacggttcta gaggatgttc aagcagctgg tatctctaga caatttactt ctatgactaa 92400
agctattaca acactatctg atctagtcac cgagggaaaa tctaaagttg ttcgtaaaaa 92460
agttaaaact tgtaagaagt aaatgcgtgc acttttttat aaagatggta aactctttac 92520
cgataataat tttttaaatc ctgtatcaga cgataatcca gcgtatgagg ttttgcaaca 92580
tgttaaaatt cctactcatt taacagatgt agtagtatat gaacaaacgt gggaggaggc 92640
gttaactaga ttaatttttg tgggaagtga ttcaaaagga cgtagacaat acttttacgg 92700
aaaaatgcat gtacagaatc gcaacgctaa aagagatcgt atttttgtta gagtatataa 92760
cgttatgaaa cgaattaatt gttttataaa caaaaatata aagaaatcgt ccacagattc 92820
caattatcag ttggcggttt ttatgttaat ggaaactatg ttttttatta gatttggtaa 92880
aatgaaatat cttaaggaga atgaaacagt agggttatta acactaaaaa ataaacacat 92940
agaaataagt cccgatgaaa tagttatcaa gtttgtagga aaggacaaag tttcacatga 93000
atttgttgtt cataagtcta atagactata taagccgcta ttgaaactga cggatgattc 93060
tagtcccgaa gaatttctgt tcaacaaact aagtgaacga aaggtatatg aatgtatcaa 93120
acagtttggt attagaatca aggatctccg aacgtatgga gtcaattata cgtttttata 93180
taatttttgg acaaatgtaa agtccatatc tcctcttcca tcaccaaaaa agttaatagc 93240
gttaactatc aaacaaactg ctgaagtggt aggtcatact ccatcaattt caaaaagagc 93300
ttatatggca acgactattt tagaaatggt aaaggataaa aattttttag atgtagtatc 93360
taaaactacg ttcgatgaat tcctatctat agtcgtagat cacgttaaat catctacgga 93420
tggatgatat agatctttac acaaataatt acaaaaccga taaatggaaa tggataagcg 93480
tatgaaatct ctcgcaatga ccgctttctt tggggagcta agcacattag atattatggc 93540
attgataatg tctatattta aacgccatcc aaacaatacc attttttcag tggataagga 93600
tggtcagttt atgattgatt tcgaatacga taattataag gcttctcaat atttggatct 93660
gaccctcact ccgatatctg gagatgaatg caagactcac gcatcgagta tagccgaaca 93720
attggcgtgt gtggatatta ttaaagagga tattagcgaa tatatcaaaa ctactccccg 93780
tcttaaacga tttataaaaa aataccgcaa tagatcagat actcgcatca gtcgagatac 93840
agaaaagctt aaaatagctc tagctaaagg catagattac gaatatataa aagacgcttg 93900
ttaataagta aatgaaaaaa aactagtcgt ttataataaa acacgatatg gatgccaacg 93960
tagtatcatc ttctactatt gcgacgtata tagacgcttt agcgaagaat gcttcggaat 94020
tagaacagag gtctaccgca tacgaaataa ataatgaatt ggaactagta tttattaagc 94080
cgccattgat tactttgaca aatgtagtga atatctctac gattcaggaa tcgtttattc 94140
gatttaccgt tactaataag gaaggtgtta aaattagaac taagattcca ttatctaagg 94200
tacatggtct agatgtaaaa aatgtacagt tagtagatgc tatagataac atagtttggg 94260
aaaagaaatc attagtgacg gaaaatcgtc ttcacaaaga atgcttgttg agactatcga 94320
cagaggaacg tcatatattt ttggattaca agaaatatgg atcctctatc cgactagaat 94380
tagtcaatct tattcaagca aaaacaaaaa actttacgat agactttaag ctaaaatatt 94440
ttctaggatc cggtgcccag tctaaaagtt ctttattaca cgctattaat catccaaagt 94500
caaggcctaa tacatctctg gaaatagaat ttacacctag agacaatgaa acagttccat 94560
atgatgaact aataaaggaa ttgacgactc tctcgcgtca tatatttatg gcttctccag 94620
agaatgtaat tctttctccg cctattaacg cgcctataaa aacctttatg ttgcctaaac 94680
aagatatagt aggtttggat ctggaaaatc tatatgccgt aactaagact gacggcattc 94740
ctataactat cagagttaca tcaaacgggt tgtattgtta ttttacacat cttggttata 94800
ttattagata tcctgttaag agaataatag attccgaagt agtagtcttt ggtgaggcag 94860
ttaaggataa gaactggacc gtatatctca ttaagctaat agagcctgtg aatgcaatca 94920
atgatagact agaagaaagt aagtatgttg aatctaaact agtggatatt tgtgatcgga 94980
tagtattcaa gtcaaagaaa tacgaaggtc cgtttactac aactagtgaa gtcgtcgata 95040
tgttatctac atatttacca aagcaaccag aaggtgttat tctgttctat tcaaagggac 95100
ctaaatctaa cattgatttt aaaattaaaa aggaaaatac tatagaccaa actgcaaatg 95160
tagtatttag gtacatgtcc agtgaaccaa ttatctttgg agagtcgtct atctttgtag 95220
agtataagaa atttagcaac gataaaggct ttcctaaaga atatggttct ggtaagattg 95280
tgttatataa cggcgttaat tatctaaata atatctattg tttggaatat attaatacac 95340
ataatgaagt gggtattaag tccgtggttg tacctattaa gtttatagca gaattcttag 95400
ttaatggaga aatacttaaa cctagaattg ataaaaccat gaaatatatt aactcagaag 95460
attattatgg aaatcaacat aatatcatag tcgaacattt aagagatcaa agcatcaaaa 95520
taggagatat ctttaacgag gataaactat cggatgtggg acatcaatac gccaataatg 95580
ataaatttag attaaatcca gaagttagtt attttacgaa taaacgaact agaggaccgt 95640
tgggaatttt atcaaactac gtcaagactc ttcttatttc tatgtattgt tccaaaacat 95700
ttttagacga ttccaacaaa cgaaaggtat tggcgattga ttttggaaac ggtgctgacc 95760
tggaaaaata cttttatgga gagattgcgt tattggtagc gacggatccg gatgctgatg 95820
ctatagctag aggaaatgaa agatacaaca aattaaactc tggaattaaa accaagtact 95880
acaaatttga ctacattcag gaaactattc gatccgatac atttgtctct agtgtcagag 95940
aagtattcta ttttggaaag tttaatatca tcgactggca gtttgctatc cattattctt 96000
ttcatccgag acattatgct accgtcatga ataacttatc cgaactaact gcttctggag 96060
gcaaggtatt aatcactacc atggacggag acaaattatc aaaattaaca gataaaaaga 96120
cttttataat tcataagaat ttacctagta gcgaaaacta tatgtctgta gaaaaaatag 96180
ctgatgatag aatagtggta tataatccat caacaatgtc tactccaatg actgaataca 96240
ttatcaaaaa gaacgatata gtcagagtgt ttaacgaata cggatttgtt cttgtagata 96300
acgttgattt cgctacaatt atagaacgaa gtaaaaagtt tattaatggc gcatctacaa 96360
tggaagatag accatctaca agaaactttt tcgaactaaa tagaggagcc attaaatgtg 96420
aaggtttaga tgtcgaagac ttacttagtt actatgttgt ttatgtcttt tctaagcggt 96480
aaataataat atggtatggg ttctgatctc ccagttctaa atgcattaaa taattccaat 96540
agagcgattt ttgttcctat aggaccttcc aactgtggat actctgtatt gttaatagat 96600
atattaatac ttttgtcggg taacagaggt tctacgtctt ttaaaaataa aagtttgata 96660
acatctggcc tgttcataaa taaaaacttg gcgattctat atatactctt attatcaaat 96720
ctagccattg tcttatagat gtgagctact gtaggtgtac catttgattt tctttctaat 96780
actatatatt tctctcgaag aagttcttgc acatcatctg ggaataaaat actactgttg 96840
agtaaatcag ttattttttt tatatcgata ttgatggaca tttttatagt taaggataat 96900
aagtatccca aagtagataa cgacgataac gaagtattta tacttttagg aaatcacaat 96960
gactttatca gattaaaatt aacaaaatta aaggagcatg tatttttttc tgaatatatt 97020
gtgactccag atacatatgg atctttatgc gtcgaattaa atgggtctag ttttcagcac 97080
ggcggtagat atatagaggt ggaggaattt atagatgctg gaagacaagt tagatggtgt 97140
tctacatcca atcatatatc taaagatata cccgaagata tgcacactga taaatttgtc 97200
atttatgata tatacacttt tgacgctttc aagaataaac gattggtatt cgtacaggta 97260
cctccgtcgt taggagatga tagtcatttg actaatccgt tattgtctcc gtattatcgt 97320
aattcagtag ccagacaaat ggtcaatgat atgattttta atcaagattc atttttaaaa 97380
tatttattag aacatctgat tagaagccac tatagagttt ctaaacatat aacaatagtt 97440
agatacaagg ataccgaaga attaaatcta acgagaatat gttataatag agataagttt 97500
aaggcgtttg tattcgcttg gtttaacggc gtttcggaaa atgaaaaggt actagatacg 97560
tataaaaagg tatctaattt gatataatga attcagtgac tgtatcacac gcgccatata 97620
ctattactta tcacgatgat tgggaaccag taatgagtca attggtagag ttttataacg 97680
aagtagccag ttggctgcta cgagacgaga cgtcgcctat tcctgataag ttctttatac 97740
agttgaaaca accgcttaga aataaacgag tatgtgtgtg cggtatagat ccgtatccga 97800
aagatggaac tggtgtaccg ttcgaatcac caaattttac aaaaaaatca attaaggaga 97860
tagcttcatc tatatctaga ttaaccggag taattgatta taaaggttat aaccttaata 97920
taatagacgg ggttataccc tggaattatt acttaagttg taaattagga gaaacaaaaa 97980
gtcacgcgat ctactgggat aagatttcca agttactgct gcagcatata actaaacacg 98040
ttagtgttct ttattgtttg ggtaaaacag atttctcgaa tatacgggcc aagttagaat 98100
ccccggtaac taccatagtc ggatatcatc cagcggctag agaccgccaa ttcgagaaag 98160
atagatcatt tgaaattatc aacgttttac tggaattaga caacaaggca cctataaatt 98220
gggctcaagg gtttatttat taatgcttta gtgaaatttt aacttgtgtt ctaaatggat 98280
gcggctatta gaggtaatga tgttatcttt gttcttaaga ctataggtgt cccgtcagcg 98340
tgcagacaaa atgaagatcc aagatttgta gaagcattta aatgcgacga gttagaaaga 98400
tatattgaga ataatccaga atgtacacta ttcgaaagtc ttagggatga ggaagcatac 98460
tctatagtca gaattttcat ggatgtagat ttagacgcgt gtctagacga aatagattat 98520
ttaacggcta ttcaagattt tattatcgag gtgtcaaact gtgtagctag attcgcgttt 98580
acagaatgcg gcgccattca tgaaaatgta ataaaatcca tgagatctaa tttttcattg 98640
actaagtcta caaatagaga taaaacaagt tttcatatta tctttttaga cacgtatacc 98700
actatggata cattgatagc tatgaaacga acactattag aattaagtag atcatctgaa 98760
aatccactaa caagatcgat agacactgcc gtatatagga gaaaaacaac tcttcgggtt 98820
gtaggtacta ggaaaaatcc aaattgcgac actattcatg taatgcaacc accgcatgat 98880
aatatagaag attacctatt cacttacgtg gatatgaaca acaatagtta ttacttttct 98940
ctacaacaac gattggagga tttagttcct gataagttat gggaaccagg gtttatttca 99000
ttcgaagacg ctataaaaag agtttcaaaa atattcatta attctataat aaactttaat 99060
gatctcgatg aaaataattt tacaacggta ccactggtca tagattacgt aacaccttgt 99120
gcattatgta aaaaacgatc gcataaacat ccgcatcaac tatcgttgga aaatggtgct 99180
attagaattt acaaaactgg taatccacat agttgtaaag ttaaaattgt tccgttggat 99240
ggtaataaac tgtttaatat tgcacaaaga attttagaca ctaactctgt tttattaacc 99300
gaacgaggag accatatagt ttggattaat aattcatgga aatttaacag cgaagaaccc 99360
ttgataacaa aactaatttt gtcaataaga catcaactac ctaaggaata ttcaagcgaa 99420
ttactctgtc caagaaaacg aaagactgta gaagctaaca tacgagacat gttagtagat 99480
tcagtagaga ccgataccta tccggataaa cttccgttta aaaatggtgt attggacctg 99540
gtagacggaa tgttttactc tggagatgat gctaaaaaat atacgtgtac tgtatcaacc 99600
ggatttaaat ttgacgatac aaagttcgtc gaagacagtc cagaaatgga agagttaatg 99660
aatatcatta acgatatcca accattaacg gatgaaaata agaaaaatag agagctatat 99720
gaaaaaacat tatctagttg tttatgcggt gctaccaaag gatgtttaac attctttttt 99780
ggagaaactg caactggaaa gtcgacaacc aaacgtttgt taaagtctgc tatcggtgac 99840
ctgtttgttg agacgggtca aacaatttta acagatgtat tggataaagg acctaatcca 99900
tttatcgcta acatgcattt gaaaagatct gtattctgta gcgaactacc tgattttgcc 99960
tgtagtggat caaagaaaat tagatctgac aatattaaaa agttgacaga accttgtgtc 100020
attggaagac cgtgtttctc caataaaatt aataatagaa accatgcgac aatcattatc 100080
gatactaatt acaaacctgt ttttgatagg atagataacg cattaatgag aagaattgcc 100140
gtcgtgcgat tcagaacaca cttttctcaa ccttctggta gagaggctgc tgaaaataat 100200
gacgcgtacg ataaagtcaa actattagac gaggggttag atggtaaaat acaaaataat 100260
agatatagat tcgcatttct atacttgttg gtgaaatggt acagaaaata tcatgttcct 100320
attatgaaac tatatcctac acccgaagag attcctgact ttgcattcta tctcaaaata 100380
ggtactctgt tagtatctag ctctgtaaag catattccat taatgacgga cctctccaaa 100440
aagggatata tattgtacga taatgtggtc actcttccgt tgactacttt ccaacagaaa 100500
atatccaagt attttaattc tagactattt ggacacgata tagagagctt catcaataga 100560
cataagaaat ttgccaatgt tagtgatgaa tatctgcaat atatattcat agaggatatt 100620
tcatctccgt aaatatatgc tcatatattt atagaagata tcacatatct aaatgaatac 100680
cggaatcata gatttatttg ataatcatgt tgatagtata ccaactatat tacctcatca 100740
gttagctact ctagattatc tagttagaac tatcatagat gagaacagaa gcgtgttatt 100800
gttccatatt atgggatcag gtaaaacaat aatcgctttg ttgttcgcct tggtagcttc 100860
cagatttaaa aaggtttaca ttctagtgcc taatatcaac attttgaaaa tttttaatta 100920
taatatgggt gtagctatga acttgtttaa tgacgaattc atagctgaga atatctttat 100980
tcattccaca acaagttttt attctcttaa ttataacgat aacgtcatta attataacgg 101040
attatctcgc tacaataact ctatttttat cgttgatgag gcacataata tctttgggaa 101100
taatactgga gaacttatga ccgtgataaa aaataaaaac aagattcctt ttctactatt 101160
gtctggatct cccattacta acacacctaa tactctgggt catattatag atttaatgtc 101220
cgaagagacg atagattttg gtgagattat tagtcgtggt aagaaagtaa ttcagacact 101280
tcttaacgaa cgcggtgtga atgtacttaa ggatttgctt aaaggaagaa tatcatatta 101340
cgaaatgcct gataaagatc taccaacgat aagatatcac ggacgtaagt ttctagatac 101400
tagagtagta tattgtcaca tgtctaaact tcaagagaga gattatatga ttactagacg 101460
acagctatgt tatcatgaaa tgtttgataa aaatatgtat aacgtgtcaa tggcagtatt 101520
gggacaactt aatctgatga ataatttaga tactttattt caggaacagg ataaggaatt 101580
gtacccaaat ctgaaaataa ataatggcgt gttatacgga gaagaattgg taacgttaaa 101640
cattagttcc aaatttaaat actttattaa tcggatacag acactcaacg gaaaacattt 101700
tatatacttt tctaattcta catatggcgg attggtaatt aaatatatca tgctcagtaa 101760
tggatattct gaatataatg gttctcaggg aactaatcca catatgataa acggcaaacc 101820
aaaaacattt gctatcgtta ctagtaaaat gaaatcgtct ttagaggatc tattagatgt 101880
gtataattct cctgaaaacg atgatggtag tcaattgatg tttttgtttt cgtcaaacat 101940
tatgtccgaa tcctatactc tgaaagaggt aaggcatatt tggtttatga ctatcccaga 102000
tactttttct caatacaacc aaattcttgg acgatctatt agaaaattct cttacgccga 102060
tatttctgaa ccagttaatg tatatctttt agccgccgta tattccgatt tcaatgacga 102120
agtaacgtca ttaaacgatt acacacagga tgaattgatt aatgttttac catttgacat 102180
caaaaagctg ttatatctaa aatttaagac taaagaaacg aatagaatat actctattct 102240
tcaagagatg tctgaaacgt attctcttcc accacatcca tcaattgtaa aagttttatt 102300
gggagaattg gtcagacaat ttttttataa taattctcgt attaagtata acgactccaa 102360
gttacttaaa atggttacat cagttataaa aaataaagaa gacgctagga attacataga 102420
tgatattgta aacggtcact tctttgtatc gaataaagta tttgataaat ctcttttata 102480
caaatacgaa aacgatatta ttacagtacc gtttagactt tcctacgaac catttgtttg 102540
gggagttaac tttcgtaaag aatataacgt ggtatcttct ccataaaact gatgaaatat 102600
ataaagaaat aaatgtcgag ctttgttacc aatggatacc ttccagttac attggaacca 102660
cacgagctga cgttagacat aaaaactaat attaggaatg ccgtatataa gacgtatctc 102720
catagagaaa ttagtggtaa aatggccaag aaaatagaaa ttcgtgaaga cgtggaatta 102780
cctctcggcg aaatagttaa taattctgta gttataaacg ttccgtgtgt aataacctac 102840
gcgtattatc acgttgggga tatagtcaga ggaacattaa acatcgaaga tgaatcaaat 102900
gtaactattc aatgtggaga tttaatctgt aaactaagta gagattcggg tactgtatca 102960
tttagcgatt caaagtactg cttttttcga aatggtaatg cgtatgacaa tggcagcgaa 103020
gtcactgccg ttctaatgga ggctcaacaa ggtatcgaat ctagttttgt ttttctcgcg 103080
aatatcgtcg actcataaaa aagagaatag cggtaagtat aaacacgaat actatggcaa 103140
taattgcgaa tgttttattc tcttcgatat atttttgata atatgaaaaa catgtctctc 103200
tcaaatcgga caaccatctc ataaaatagt tctcgcgcgc tggagaggta gttgctgctc 103260
gtataatctc cccagaataa tatacttgcg tgtcgtcgtt caatttatac ggatttctat 103320
agttctctgt tatataatgc ggttttccat catgattaga cgacgacaat agtgttctga 103380
atttagatag ttgatcagaa tgaatgttta ttggcgttgg aaaaattatc catacagcgt 103440
ctgcagagtg gttgatagtt gttcctagat atgtaaaata atccaactta ctaggcagca 103500
aattgtctag ataaaatact gaatcaaacg gtgcagacgt attggcggat ctaatggaat 103560
ccaattgatt aactatcttt tgaaaatata catttttatg atccaatact tgtaagaata 103620
tagaaataat gataagtcca tcatcgtgtt tttttgcctc ttcataagaa ctatattttt 103680
tcttattcca atgaacaaga ttaatctctc cagagtattt gtacacatct atcaagtgat 103740
tggatccata atcgtcttcc tttccccaat atatatgtag tgatgataac acatattcat 103800
tggggagaaa ccctccactt atatatcctc ctttaaaatt aatccttact agttttccag 103860
tgttctggat agtggttggt ttcgactcat tataatgtat gtctaacggc ttcaatcgcg 103920
cgttagaaat tgctttttta gtttctatat taataggaga tagttgttgc ggcatagtaa 103980
aaatgaaatg ataactgttt aaaaatagct cttagtatgg gaattacaat ggatgaggaa 104040
gtgatatttg aaactcctag agaattaata tctattaaac gaataaaaga tattccaaga 104100
tcaaaagaca cgcacgtgtt tgctgcgtgt ataacaagtg acggatatcc gttaatagga 104160
gctagaagaa cttcattcgc gttccaggcg atattatctc aacaaaattc agattctatc 104220
tttagagtat ccactaaact attacggttt atgtactaca atgaactaag agaaatcttt 104280
agacggttga gaaaaggttc tatcaacaat atcgatcctc actttgaaga gttaatatta 104340
ttgggtggta aactagataa aaaggaatct attaaagatt gtttaagaag agaattaaaa 104400
gaggaaagtg atgaacgtat aacagtaaaa gaattcggaa atgtaattct aaaacttaca 104460
acgcgcgata aattatttaa taaagtatat ataggttatt gcatggcgtg ttttattaat 104520
caatcgttgg aggatttatc gcatactagt atttacaatg tagaaattag aaagattaaa 104580
tcattaaatg attgtattaa cgacgataaa tacgaatatc tgtcttatat ttataatatg 104640
ctagttaata gtaaatgaac ttttacagat ctagtataat tagtcagatt attaagtata 104700
atagacgact agctaagtct attatttgcg aggatgactc tcaaattatt acactcacgg 104760
cattcgttaa ccaatgccta tggtgtcata aacgagtatc cgtgtccgct attttattaa 104820
ctactgataa caaaatatta gtatgtaaca gacgagatag ttttctctat tctgaaataa 104880
ttagaactag aaacatgttt agaaagaaac gattatttct gaattattcc aattatttga 104940
acaaacagga aagaagtata ctatcgtcat ttttttctct agatccagct actgctgata 105000
atgatagaat agacgctatt tatccgggtg gcatacccaa aaggggtgag aatgttccag 105060
agtgtttatc cagggaaatt aaagaagaag ttaatataga caattctttt gtattcatag 105120
acactcggtt ttttattcat ggcatcatag aagataccat tattaataaa ttttttgagg 105180
taatcttctt tgtcggaaga atatctctaa cgagtgatca aatcattgat acatttaaaa 105240
gtaatcatga aatcaaggat ctaatatttt tagatccgaa ttcaggtaat ggactccaat 105300
acgaaattgc aaaatatgct ctagatactg caaaactcaa atgttatggc catagaggat 105360
gttattacga atcattaaaa aaattaactg aggatgattg attagaaaat ataaattaat 105420
ttaccatcgt gtatttttat aacgggattg tccggcatat catgtagata gttaccgtct 105480
acatcgtata ctcgaccatc tacgccttta aatcctctat ttattgacat taatctatta 105540
gaattggaat accaaatatt agtaccctca attagtttat tggtaatatt tttgttagac 105600
gatagatcga tggctcttga aaccaaggtt ttccaaccgg actcattgtc gatcggtgag 105660
aagtcttttt cattagcatg aatccattct aatgatgtat gtttaaacac tctaaacaat 105720
tggacaaatt cttttgattt gctttgaatg atttcaaata ggtcttcgtc tacagtaggc 105780
ataccattag ataatctagc cattataaag tgcacgttta catatctacg ttctggagga 105840
gtaagaacgt gactattgag acgaatggct cttcctacta tctgacgaag agacgcctcg 105900
ttccatgtca tatctaaaat gaagatatca ttgattgaga agaagctaat accctcgcct 105960
ccactagaag agaatacgca tgttttaatg cattctccgt tagtgtttga ttcttggtta 106020
aactcagcca ccgccttgat tctagtatct tttgttctag atgagaactc tatattagag 106080
ataccaaaga ctttgaaata tagtaataag atttctattc ctgactgatt aacaaatggt 106140
tcaaagacta gacatttacc atgggatgct aatattccca aacatacatc tataaatttg 106200
acgcttttct cttttaattc agtaaataga gagatatcag ccgcactagc atcccctccc 106260
aatagttctc cccttttaaa ggtatctaat gcagatttag aaaattctct atctcttaat 106320
gaatttttaa aatcattata tagtgttgct atctcttgcg cgtattcgcc cggatcacga 106380
ttttgtcttt caggaaagct atcgaacgta aacgtagtag ccatacgtct cagaattcta 106440
aatgatgata tacctgtttt tatttcagcg agtttagcct tttgataaat ttcttcttgc 106500
tttttcgaca tattaacgta tcgcattaat actgttttct tagcgaatga tgcagaccct 106560
tctacgtcat caaaaataga aaactcgtta ttaactatgt acgaacatag gcctcctagt 106620
ttggagacta attctttttc atcaactaga cgtttattct caaatagcga ttggtgttgt 106680
aaggatcctg gtcgtagtaa gttaaccaac atggtgaatt cttgcacact attgacgata 106740
ggtgtagccg ataaacaaat catcttatgg ttttttaatg cgatggtctt agataaaaaa 106800
ttatatactg aacgagtagg acggatctta ccatcttctt tgattaatga tttagaaatg 106860
aagttatgac attcatcaat aatgacgcat attctactct tggaattaat agttttgata 106920
ttagtaaaaa atttatttct aaaattttga tcatcgtaat taataaaaat acaatccttc 106980
gttatctctg gagcgtatct gagtatagtg ttcatccaag gatcttctat caaagccttt 107040
ttcaccaata agataatagc ccaattcgta taaatatcct taagatgttt gagaatatat 107100
acagtagtca ttgttttacc gacacccgtt tcatggaaca ataaaagaga atgcatactg 107160
tctaatccta agaaaactct tgctacaaaa tgttgataat ccttgaggcg tactacgtcc 107220
gaccccatca tttcaacagg catattagta gttctgcgca atgcataatc gatataggcc 107280
gcgtgtgatt tactcattta tgagtgataa gtaataacta tgttttaaaa atcacagcag 107340
tagtttaact agtcttctct gatgtttgtt ttcgatactt tttgaatcag aagtcatact 107400
agaataaagc aacgagtgaa cgtaatagag agcttcgtat actctattcg aaaactctaa 107460
gaacttatta atgaattccg tatccactgg attgtttaaa atactaaatt gaacactgtt 107520
cacatccttc caagaagaag acttagtgac ggacttaaca tgagacataa ataaatccaa 107580
atttttttta caaacatcac tagccaccat aatggcgcta tcttttaacc agctatcgct 107640
tacgcatttt agcagtctaa catttttaaa gagactacaa tatattctca tagtatcgat 107700
tacacctcta ccgaataaag ttggaagttt aataatacaa tatttttcgt ttacaaaatc 107760
aaataatggt cgaaacacgt cgaaggttaa catcttataa tcgctaatgt atagattgtt 107820
ttcagtgaga tgattattag atttaatagc atctcgttca cgtttgaaca gtttattgcg 107880
tgcgctgagg tcggcaacta cggcgtccgc tttagtactc ctcccataat actttacgct 107940
attaatcttt aaaatttcat agactttatc tagatcgctt tctggtaaca tgatatcatg 108000
tgtaaaaagt tttaacatgt cggtcggcat tctatttaga tcattaactc tagaaatctg 108060
aagaaagtaa ttagctccgt attccagact aggtaatggg cttttaccta gagacagatt 108120
aagttctggc aatgtttcat aaaatggaag aaggacatgc gttccctccc ggatattttt 108180
tacaatttca tccatttaca actctatagt ttgttttcat tattattagt tattatctcc 108240
cataatcttg gtaatactta ccccttgatc gtaagatacc ttatacaggt cattacatac 108300
aactaccaat tgtttttgta cataatagat tggatggttg acatccatgg tggaataaac 108360
tactcgaaca gatagtttat ctttccccct agatacatta gccgtaatag ttgtcggcct 108420
aaagaatatc tttggtgtaa agttaaaagt tagggttctt gttccattat tgctttttgt 108480
cagtagttca ttataaattc tcgagatggg tccgttctct gaatatagaa catcatttcc 108540
aaatctaact tctagtctag aaataatatc ggtcttattc ttaaaatcta ttcccttgat 108600
gaagggatcg ttaatgaaca aatccttggc ctttgattcg gctgatctat tatctccgtt 108660
atagacgtta cgttgactag tccaaagact tacaggaata gatgtatcga tgatgttgat 108720
actatgtgat atgtgagcaa agattgttct cttagtggca tcactatatg ttccagtaat 108780
ggcggaaaac tttttagaaa tgttatatat aaaagaattt tttcgtgttc caaacattag 108840
cagattagta tgaagataaa cactcatatt atcaggaaca ttatcaattt ttacatacac 108900
atcagcatct tgaatagaaa cgataccatc ttctggaacc tctacgatct cggcagactc 108960
cggataacca gtcggtggac catcgctaac aataactaga tcatccaaca atctactcac 109020
atatgcatct atataatctt tttcatcttg tgagtaccct ggatacgaaa taaatttatt 109080
atccgtattt ccataataag gtttagtata aacagagagc gatgttgccg catgaacttc 109140
agttacagtc gccgttggtt ggtttatttg acctattact ctcctaggtt tctctataaa 109200
tgatggttta atttgtacat tcttaaccat atatccaata aagctcaatt caggaacata 109260
aacaaattct ttgttgaacg tttcaaagtc gaacgaagag tcacgaataa cgatatcgga 109320
tactggattg aaggttaccg ttacggtaat ttttgaatcg gatagtttaa gactgctgaa 109380
tgtatcttcc acatcaaacg gagttttaat ataaacgtat actgtagatg gttctttaat 109440
agtgtcatta ggagttaggc caatagaaat atcattaagt tcactagaat atccagagtg 109500
tttcaaagca attgtattat tgatacaatt attatataat tcttcgccct caatttccca 109560
aataacaccg ttacacgaag agatagatac gtgattaata catttatatc caacatatgg 109620
tacgtaaccg aatcttccca tacctttaac ttctggaagt tccaaactca gaaccaaatg 109680
attaagcgca gtaatatact gatccctaat ttcgaagcta gcgatagcct gattgtctgg 109740
accatcgttt gtcataactc cggatagaga aatatattgc ggcatatata aagttggaat 109800
ttgactatcg actgcgaaga cattagaccg tttaatagag tcatccccac cgatcaaaga 109860
attaatgata gtattattca ttttctattt aaaatggaaa aagcttacaa taaactccgt 109920
agagaaatat ctataatttg tgagttttcc ttaaagtaac agcttccgta aacgccgtct 109980
ttatctctta gtaagtttat tgtatttata accttttcct tatcttcata gaatactaaa 110040
ggcaacaaag aaatttttgg ttcttctcta agagctacgt gagacttaac catagacgcc 110100
aacgaatccc tacatatttt agaacagaaa tacccaactt caccaccctt gaatgtctca 110160
atactaatag gtttaaaaac caaatcttga ttacaaaacc aacacttatc aattacacta 110220
tttgtcttaa tagacacatc tgccatagat ttataatact ttggtagtat acaagcgagt 110280
gcttcttctt tagcgggctt aaagactgct ttaggtgctg aaataaccac atctggaagg 110340
cttactcgct tagccattta attacggaac tattttttta tacttctaat gagcaagtag 110400
aaaacctctc atctacaaaa acatactcgt gtccataatc ctctaccata gttacacgtt 110460
ttttagatct catatgtgct aaaaagtttt cccatactaa ttggttacta ttatttttcg 110520
tataattttt aacagtttga ggttttagat ttttagttac agaagtgata tcgaatattt 110580
tatccaaaaa gaatgaataa ttaattgtct tagaaggagt gttttcttgg caaaagaata 110640
ccaagtgctt aaatatttct actacttcat taatcttttc tgtactcaga ttcagtttct 110700
catcttttac ttgattgatt atttcaaaga ctaacttata atccttttta tttattctct 110760
cgttagcctt aagaaaacta gatacaaaat ttgcatctac atcatccgtg gatatttgat 110820
ttttttccat gatatccaag agttccgaga taatttctcc agaacattga tgagacaata 110880
atctccgcaa tacatttctc aaatgaataa gtttattaga cacatggaag tttgactttt 110940
tttgtacctt tgtacatttt tgaaataccg actcgcaaaa aatacaatat tcatatcctt 111000
gttcagatac tataccgttg tgtctacaac cgctacataa tcgtagattc atgttaacac 111060
tctacgtatc tcgtcgtcca atattttata taaaaacatt ttatttctag acgttgccag 111120
aaaatcctgt aatattttta gttttttggg ctgtgaataa agtatcgccc taatattgtt 111180
accgtcttcc gccaatatag tagttaaatt atccgcacat gcaaaagaac accgcttagg 111240
cggattcagt acaatgttat atttttcgta ccaactcatt taaatatcat aatctaaaat 111300
agttctgtaa tatgtctagc gctaatatat tgatcataat cctgtgcata aattaagata 111360
caacaatgtc tcgaaatcat cgacatggct tcttccatag ttagaagatc gtcgtcaaag 111420
ttagcaacgt gattcatcaa catttgctgt tttgaggcag caaatactga accgtcgcca 111480
ttcaaccatt cataaaaacc atcgtctgaa tccattgata atttcttgta ctggtttttg 111540
agagctcgca tcaatctagc atttctagct cccggattga aaacagaaag aggatcgtac 111600
atccagggtc cattttctgt aaatagaatc gtataatgtc ccttcaagaa gatatcagac 111660
gatccacaat caaagaattg gtctccgagt ttgtaacaaa ctgcggactt taacctatac 111720
atgataccgt ttagcatgat ttctggtgat acgtcaatcg gagtatcatc tattagagat 111780
ctaaagccgg tgtaacattc tccaccaaac atattcttat tctgacgtcg ttctacataa 111840
aacatcattg ctccattaac gataacaggg gaatgaacag cactacccat cacattagtt 111900
cccaatggat caatgtgtgt aactccagaa catcttccat atcctatgtt aggaggagcg 111960
aacaccactc ttccactatt gccatcgaat gccatagaat aaatatcctt ggaattgata 112020
gaaatcggac tgtcggatgt tgtgatcatc ttcataggat taacaactat gtatggtgcc 112080
gcctgaagtt tcatatcgta actgatgccg tttataggtc tagccacaga aaccaacgta 112140
ggtctaaatc caactataga caaaatagaa gccaatatct gttcctcatc tgtcataact 112200
tgagagcatc cagtatgaat aatcttcatt agatggggat ctaccgcatc atcatcgtta 112260
caataaaaaa ttcccattct aatgttcata attgcttttc taatcatggt atgcatgttt 112320
gctctctgaa tctctgtgga aattagatct gatacacctg taatcactat cggattatcc 112380
tccgtaagac gattaaccaa caacatataa ttataagact ttacttttct aaattcataa 112440
agttgctgga ttaggctata ggtgtctcca tgtacatacg cgttctcgag cgcaggaagt 112500
ttaataccga atagtgccat cagaatagga tgaatatagt aattagtttc tggttttcta 112560
taaataaaag acaaatcttg tgaactagac atatcggtaa aatgcatgga ttggaatcgt 112620
gtagtcgaca gaagaatatg atgattagat ggagagtata ttttatctaa ctctttgagt 112680
tggtcaccga ttctaggact agctcgagaa tgaataagta ctaaaggatg agtacatttc 112740
acagaaacac tagcattgtt caatgtgctc tttacatggg taaggagttg aaatagctcg 112800
tttctatttg ttctgacaat atttagttta ttcataatgt taagcatatc ctgaatagta 112860
aagttagatg tgtcatactt gttagtagtt agatatttag caattgcatt cccatcattt 112920
ctcaatctcg tactccaatc atgtgtagat gctacttcgt cgatggaaac catacaatcc 112980
tttttgatag gctgttgaga ttgattattt cctgcacgtt taggtttggt acgttgattt 113040
ctagcccctg cggatataaa gtcatcgtct acaatttggg acaatgaatt gcatacacta 113100
caagacaaag atttatcaga agtgtgaata tgatcttcat ctaccaaaga aagagtttga 113160
ttagtataac tagattttag tcctgcgtta gatgttaaaa aaacatcgct attgaccacg 113220
gcttccatta tttatattcg tagtttttac tcgaaagcgt gattttaata tccaatctta 113280
ttacttttgg aatcgttcaa aacctttgac tagttgtaga atttgatcta ttgccctacg 113340
cgtatactcc cttgcatcat atacgttcgt caccagatcg tttgtttcgg cctgaagttg 113400
gtgcatatct ctttcaacat tcgacatgag atccttaagg gccatatcgt ctagattttg 113460
ttgagatgct gctcctggat ttggattttg ttgtgctgtt gtacatactg taccaccagt 113520
aggtgtagga gtacatacag tggccacaat aggaggttga ggaggtgtaa ccgttggagt 113580
agtacaagaa atatttccat ccgattgttg tgtacatgta gttgttggta acgtctgaga 113640
aggttgggta gatggcggtg tcgtcgtctt ttgatcttta ttaaatttag agataatatc 113700
ctgaacagca ttgctcggcg tcaacgctgg aaggagtgaa ctcgccggcg catcagtatc 113760
ttcagacagc caatcaaaaa gattagacat atcagatgat gtattagttt gttgtcgtgg 113820
ttttggtgta ggaacagtac tactaggtag aagaatagga gccggtgtag ctgttggaac 113880
cggctgtgga gttatatgaa tagttggttg tagcggttgg ataggctgtc tgctggcgac 113940
cgtcatatta tctctagcta gttgttctcg caactgtctt tgataatacg actcttgaga 114000
ctttagtcct atttcaatcg cttcatcctt tttcgtatcc ggatcctttt cttcagaata 114060
atagattgac gactttggtg tagaggattc tgccagcccc tgtgagaact tgttaaagaa 114120
gtccatttaa ggctttaaaa ttgaattgcg attataagat taaatggcag acacagacga 114180
tattatcgac tatgaatccg atgatctcac cgaatacgag gatgatgaag aagaggaaga 114240
agatggagag tcactagaaa ctagtgatat agatcccaaa tcttcttata agattgtaga 114300
atcagcatcc actcatatag aagatgcgca ttccaatctt aaacatatag ggaatcatat 114360
atctgctctt aaacgacgct atactagacg tataagtcta tttgaaatag cgggtataat 114420
agcagaaagc tataacttgc ttcaacgagg aagattacct ctagtttcag aattttctga 114480
cgaaacgatg aagcaaaata tgctacatgt aattatacaa gagatagagg agggttcttg 114540
tcctatagtc atcgaaaaga acggagaatt gttgtcggta aacgattttg acaaagatgg 114600
tctaaaattc catctagact atattatcaa aatttggaaa cttcaaaaac gatattagaa 114660
tttatacgaa tatcgttctc taaatgtcac aatcaagtct cgcatgttca gcaatttatt 114720
gtcgtacttt atatcgtgtt cattaacgat atcttgcaaa atagtaatga ttctatcttc 114780
cttcgataga tattcttcag agattattgt cttatatttt ttcttgttat ccgatatgaa 114840
tttgataaga ctttgaacat tattgatacc cgtctgttta attttttcta cagatatttt 114900
agttttggca gattctatcg tatctgtcaa tagacatcca acatcgacat tcgacgtcaa 114960
ttgtctataa atcaacgtat aaattttaga aataacatta gcgaattgtt gtgcattgat 115020
gtcgttattc tgaaacagta tgattttagg tagcattttc ttaacaaaga gaacgtattt 115080
attgttactc agttgaacag atgatatatc cagattacta acgcatctga ttccgtatac 115140
caaactttca gaagaaatgg tgtacaattg tttgtattca ttcaatgtct ctttttcaga 115200
aattagttta gagtcgaata ctgcaataat tttcaagaga tagttttcat cagataagat 115260
tttatttagt gtagatatga taaaactatt gttttgttgg agaacttgat acgccgcgtt 115320
ctctgtagtc gacgctctca aatgggaaac aatctccatt atttttttgg aatcggatac 115380
tatatcttcg gtatcttgac gcagtctagt atacatagag ttaagagaga ttagagtttg 115440
tacattaagc aacatgtctc taaatgtggc tacaaacttt tcctttttca cataatctag 115500
tttattatat accgatttca caacggcacc agatttaagg aaccagaatg aaaaactctg 115560
ataactacaa tatttcatca tagttacgat tttatcatct tctatagttg gtgtaatagc 115620
gcataccttt ttctccaaga ctggaaccaa cgtcataaaa atgtttaaat caaaatccat 115680
atcaacatct gatgcgctaa gaccagtctc gcgttcaaga ttatctttac taatggtgac 115740
gaactcatca tatagaactc taagtttgtc cattatttat ttacagattt agttgtttaa 115800
tttatttgtg ctcttccaga gttgggatag tatttttcta acgtcggtat tatattatta 115860
ggatctacgt tcatatgtat cataatatta atcatccacg ttttgataaa tctatcttta 115920
gcttctgaaa taacgtattt aaacaaagga gaaaaatatt tagctacggc atcagacgca 115980
ataacatttt ttgtaaatgt aacgtattta gacgacagat cttcgttaaa aagttttcca 116040
tctatgtaga atccatcggt tgttaacacc attcccgcgt cagattgaat aggagtttga 116100
atagtttgtt ttggaaatag atccttcaat aacttatagt tgggtgggaa aaaatcgatt 116160
ttatcactag actctttctt ttttactatc attacctcat gaactatttc ttgaatgagt 116220
atatgtattt tctttcctat atcggacgcg ttcattggaa aatataccat gtcgttaact 116280
ataagaatat ttttatcctc gtttacaaac tgaataatat cagatgtagt tcgtaaacga 116340
actatatcat caccagcaca acatctaact atatgatatc cactagtttc ctttagccgt 116400
ttattatctt gttccatatt agcagtcatt ccatcattta agaaggcgtc aaagataata 116460
gggagaaatg acattttgga ttctgttacg actttaccaa aattaaggat atacggactt 116520
actatctttt tctcaacgtc gatttgatga acacacgatg aaaatgtgct tctatgagat 116580
tgatcatgta gaaaacaaca agggatacaa tatttccgca tatcatgaaa tatattaaga 116640
aatcccacct tattatattt ccccaaagga tccatgcatg taaacattat gccgttatca 116700
ttaataaaga cttctttctc atcggatttg taaaagttgt tactgatttt tttcattcca 116760
ggatctagat aattaataat gatgggtttt ctattcttat tctttgtatt ttggcatatc 116820
ctagaccagt aaacagtttc cactttggta aaatcagcag acttttgaac gctattaaac 116880
atggcattaa tggcaataac taaaaatgta aaatattttt ctatgttagg aatatggttt 116940
ttcactttaa tagatatatg gtttttggcc aaaatgatag atattttttt atccgaggat 117000
agtaaaatat tattagtcgc cgtctctata aaaatgaagc tagtctcgat atccaatttt 117060
attctagaat tgataggagt cgccaaatgt accttatacg ttatatctcc cttgatgcgt 117120
tccatttgtg tatctatatc ggacacaaga tctgtaaata gttttacgtt attaatcatc 117180
acggtatcgc cgtcgctaga taacgctaat gtaccatcca agtcccaaat ggagagattt 117240
aactgttcat cgtttagaat aaaatgatta ccggtcatat taataaagtg ttcatcgtat 117300
ctagataaca acgacttata attaatgtcc aagtcttgaa ctcgctgaat gatctttttt 117360
aacccagtta gttttagatt ggtacgaaat atattgttaa actttgattc tacagtaatg 117420
tccaaatcta gttgtggaaa tacttccatc aacattgttt caaacttgat aatattatta 117480
tctacatctt catacgatcc aaattccgga atagatgtat cacatgctct tgccacccag 117540
ataaccaaaa agtcacacgc tccaggatat acattgtata aaaagctatc gttttttagt 117600
agtgtttttt tctgagtata tacgaaggga ttaaaaatag tattatcaac gtaactatat 117660
tccaaattat tcttatgaga atagataata atatcgtcct taatatctaa caaatttcct 117720
aaatatccct ttaattgagt cattcgaagc gtcaatagaa tatgtctctt aactatttcc 117780
ggctgttgta tatttaaatg acttcgtaaa aaataatata tgggcgactt ctcatctatg 117840
taatcatatg gagtgagata tagggctcgt tctacctcct gccccttacc cacctgtaat 117900
accaattgcg gacttactat atatcgcata tttatatcgt ggggtaaagt gaaaatctac 117960
taccgatgat gtaagtctta caatgttcga accagtacca gatcttaatt tggaggcctc 118020
cgtagaacta ggggaggtaa atatagatca aacaacacct atgataaagg aaaatagcgg 118080
ttttatatcc cgtagtagac gtctattcgc ccatagatct aaggatgatg agagaaaact 118140
agcactacga ttctttttac aaagacttta ttttttagat catagagaga ttcattattt 118200
gttcagatgc gttgacgctg taaaagacgt cactattacc aaaaaaaata acattatcgt 118260
ggcgccttat atagcacttt taactatcgc atcaaaagga tgcaaactta cagaaacaat 118320
gattgaagca ttttttccag aactatataa tgaacatagt aagaaattta aattcaactc 118380
tcaagtatcc atcatccaag aaaaactcgg ataccagttt ggaaactatc acgtttatga 118440
ttttgaaccg tattactcta cagtagctct ggctattcga gatgaacatt catctggcat 118500
ttttaatatc cgtcaagaga gttatctggt aagttcatta tctgaaataa catatagatt 118560
ttatctaatt aatctaaaat ctgatcttgt tcaatggagt gctagtacgg gcgctgtaat 118620
taatcaaatg gtaaatactg tattgattac agtgtatgaa aagttacaac tggtcataga 118680
aaatgattca caatttacat gttcattggc tgtggaatca aaacttccaa taaaattact 118740
taaagataga aatgaattat ttacaaaatt cattaacgag ttaaaaaaga ccagttcatt 118800
caagataagc aaacgcgata aggatacgct actaaaatat tttacttagg actggagtta 118860
gaatttatag acgactcatt tcgtttatca ttgttactat tattactatt actatcatta 118920
ttagtgttgg cattattagt attcttcttg tcatcttgtt cagaaatata cagcaatgct 118980
atacctaata ctaaatacat tatcatgctc gcaatggctc taacaacaac gaaccaaaat 119040
gaatttggtc gtagcttttg ttcacaaaaa tacataaaga aatgtctaca taaatctatg 119100
gcgccattgg ctacttgaaa tagcgccagt cctcctacag attttaatat agctgtataa 119160
catgacattt attcatcatc aaaagagaca gagtcaccat ctgtcatatt tagatttttt 119220
ttcatgtgtt caaagtatcc tctactcatt tcattataat agtttatcat acttagaatt 119280
ttaggacgga tcaatgagta agacttgact agatcgtcag tagtaatttg tgcatcgtct 119340
attctgcatc cgcttcgtcg aataatgtat agcatcgctt tgagattctc catagctatc 119400
aagtctttat acaatgacat ggaaatatct gtgaatactt tatacttctc caacatcgat 119460
gccttaacat catcgcctac tttagcattg aaaatacgtt ctattgtgta gatggatgta 119520
gcaagatttt taaacaacaa tgccatctta cacgatgatt gcctcaagtc tccaatcttt 119580
tgtttagaac gattagctac agagttcaac gcttggctga ctagcatatt attatcttta 119640
gaaattgtat tcttcaatga ggcgtttatc atatctgtga tttcgttagt catattacag 119700
tctgactggg ttgtaatgtt atccaacata tcacctatgg atacggtaca cgtaccagca 119760
tttgtaataa tcctatctaa gatgttgtat ggcattgcgc agaaaatatc ttctcctgta 119820
atatctccac tctcgataaa tctactcaga ttattcttaa atgccttatt ctctggagaa 119880
aagatatcag tgtccatcat ttcattaata gtatacgcag aaaagatacc acgagtatca 119940
attctatcca agatacttat cggttccgag tcacagataa tggtttcctc tccttcggga 120000
gatcctgcat agaaatatct aggacaatag tttctatact gtctgtaact ctgataatct 120060
ctaaagtcac taactgatac catgaaattg agaagatcaa acgctgaagt aatcaatttt 120120
tctgcctcgt ttttactaca actagttttc atcaatgtag cgacgatgta ttgtttagtt 120180
actcttggtc taatactgat gatagagata ttattgcttc ccataatgga tcttctagta 120240
gtcaccttaa agcccattga tgcgaatagc agatagataa agtcttggta tgactccttt 120300
ctaatatagt acggactacc tttgtcaccc aactttatac ccacataagc cataacaacc 120360
tctttaatag ccgtttcatg aggtttatca gccatgagcc tgagtagttg gaagaatctc 120420
atgaatcccg tctcagaaag tcctatatgc atgatagatt tatctttcct gggaaactct 120480
cgtatagtca tagatgaaat actcttcaaa gtttctgaaa taagattagt aacagtctta 120540
cctccgacta ctctgggtaa caaacatact ctaataggtg ttttctctgc ggagataata 120600
tcagaaagga tagagcaata agtagtatta ttgtgattat aaagaccgaa tacataacag 120660
gtagaattta taaacatcat gtcctgaagg tttttagact tgtattcctc gtaatccata 120720
ccgtcccaaa acatggattt ggtaactttg atagccgtag atctttgttc cttcgccaac 120780
aggttaaaga aattaataaa gaatttgttg tttctattta tgtccacaaa ttgcacgttt 120840
ggaagcgcca cggttacatt cactgcagca ttttgaggat cgcgagtatg aagtacgatg 120900
ttattgttta ctggtatatc tggaaagaaa tctaccagtc taggaataag agattgatat 120960
cgcatagaaa tagtaaagtt tataatctca tcatcgaaga gcattttgtt accattgtaa 121020
taaatatcca ctctgtcata tgtataaatg aagtactgtt caaacatgat gagatgttta 121080
tatgttggca tagtagtgag atcgacgttt ggtaatggca atgtattaag attaactcca 121140
taatgtctag cagcatctgc gatgttataa gcgtcgtcaa agcggggtcg atcttgtatt 121200
gttatatatt gtctaacacc tataagatta tcaaaatctt gtctgcttaa tacaccgtta 121260
acaatttttg ccttgaattc ttttattggt gcattaataa catccttata gaggatgtta 121320
aacaaataag tgttatcaaa gttaagatct ggatatttct tttctgctag aacatccatt 121380
gagtcggagc catctggttt aatataacca ccgataaatc tagctctgta ttctgtatcc 121440
gtcaatctaa tattaagaag gtgttgagtg aaaggtggaa gatcgtaaaa gctgtgagta 121500
ttaatgatag gattagtttc cgaactaatg ttaattgggg tattaataat atctatattt 121560
ccagcgttaa gtgtaacatt aaacagtttt aattcacgtg acgtggtatc aattaaataa 121620
ttaatgccca atttggatat agcagcctga agctcatctt gtttagttac ggatcctaat 121680
gagttattaa gcaatatatc gaacggatga acgaaggttg ttttaagttg gtcacatact 121740
ttgtaatcta gacatagatg cggaagaacg gtagaaacta tacgaaataa atattcagag 121800
tcctctaatt gatcaagagt aactattgac ttaataggca tcatttattt agtattaaat 121860
gacgaccgta ccagtgacgg atatacaaaa cgatttaatt acagagtttt cagaagataa 121920
ttatccatct aacaaaaatt atgaaataac tcttcgtcaa atgtctattc taactcacgt 121980
taacaacgtg gtagatagag aacataatgc cgccgtagtg tcatctccag aggaaatatc 122040
ctcacaactt aatgaagatc tatttccaga tgatgattca ccggccacta ttatcgaacg 122100
agtacaacct catactacta ttattgacga tactccacct cctacttttc gtagagagtt 122160
attgatatcg gaacaacgtc aacaacgaga aaaaagattt aatattacag tatcgaaaaa 122220
tgctgaagca ataatggaat ctagatctat gataacttct atgccaacac aaacaccatc 122280
cttgggagta gtttatgata aagataaaag aattcagatg ttggaggatg aagtggttaa 122340
tcttagaaat caacgatcta atacaaaatc atctgataat ttagataatt ttaccaaaat 122400
actatttggt aagactccgt ataaatcaac agaagttaat aagcgtatag ccatcgttaa 122460
ttatgcaaat ttgaacgggt ctcccttatc agtcgaggac ttggatgttt gttcagagga 122520
tgaaatagat agaatctata aaacgattaa acaatatcac gaaagtagaa aacaaaaaat 122580
tatcgtcact aacgtgatta ttattgtcat aaacattatc gagcaagcat tgctaaaact 122640
cggatttgaa gaaatcaaag gactgagtac cgatatcact tcagaaatta tcgatgtgga 122700
gatcggagat gactgcgatg ctgtagcatc aaaactagga atcggtaaca gtccggttct 122760
taatattgta ttgtttatac tcaagatatt cgttaaacga attaaaatta tttaatttaa 122820
tacattccca tatccagaca acaatcgtct ggattaatct gttcctgtcg tctcataccg 122880
gacgacatat taatcttttt attagtaggc atctttttag atggtttctt tttcccagca 122940
ttaactgagt cgatacctag aagatcgtga ttgatctctc cgaccattcc acgaacttct 123000
aattggccgt ctctaacggt accataaact attttaccag cattagtaac agcttggaca 123060
atctgaccat ccatcgcatt gtacgatgta gtagtaactg ttgttctacg tctaggagca 123120
ccagaagtat ttttggagcc cttggaggct gatgtagaag aagacgagga ttttgatttt 123180
ggtttacatg taatacattt tgaactcttt gattttgtat cacatgcgcc ggcagtcaca 123240
tctgtttgag aattaagatt attgttgcct cctttgacgg ctgcatctcc accgatttgc 123300
gctagtagat ttttaagctg tggtgtaatc ttattaactg tttcgatata atcatcgtaa 123360
ctgcttctaa cggctaaatt ttttttatcc gccatttaga agctaaaaat atttttattt 123420
atacagaaga tttaactaga ttatacaatg aactaatatg atccttttcc agattattta 123480
caaacttggt attttttggt tctggaggag gcgaatttaa attcggactt ggattcggat 123540
tttgtgagtt cttgatctta ttatacatcg agtataggat ggcgacggta actgctacac 123600
aaataccgat caacaaaaga ataccaatca tttattgaca ataacttcac tattgatcaa 123660
gtatgcaata tatcatcttt tcactaaata agtagtaata atgattcaac aatgtcgaga 123720
tatatggacg ataataattt agttcatgga aatatcgcta tgattggtat gaatgactcc 123780
gctaactctg tggggcgcgc agtgctttcc ccacatagaa taaattagca ttccgactgt 123840
gataataata ccaagtataa acgccataat actcaatact ttccatgtac gagtgggact 123900
ggtagactta ctaaagtcaa taaaggcgaa gatacacgaa agaatcaaaa gaatgattcc 123960
agcgattagc acgccggaaa aataatttcc aatcataagc atcatgtcca tttaactaat 124020
aaaaatttta aatcgccgaa tgaacaaagt ggaatataaa ccatataaaa acaatagttt 124080
gtactgcaaa aataatatct atttttgttt tcgaagatat ggtaaaatta aatagtagta 124140
cacagcatgt tataactaac agcagcaacg gctcgtaatt acttatcatt tactagacga 124200
aaaggtggtg ggatattttc ttgctcaaat aatacgaata tatcacccat ccattttatg 124260
cgatgtttat atactctaat ctttaataga tctatagacg acgggtttac caacaatata 124320
gattttatcg attcatctaa tttaaaccct tccttaaacg tgaatgatct attatctggc 124380
ataacgatga ccctacctga tgaatcggac aatgtactgg gccatgtaga ataaattatc 124440
aacgaattat cgtctacgaa catttatatc atttgtttta attttaggac gcgaataaat 124500
agatataaaa tagaaaataa cagatattac aaccagtgtt atggccgcgc ccaaccaggt 124560
aggcagtttt attttatctt ttactacagg ttctcctgga tgtacgtcac caacggcgga 124620
cgtagttcta gtacaattag acgtaagttc cgcttgggaa ttttttaacg ctaaagagtt 124680
aacgttaatc gtgcacccaa cgtatttaca tctagttctt tgaacatctt gattataata 124740
taaccatttt ctatctctag attcgtcggt gcactcatgt aaccaacata ccctaggtcc 124800
taaatattta tctccggaat tagattttgg ataattcgcg caccaacaat ttctatttcc 124860
tttatgatcg ttacaaaaga cgtataatgc cgtatcccca aaagtaaaat aatcaggacg 124920
aataattcta ataaactcag aacaatatct cgcatccata tgtttggagc aaatatcgga 124980
ataagtagac atagccggtt tccgttttgc acgtaaccat tctaaacaat tggggtttcc 125040
aggatcgttt ctacaaaatc cagtcatgaa atcgtcacaa tgttctgtct tgtaattatt 125100
attaaatatt tttggacagt gtttggtatt tgtcttagaa caacattttg ccacgctatc 125160
actatcgccc aggagataat ccttttttat aaaatgacat cgttgcccgg atgctatata 125220
atcagtagcg tgttttaaat ccttaatata ttcaggagtt acctcgttct gataatagat 125280
taatgatcca ggacgaaatt tgaaagaact acatggttct ccatgaatta atacatattg 125340
tttagcaaat tcaggaacta taaaactact acaatgatct atcgacatac catctatcaa 125400
acaaaacttg ggtttaattt ctcccggaga tgtttcataa tagtacgtat aactttcttc 125460
tgcaaactta acagctctat tatattcagg ataattaaaa cctaattcca tatatttgtc 125520
tcgtatatct gctattcctg gtgctatttt gattctatta agagtaacag ctgcccccat 125580
tcttaataat cgtcagtatt taaactgtta aatgttggta tatcaacatc taccttattt 125640
cccgcagtat aaggtttgtt gcaggtatac tgttcaggaa tggttacatt tatacttctt 125700
ctatagtcct gtctttcgat gttcatcaca tatgcaaaga acagaataaa caaaataatg 125760
taagaaataa tattaaatat ctgtgaattc gtaaatacat tgattgccat aataattaca 125820
gcagctacaa tacacacaat agacattccc acagtgttgc cattacctcc acgatacatt 125880
tgagttacta agcaataggt aataactaag ctagtaagag gcaatagaaa agatgagata 125940
aatatcatca atatagagat tagaggaggg ctatatagag ccaagacgaa caaaatcaaa 126000
ccgagtaacg ttctaacatc attatttttg aagattccca aataatcatt cattcctcca 126060
taatcgtttt gcatcatacc tccatcttta ggcataaacg attgctgctg ttcctctgta 126120
aataaatctt tatcaagcac tccagcaccc gcagagaagt cgtcaagcat attgtaatat 126180
cttaaataac tcatttatat attaaaaaat gtcactatta aagatggagt ataatcttta 126240
tgccgaacta aaaaaaatga cttgtggtca acccctaagt ctttttaacg aagacgggga 126300
tttcgtagaa gttgaaccgg gatcatcctt taagtttctg atacctaagg gattttacgc 126360
ctctccttcc gtaaagacga gtctagtatt tgaaacatta acaacgaccg ataataaaat 126420
cactagtatc aatccaacaa atgcgccaaa gttatatcct cttcaacgca aagtcgtatc 126480
tgaagtagtt tctaatatga ggaaaatgat cgaatcaaaa cgtcctctat acattactct 126540
tcacttggcg tgtggatttg gtaagactat taccacgtgt tatcttatgg ctacacacgg 126600
tagaaaaacc gtcatttgcg tacccaataa aatgttaata catcaatgga agacacaggt 126660
agaggcagtc ggattggaac ataagatatc catagatgga gtaagtagtc tattaaagga 126720
actaaagact caaagtccgg atgtattaat agtagtcagt agacatctga caaacgatgc 126780
cttttgtaaa tatatcaata agcattatga tttgttcatc ttggatgaat cacatacgta 126840
taatctgatg aacaatacag cagttacaag atttttagcg tattatcctc cgatgatgtg 126900
ttatttttta actgctacac ctagaccagc taaccgaatt tattgtaaca gtattattaa 126960
tattgccaag ttatccgatc taaaaaaaac tatctatgcg gtagatagtt tttttgagcc 127020
atattccaca gacaatatta gacatatggt aaaacgacta gatggaccat ctaataaata 127080
tcatatatat accgagaagt tattatctgt agacgagcct agaaatcaac ttattcttaa 127140
taccctggta gaagaattca agtcaggaac tattaatcgc attttagtta ttactaaact 127200
acgtgaacat atggtattat tctacaaacg attattagat cttttcggac cagaggttgt 127260
atttatagga gacgcccaaa atagacgtac tccagatatg gtcaaatcaa tcaaggaact 127320
aaatagattt atattcgtat ccaccttatt ttattccggt actggtttag atattcctag 127380
tttggattcg ttgttcattt gctcggcagt aatcaacaat atgcaaatag agcaattact 127440
agggagggta tgtcgagaaa cagaactatt agataggacg gtatatgtat ttcctaacac 127500
atccatcaaa gaaataaagt acatgatagg aaatttcatg caacgaatta ttagtctgtc 127560
tgtagataaa ctaggattta aacaagaaag ttatcggaaa catcaagaat ccgatcccac 127620
ttctgtatgt acaacatcct ccagagaaga acgtgtatta aatagaatat ttaactcgca 127680
aaatcgttaa gaagtttaag cgacgatccg catgctgcgc aggccagtgt attacccctc 127740
atagtattaa tataatccaa tgatactttt gtgatgtcgg aaatcttaac caatttagac 127800
tgacaggcag aacacgtcat gcaatcatca tcgtcatcga taactgtagt cttgggcttc 127860
tttttgcggc tcttcattcc ggaacgcaca ttggtgctat ccatttaggt agtaaaaaat 127920
aagtcagaat atgccctata acacgatcgt gcaaaacctg gtatatcgtc tctatcttta 127980
tcacaatata gtgtatcgac atctttatta ttattgacct cgtttatctt ggaacatgga 128040
atgggaacat ttttgttatc aacggccacc tttgccttaa ttccagatgt tgtaaaatta 128100
taactaaaca gtctatcatc gacacaaatg aaattcttgt ttagacgttt gtagtttacg 128160
tatgcggctc gttcgcgtct cattttttca gatattgcag gtactataat attaaaaata 128220
agaatgaaat aacataggat taaaaataaa gttatcatga cttctagcgc tgatttaact 128280
aacttaaaag aattacttag tctgtacaaa agtttgaaat tttcagattc tgcggctata 128340
gaaaagtata attctttggt agaatgggga acatctactt actggaaaat aggcgtgcaa 128400
aaggtagcta atgtcgagac gtcaatatct gattattatg atgaggtaaa aaataaaccg 128460
tttaatattg atccgggcta ttacattttc ttaccggtat attttgggag cgtctttatt 128520
tattcgaagg gtaaaaatat ggtagaactt ggatctggaa actcttttca aataccagat 128580
gatatgcgaa gtgcgtgtaa caaagtatta gacagcgata acggaataga ctttctgaga 128640
tttgttttgt taaacaatag atggataatg gaagatgcta tatcaaaata tcagtctcca 128700
gttaatatat ttaaactagc tagtgagtac ggattaaaca tacccaaata tttagaaatt 128760
gaaatagagg aagacacatt atttgacgac gagttatact ctattataga acgctctttt 128820
gatgataaat ttccaaaaat atccatatcg tatattaagt tgggagaact taggcggcaa 128880
gttgtagact ttttcaaatt ctcgttcatg tatattgagt ccatcaaggt agatcgtata 128940
ggagataata tttttattcc tagcgttata acaaaatcag gaaaaaagat attagtaaaa 129000
gatgtagacc atttaatacg atctaaggtt agagaacata catttgtaaa agtaaaaaag 129060
aaaaacacat tttccatttt atacgactat gatgggaacg gaacagaaac tagaggagaa 129120
gtaataaaac gaattataga cactatagga cgagactatt atgttaacgg aaagtatttc 129180
tctaaggttg gtagtgcagg cttaaagcaa ttgactaata aattagatat taatgagtgc 129240
gcaactgtcg atgagttagt tgatgagatt aataaatccg gaactgtaaa acgaaaaata 129300
aaaaaccaat cagcatttga tttaagcaga gaatgtttgg gatatccaga agcagatttt 129360
ataacgttag ttaataacat gcggttcaaa atagaaaatt gtaaggttgt aaatttcaat 129420
attgaaaata ctaattgttt aaataacccg agtattgaaa ctatatatgg aaactttaac 129480
cagttcgtct caatctttaa tatcgtcacc gatgtcaaaa aaagattatt cgagtgaaat 129540
aatatgcgcc tttgatatag gtgcaaaaaa tcctgccaga actgttttag aagtcaagga 129600
taactccgtt agggtattgg atatatcaaa attagactgg agttctgatt gggaaaggcg 129660
catagctaaa gatttgtcac aatatgaata cactacagtt cttctagaac gtcagcctag 129720
aaggtcgccg tatgttaaat ttatctattt tattaaaggc tttttatatc atacatcggc 129780
tgccaaagtt atttgcgtct cgcctgtcat gtctggtaat tcatatagag atcgaaaaaa 129840
gagatcggtc gaagcatttc ttgattggat ggacacattc ggattgcgag actccgttcc 129900
ggatagacgc aaattagacg atgtagcgga tagtttcaat ttggctatga gatacgtatt 129960
agataaatgg aatactaatt atacacctta taataggtgt aaatctagaa attacataaa 130020
aaaaatgtaa taacgttagt aacgccatta tggataatct atttaccttt ctacatgaaa 130080
tagaagatag atatgccaga actattttta actttcatct aataagttgc gatgaaatag 130140
gagatatata tggtcttatg aaagaacgca tttcctcaga ggatatgttt gataatatag 130200
tatataataa agatatacat cctgccatta agaaactagt gtattgcgac atccaactta 130260
ctaaacacat tattaatcag aatacgtatc cggtatttaa cgattcttca caagtgaaat 130320
gttgtcatta tttcgacata aactcagata atagcaatat tagctctcgt acagtagaga 130380
tatttgagag ggaaaagtca tctcttgtat catatattaa aactaccaat aagaagagaa 130440
aggtcaatta cggcgaaata aagaaaactg ttcatggagg cactaatgca aattactttt 130500
ccggtaaaaa gtctgacgag tatctgagta ctacagttag atccaacatt aatcaacctt 130560
ggatcaaaac catttctaag agaatgagag tagatatcat taatcactct atagtaacgc 130620
gtggaaaaag ctctatatta caaactatag aaattatttt tactaataga acatgtgtga 130680
aaatattcaa ggattctact atgcacatta ttctatccaa ggacaaggat gaaaaggggt 130740
gtatacacat gattgacaaa ttattctatg tctattataa tttatttctg ttgttcgaag 130800
atatcatcca aaacgagtac tttaaagaag tagctaatgt tgtaaaccac gtacttacgg 130860
ctacggcatt agatgagaaa ttattcctaa ttaagaaaat ggctgaacac gatgtttatg 130920
gagttagcaa tttcaaaata gggatgttta acctgacatt tattaagtcg ttggatcata 130980
ccgttttccc ctctctgtta gatgaggata gcaaaataaa gttttttaag gggaaaaagc 131040
tcaatattgt agcattacga tctctggagg attgtataaa ttacgtgact aaatccgaga 131100
atatgataga aatgatgaag gaaagatcga ctattttaaa tagcatagat atagaaacgg 131160
aatcggtaga tcgtctaaaa gaattgcttc taaaatgaaa aaaaacactg attcagaaat 131220
ggatcaacga ctagggtata agtttttggt gcctgatcct aaagccggag ttttttatag 131280
accgttacat ttccaatatg tatcgtattc taattttata ttgcatcgat tgcatgaaat 131340
cttgaccgtc aagcggccac tcttatcgtt taagaataat acagaacgaa ttatgataga 131400
aattagcaat gttaaagtga ctcctccaga ttactcacct ataatcgcga gtattaaagg 131460
taagagttat gatgcattag ccacgttcac tgtaaatatc tttaaagagg taatgaccaa 131520
agagggtata tccatcacta aaataagtag ttatgaggga aaagattctc atttgataaa 131580
aattccgcta ctaataggat acgggaataa aaatccactt gatacagcca agtatcttgt 131640
tcctaatgtc ataggtggag tctttatcaa taaacaatct gtcgaaaaag taggaattaa 131700
tctagtagaa aagattacaa catggccaaa atttagggtt gttaagccaa actcattcac 131760
tttctcgttt tcctccgtat cccctcctaa tgtattaccg acaagatatc gccattacaa 131820
gatatctctg gatatatcac aattggaagc gttgaatata tcatcgacaa agacatttat 131880
aacggtcaat attgttttgc tgtctcaata tttatctaga gtgagtctag aattcattag 131940
acgtagttta tcatacgata tgcctccaga agttgtctat ctagtaaacg cgataataga 132000
tagtgctaaa cgaattactg aatctattac tgactttaat attgatacat acattaatga 132060
cctggtggaa gctgaacaca ttaaacaaaa atctcagtta acgatcaacg agttcaaata 132120
tgaaatgctg cataactttt tacctcatat gaactataca cccgatcaac taaagggatt 132180
ttatatgata tctttactaa gaaagtttct ctactgtatc taccacactt ctagatatcc 132240
agatagagat tcgatggttt gtcatcgcat cctaacgtac ggcaaatatt ttgagacgtt 132300
ggcacatgat gaattagaga attacatagg caacatccga aacgatatca tgaacaatca 132360
caagaacaga ggcacttacg cggtaaacat tcatgtacta acaactcccg gacttaatca 132420
cgcgttttct agcttattga gtggaaagtt caaaaagtca gacggtagtt atcgaacaca 132480
tcctcactat tcatggatgc agaatatttc tattcctagg agtgttggat tttatccgga 132540
tcaagtaaag atttcaaaga tgttttctgt cagaaaatac catccaagtc aatatcttta 132600
cttttgttca tcggacgttc cggaaagagg tcctcaggta ggtttagtat ctcaattgtc 132660
tgtcttgagt tccattacaa atatactaac gtctgagtat ttggatttgg aaaagaaaat 132720
ttgtgagtat atcagatcat attataaaga tgatataagt tactttgaaa caggatttcc 132780
aatcactata gaaaatgctc tagtcgcatc tcttaatcca aatatgatat gtgattttgt 132840
aactgacttt agacgtagaa aacggatggg attcttcggt aacttggagg taggtattac 132900
tttagttagg gatcacatga atgaaattcg cattaatatt ggagcgggaa gattagtcag 132960
accattcttg gttgtggata acggagagct catgatggat gtgtgtccgg agttagaaag 133020
cagattagac gacatgacat tctctgacat tcagaaagag tttccgcatg tcatcgaaat 133080
ggtagatata gaacaattta cttttagtaa cgtatgtgaa tcggttcaaa aatttagaat 133140
gatgtcaaag gatgaaagaa agcaatacga tttatgtgac tttcctgccg aatttagaga 133200
tggatatgtg gcatcttcat tagtgggaat caatcacaat tctggaccca gagctattct 133260
tggatgtgct caagctaaac aagctatctc ttgtctgagt tcggatatac gaaataaaat 133320
agacaatgga attcatttga tgtatccaga gaggccaatc gtgattagta aggctttaga 133380
aacttcaaag attgcggcta attgcttcgg ccaacatgtt actatagcat taatgtcgta 133440
caaaggtatc aatcaagagg atggaattat catcaaaaaa caatttattc agagaggcgg 133500
tctcgatata gttaccgcaa agaaacatca agtagaaatt ccgttggaaa actttaataa 133560
caaagaaaga gataggtcta acgcctattc aaaattagaa agtaatggat tagttagact 133620
gaatgctttc ttggaatccg gagacgctat ggcacgaaat atctcatcaa gaactcttga 133680
agatgatttt gctagagata atcagattag cttcgatgtt tccgagaaat ataccgatat 133740
gtacaaatct cgcgttgaac gagtacaagt agaacttact gacaaagtta aggtacgagt 133800
attaaccatg aaagaaagaa gacccattct aggagataaa tttaccacta gaacgagtca 133860
aaagggaaca gtcgcgtatg tcgcggatga aacggaactt ccatacgacg aaaatggtat 133920
cacaccagat gtcattatta attctacatc catcttctct agaaaaacta tatctatgtt 133980
gatagaggtt attttaacag ccgcatattc tgctaagccg tacaacaata agggagaaaa 134040
ccgacctgtc tgttttccta gtagtaacga aacatccatc gatacatata tgcaattcgc 134100
taaacaatgt tatgagcatt caaatccgaa attgtccgat gaagaattat cggataaaat 134160
cttttgtgaa aagattctct atgatcctga aacggataag ccttatgcat ccaaagtatt 134220
ttttggacca atttattact tgcgtctgag gcatttaact caggacaagg caaccgttag 134280
atgtagaggt aaaaagacga agctcattag acaggcgaat gagggacgaa aacgtggagg 134340
aggtatcaag ttcggagaaa tggagagaga ctgtttaata gcgcatggcg cagccaatac 134400
tattacagaa gttttaaaag actcagaaga ggattatcaa gatgtgtatg tttgtgaaaa 134460
ttgtggagac atagcagcac aaatcaaggg tattaataca tgtcttagat gttcaaaact 134520
taatctctct cctctcttaa caaaaattga taccacgcac gtatctaaag tatttcttac 134580
tcaaatgaac gccagaggcg taaaagtcaa attagatttc gaacgaaggc ctccttcgtt 134640
ttataaacca ttagataaag ttgatctcaa gccgtctttt ctggtgtaat attctagttt 134700
ggtagtagat acatatcaat atcatcaaat tcgagatccg aattataaaa tgggcgtgga 134760
ttgttaacta tagaatcgga cgtctgatat tcgaaaatct gtggagtttt aggttttggt 134820
ggaggtgtaa ctgctacttg ggatactgaa gtctgatatt cagaaagctg ggggatgttc 134880
tggttcgaca tccaccgatg gtgtcacatc actaatcggt tcggtaacgt ctgtggatgg 134940
aggtgctact tctacagaac ctgtagcctc agttgtcaac ggagatacat ttttaatgcg 135000
aggaaatgta taatttggta atggtttctc atgtggatct gaagaagagg taagatatct 135060
actagaaaga taccgatcac gttctagttc tcttttgtag aacttaactt tttctttctc 135120
agcatctagt tgatattcca acctcttcac gttactacgt tcagattcca attcacgttc 135180
gcatgggtta cctccgcagt ttttacgagc gatttcacgt tcagccttca tgcgtctctc 135240
cttctctcta tcgagtttat cagagcagtc tttctgaagg cgatcgaact ccataaattt 135300
ctccaacgct ttgattgttt ccatagattt ccgaagttca gcttttagga ctgtgattct 135360
ttttctttcg aattcacagc tggatgtgca accgtttcca ttaccgccat ctctaagttt 135420
cttttctaga tcggcaacat ttcatcccca tgccttttac attcctcgag tctactgtcg 135480
tcgaaatatc gttccagctc cttttcgaca tcaataactt tagcacgttg tctctcaagc 135540
tctcttttgt agttatctga ttccctggca cgtttaagat cttcatgcaa ttgagtcagc 135600
tcttaacaca atctcttgct tcttcgtcat agtacttaca atcactatgg gatccattgt 135660
taccacgtct acactcggcg agctcgcgtt taagagattc aatttcccgt ttgtattggt 135720
ccatgtttcc attgctacca ccattagatt tacaggctgc tagttgtcgt tcgagatcag 135780
aaatacgggt tttcttggaa ttgatttcgt cgatgtactt ggcatcgaaa cacttattaa 135840
gttctttttc caattctacg attttatttc tttcgcgagt caattccctc ctgtagtaac 135900
tatctgtttt gtcagattca cgctctctac gtagactttc ttgcaagtta ctaatttgtt 135960
ccctagcacg tccgagttta gttttatatg ctgaatagag ttctgattca tcctttgagc 136020
agatctctag cgatcgttta agattcctga ttctagtctt tagcctattt acctcctcag 136080
aagatgttcc gttaccgttg cgtttacact cgttaagctg tctatcaaga tccatgattc 136140
tatctctaag acgttgcatc tctctttcca tatcagcatt gctttcatta ttacgtctgc 136200
agtcactcaa ctgtctttca atatctgaga ttctatctct aagacgtcgc atctctctct 136260
gtttcggcat tggtttcatt attacgtcta cagtcgttca actgtctttc aagatctgat 136320
attctagatt ggagtctgct aatctctgta gcattttcac ggcattcact cagttgtctt 136380
tcaagatctg agattttaga ttggagtctg ctaatctctg taagatttcc tcctccgctc 136440
tcgatgcagt cggtcaactt attctctagt tctctaatac gcgaacgcag tgcatcaact 136500
tcttgcgtgt cttcctggtt gcgtgtacat tcatcgagtc tagattcgag atctctaacg 136560
cgtcgtcgtt cttcctcaag ttctctgcgt actacagaaa gcgtgtccct atcttgttga 136620
tatttagcaa tttctgattc tagagtactg attttgctta cgtagttact aatagttgtc 136680
ttggccttat caagatcctc cttgtatttg tcgcattcct tgatatccct acgaagtctg 136740
gacagttccc attcgacatt acgacgttta tcgatttcag ctcggagatc gtcatcgcgt 136800
tgttttagcc acatacgact gagttcaagt tctcgttgac aagatccatc tacttttcca 136860
ttcctaatag tatccagttc cttttctagt tctgaacgca tttctcgttc cctatcaagc 136920
gattctctca attctcggat agtcttctta tcaatttcta ataaatctga accatcatct 136980
gtcccatttt gaatatccct gtgttctttg atctcttttg taagtcggtc gattctttcg 137040
gttttataaa cagaatccct ttccaaagtc ctaatcttac tgagtttatc actaagttct 137100
gcattcaatt cggtgagttt tctcttggct tcttccaact ctgttttaaa ctctccacta 137160
tttccgcatt cttcctcgca tttatctaac cattcaatta gtttattaat aactagttgg 137220
taatcagcga ttcctatagc cgttcttgta attgtgggaa cataattagg atcttctaat 137280
ggattgtatg gcttgatagc atcatcttta tcattattag ggggatggac aaccttaatt 137340
ggttggtcct catctcctcc agtagcgtgt ggttcttcaa taccagtgtt agtaataggc 137400
ttaggcaaat gcttgtcgta cgcgggcact tcctcatcca tcaagtattt ataatcgggt 137460
tctacgtctg aatattcttt tctaagagac gcgacttcgg gagttagtag aagaactctg 137520
tttctgtatc tatcaacgct ggaatcaata ctcaagttaa ggatagcgaa tacctcatcg 137580
tcatcatccg tatcttctga aacaccatca tatgacattt catgaagtct aacgtattga 137640
taaatagaat cagatttagt attaaacaga tccttaacct ttttagtaaa cgcatatgta 137700
tattttagat ctccagattt cataatatga tcacatgcct taaatgtcag tgcttccatg 137760
atataatctg gaacactaat gggtgacgaa aaagatacag caccatatgc tacgttgata 137820
aataaatctg aaccactaag tagataatga ttaatgttaa ggaagaggaa atattcagta 137880
tatagatatg ccttagcatc atatcttgta ctaaacacgc taaacagttt attgatgtga 137940
tcaatttcca acagaataat tagagcagcg ggaataccaa caaacatatt accacatccg 138000
tattttctat gaatatcaca tatcatgtta aaaaatcttg atagaagagc gaatatctcg 138060
tctgacttaa tgagtcgtag ttcagcagca acataagtca taactgtaaa tagaacatac 138120
tttcctgtag tgttgattct agactccaca tcaacaccat tattaaaaat agttttatat 138180
acatctttaa tctgctctcc gttaatcgtc gaacgttcta gtatacggaa acactttgat 138240
ttcttatctg tagttaatga cttagtgata tcacgaagaa tattacgaat tacatttctt 138300
gtttttcttg agagacctga ttcagaactc aactcatcgt tccatagttt ttttacctca 138360
gtggcgaaat ctttggagtg cttggtacat ttttcaataa ggttcgtgac ctccatttat 138420
tataaaaaat tttattcaaa acttaactac aatcgggtaa ttataaaatc gtagatctcc 138480
catgtggtgg aatactacca tctatcgcat gtggatggac agtaggtaat ggccatggga 138540
acagtaatgt ttgcatattt atctttcttg ccagtattac tgcatattgt cccaatgttt 138600
cgatgtgatg ttctaaccta tcaactgccg ctgtatcaca acaatagtgt ccgatgaaat 138660
taagattatg atccaatgtg tttaatatat gattatcaag tcttatacga tccgcgtctt 138720
ttttgacagg atcaggttct tctacaggaa gaagtttcgg cctcttatga tattcatgtc 138780
tgggaaacgg tggtctaggg tgaggctccg gtatcggagt gggttttgga ttataatcat 138840
catcgtctat gacatcatct tcgacttcga tatttatttt gctatcttga tgatgtcctg 138900
tatcagttgc attttcagca ctcgactgaa tattagcgca ttcattgtct attattacca 138960
tatttctaaa cccaaaatgt atgtgttgaa catcagtact atcgttgatg agtcttatag 139020
catgaattcg cttatcgtta tcgggtttat cttctgtcac cttagcaatt ccttttttat 139080
taaactctac ataatcatat ccatttctat tgtttgttct aatataaacg agtatagcat 139140
cattgctaaa tttttcaata gtatcgaaaa cagaatatcc taaaccatat aatatatatt 139200
cagggacact caaactaaat gtccaggatt ctcctaaata cgtaaacttt aatagtgcga 139260
aatcattcaa aaatctacca cttatagata gatagtacat aaatgcgtat agtagtctac 139320
ctatctcttt attatgaaaa ccggcattac gatcatatat gtcgtgatat acctgtgatc 139380
cgtttacgtt aaaccataaa tacatgggtg atcctataaa catgaattta tttctaattc 139440
tcagagctat agttaattga ccgtgtaata tttgcttaca tgcatacttg atacgctcat 139500
taataaaatt tttatcattg ctcgttatct cagaatcgta tatataagga gtaccatcgt 139560
gattcttacc agatattata caaaatacta tatataaaat atattgacca acgttagtaa 139620
tcatataaat gtttaacgtt ttaaattttg tattcaatga tccattatca tacgctagca 139680
tggtcttatg atattcattc tttaaaatat aatattgtgt tagccattgc attggggctc 139740
ctaatggaga ttttttattc tcatccattt taggataggc tttcataaag tccctaataa 139800
cttcgtgaat aatgtttcta tgttttctac tgatgcatgt atttgcttcg atttttttat 139860
cccatgtttc atctatcata gatttaaacg cagtaatgct cgcaacatta acatcttgaa 139920
ccgttggtac aattccgttc cataaattta taatgttcgc catttatata actcattttt 139980
tgaatatact tttaattaac aaaagagtta agttactcat atgggcgccg tccagtctga 140040
acatcaatct ttttagccag agatatcata gccgctctta gagtttcagc gtgattttcc 140100
aacctaaata gaacttcatc gttgcgttta caacactttt ctatttgttc aaactttgtt 140160
gttacattag taatcttttt ttccaaatta gttagccgtt gtttgagagt ttcctcattg 140220
tcgtcttcat cggctttaac aattgcttcg cgtttagcct ctggcttttt agcagccttt 140280
gtagaaaaaa attcagttgc tggaattgca agatcgtcat ctccggggaa aagagttccg 140340
tccatttaaa gtacagattt tagaaactga cactctgcgt tatttatatt tggtacaaca 140400
catggattat aaatatcgat gttaataaca tcagaaaatg taaagtctat acattgttgc 140460
atcgtgttaa attttctaat ggatctagta ttattgggtc caacttctgc ctgaaatcca 140520
aatatggaag cggatacaaa accgtttcct ggataaacca cacatctcca cttttgcttt 140580
acatcagaaa ttgtgtcgtt gacatcttga actctcctat ctaatgccgg tgttccacct 140640
atagattttg aatattcgaa tgctgcatga gtagcattaa attccttaat attgccataa 140700
ttttcatata ttgagtaacc ctggataaaa agtaaacaca ccgcagccgt cgctaccaca 140760
ataaaaaaaa ttgatagaga gttcatttat aatctattag aagctgacaa aattttttta 140820
cacgcatcag acaatgcttt aataaatagt tcaacatcta cttttgtcat atcgaaccga 140880
tggtatgatt ctaacctaga attacatccg aaaaagttga ctatgttcat agtcattaag 140940
tcattaacaa acaacattcc agactctgga ttataagacg atactgtttc gtcacaatta 141000
cctaccttaa tcatgtgatt atgaatattg gctattagag caccttctaa gaaatctata 141060
atatctttga aacacgattt aaaatcaaac cacgaatata cttctacgaa gaaagttagt 141120
ttacccatag gagaaataac tataaatgga gatctaaata caaaatccgg atctatgata 141180
gttttaacat tattatattc tctattaaat acctccacat ctaaaaatgt taattttgaa 141240
actatgtctt cgtttattac cgtacctgaa ctaaacgcta taagctctat tgtttgagaa 141300
ctctttaaac gatattcttg aaatacatgt aacaaagttt cctttaactc ggtcggttta 141360
tctaccatag ttacagaatt tgtatcctta tctataatat aataatcaaa atcgtataaa 141420
gttatataat tatcgcgttc agattgggat cttttcaaat agactaaaaa ccccatttct 141480
ctagtaagta tcttatgtat atgtttgtaa aatatcttca tggtgggaat atgctctacc 141540
gcagttagcc attcctcatt gacagcggta gatgtattag acaaaactat tccaatgttt 141600
aacaagggcc attttacgag attattaaat ccttgtttga taaatgtagc caatgagggt 141660
tcgagttcaa cgacgattga attctcttcc cgcggatgct gcatgatgaa cgacgggatg 141720
ttgttcgatt gatttggaat tctttttcga ctttttgttt atattaaata ttttaaaatt 141780
tatagcggat agcaattcat gtaccacgga taatgtagac gcgtattgcg catcgatatc 141840
tttattatta gataaattta tcaataaatg tgagaagttt gcctcgttaa ggtcttccat 141900
ttaaatatta tataaacatt tgtgtttgta tcttattcgt cttttatgga atagtttttt 141960
actagtaaag ctgcaattac acactttgtc cgtaaaacat aaatataaac accagctttt 142020
atcaatcgtt ccaaaaagtc gacggcggac atttttaaca tggcatctat tttaaataca 142080
cttaggtttt tggaaaaaac atcattttat aattgtaacg attcaataac taaagaaaag 142140
attaagatta aacataaggg aatgtcattt gtattttata agccaaagca ttctaccgtt 142200
gttaaatact tgtctggagg aggtatatat catgatgatt tggttgtatt ggggaaggta 142260
acaattaata atctaaagat gatgctattt tacatggatt tatcatatca tggagtgaca 142320
agtagtggag caatttacaa attgggatcg tctatcgata gactttctct aaataggact 142380
attgttacaa aagttaataa ttatgatgat acattttttg acgacgatga ttgatcgcta 142440
ttgcacaatt ttgttttttt actttctaat atagcgttta gattcttttt catgtgcgaa 142500
tattgattta ctaaaatatc gatgtttaac ttttgttcta tgacgtcctt atcagcggta 142560
tcggtacata tacgtaattc accttcacaa aatacggagt cttcgataat aatagccaat 142620
cgattattgg atctagctgt ctgtatcata ttcaacatgt ttaatatatc ctttcgtttc 142680
ccctttacag gcatcgatcg tagcatattt tccgcgtctg agatggaaat gttaaaacta 142740
caaaaatgcg taatgttagc ccgtcctaat attggtacgt gtctataagt ttggcatagt 142800
agaataatag acgtgtttaa atgccttcca aagtttaaga attctattag agtattgcat 142860
tttgatagtt tatcacctac atcatcaaaa ataagtaaaa agtgtgctga ttttttatga 142920
ttttgtgcga cagcaataca tttttctatg ttacttttag ttcgtatcag attatattct 142980
agagattcct gactactaac gaaattaata tgatttggcc aaatgtatcc atcataatct 143040
gggttataaa cgggtgtaaa caagaatata tgtttatatt ttttaactag tgtagaaaac 143100
agagatagta aatagatagt ttttccagat ccagatcctc ccgttaaaac cattctaaac 143160
ggcattttta ataaattttc tcttgaaaat tgtttttctt ggaaacaatt cataattata 143220
tttacagtta ctaaattaat ttgataataa atcaaaatat ggaaaactaa ggtcgttagt 143280
agggaggaga acaaagaagg cacatcgtga cataaataac atttattatc atgatgacac 143340
cagaaaacga cgaagagcag acatctgtgt tctccgctac tgtttacgga gacaaaattc 143400
aaggaaagaa taaacgcaaa cgcgtgattg gtctatgtat tagaatatct atggttattt 143460
cactactatc tatgattacc atgtccgcgt ttctcatagt gcgcctaaat caatgcatgt 143520
ctgctaacga ggctgctatt actgacgccg ctgttgccgt tgctgctgca tcatctactc 143580
atagaaaggt tgcgtctagc actacacaat atgatcacaa agaaagctgt aatggtttat 143640
attaccaggg ttcttgttat atattacatt cagactacca gttattctcg gatgctaaag 143700
caaattgcac tgcggaatca tcaacactac ccaataaatc cgatgtcttg attacctggc 143760
tcattgatta tgttgaggat acatggggat ctgatggtaa tccaattaca aaaactacat 143820
ccgattatca agattctgat gtatcacaag aagttagaaa gtatttttgt gttaaaacaa 143880
tgaactaata tttatttttg tacattaata aatgaaatcg cttaatagac aaactgtaag 143940
taggtttaag aagttgtcgg tgccggccgc tataatgatg atactctcaa ccattattag 144000
tggcatagga acatttctgc attacaaaga agaactgatg cctagtgctt gcgccaatgg 144060
atggatacaa tacgataaac attgttattt agatactaac attaaaatgt ctacagataa 144120
tgcggtttat cagtgtcgta aattacgagc cagattgcct agaccggata ctagacatct 144180
gagagtattg tttagtattt tttataaaga ttattgggta agtttaaaaa agaccaatga 144240
taaatggtta gatattaata atgataaaga tatagatatt agtaaattaa caaattttaa 144300
acaactaaac agtacgacgg atgctgaagc gtgttatata tacaagtctg gaaaactggt 144360
taaaacagta tgtaaaagta ctcaatctgt actatgtgtt aaaaaattct acaagtgaca 144420
acaaaaaatg aattaataat aagtcgttaa cgtacgccgc catggacgcc gcgtttgtta 144480
ttactccaat gggtgtgttg actataacag atacattgta tgatgatctc gatatctcaa 144540
tcatggactt tataggacca tacattatag gtaacataaa aactgtccaa atagatgtac 144600
gggatataaa atattccgac atgcaaaaat gctactttag ctataagggt aaaatagttc 144660
ctcaggattc taatgatttg gctagattca acatttatag catttgtgcc gcatacagat 144720
caaaaaatac catcatcata gcatgcgact atgatatcat gttagatata gaagataaac 144780
atcagccatt ttatctattc ccatctattg atgtttttaa cgctacaatc atagaagcgt 144840
ataacctgta tacagctgga gattatcatc taatcatcaa tccttcagat aatctgaaaa 144900
tgaaattgtt gtttaattct tcattctgca tatcagacgg caatggatgg atcataattg 144960
atgggaaatg caatagtaat tttttatcat aaaagttgta aagtaaataa taaaacaata 145020
aatattgaac tagtagtacg tatattgagc aatcagaaat gatgctggta cctcttatca 145080
cggtgaccgt agttgcggga acaatattag tatgttatat attatatatt tgtaggaaaa 145140
agatacgtac tgtctataat gacaataaaa ttatcatgac aaaattaaaa aagataaaga 145200
gttctaattc cagcaaatct agtaaatcaa ctgatagcga atcagactgg gaggatcact 145260
gtagtgctat ggaacaaaac aatgacgtag ataatatttc taggaatgag atattggacg 145320
atgatagctt cgctggtagt ttaatatggg ataacgaatc caatgtcatg gcgcctagca 145380
cagaacacat ttacgatagt gttgctggaa gcacgctgct aataaataat gatcgtaatg 145440
aacagactat ttatcagaac actacagtag taattaatga gacggagact gttgaagtac 145500
ttaatgaaga taccaaacag aatcctaact attcatccaa tcctttcgta aattataata 145560
aaaccagtat ttgtagcaag tcaaatccgt tcattacaga actcaacaat aaatttagtg 145620
agaataatcc gtttagacga gcacatagcg atgattatct taataagcaa gaacaagatc 145680
atgaacacga tgatatagaa tcatcggtcg tatcattggt gtgattagtt tcctttttat 145740
aaaattgaag taatatttag tattattgct gccgtcacgt tgtacaaatg gagatattcc 145800
ctgtattcgg catttctaaa attagcaatt ttattgctaa taatgactgt agatattata 145860
tagatacaga acatcaaaaa attatatctg atgagatcaa tagacagatg gatgaaacgg 145920
tacttcttac caacatctta agcgtagaag ttgtaaatga caatgagatg taccatctta 145980
ttccccatag actatcgact attatactct gtattagttc tgtcggagga tgtgttatct 146040
ctatagataa tgacatcaat gacaaaaata ttctaacatt tcccattgat catgctgtaa 146100
tcatatcccc actgagtaaa tgtgtcgtag ttagcaaggg tcctacaacc atattggttg 146160
ttaaagcgga tatacccagc aaacgattgg taacatcgtt tacaaacgac atactgtatg 146220
taaacaatct gtcactgatt aattatttgc cgttgtctgt attcattatt agacgagtca 146280
ccgactattt ggatagacac atatgcgatc agatatttgc gaataataag tggtattcca 146340
ttataaccat cgacgataag caatatccta ttccatcaaa ctgtataggt atgtcctctg 146400
ccaagtacat aaattctagc atcgagcaag atactttaat acatgtttgt aacctcgagc 146460
atccattcga cttagtatac aaaaaaatgc agtcgtacaa ttctgtacct atcaaggaac 146520
aaatattgta cggtagaatt gataatataa atatgagcat tagtatttct gtggattaat 146580
agatttctag tatggggatc attaatcatc tctaatctct aaatacctca taaaacgaaa 146640
aaaaagctat tatcaaatac tgtacggaat ggattcattc tcttctcttt ttatgaaact 146700
ctgttgtata tctactgata aaactggaag caaaaaatct gataaaaaga ataagaataa 146760
gatcaaggat tatatggaac acgattatta taaaataaca atagttcctg gttcctcttc 146820
cacgtctact agctcgtggt attatacaca tgcctagtaa tagtctcttt gcgttgacgg 146880
aaagcagact agaaataaca ggctaaaatg ttcagacacc ataatagttc ccaacccaga 146940
taataacaga gtaccatcaa cacattcctt taaactcaat cccaaaccca aaaccgttaa 147000
aatgtatccg gccaattgat agtagataat gaggtgtaca gcgcatgata atttacacag 147060
taaccaaaat gaaaatactt tagtaattat aagaaatata gatggtaacg tcatcatcaa 147120
caatccaata atatgccgga gagtaaacat tgacggataa aacaaaaatg ctccgcataa 147180
ctctatcatg gcaataacac aaccaaatac ttgtaagatt cctaaattag tagaaaatac 147240
aacggatatc gatgtataag tgatctcgag aaataataag aataaagtaa tgcccgtaaa 147300
gataaacatc aacattgttt ggtaatcatt aaaccaatta gtatgaagtt gaactaattt 147360
cacagtagat tttattccag tgttatcctc gcatgtatac gtacctggta agatatcttt 147420
atattctata atcaatgaga catcactatc cgataacgaa tgaagtctag cactagtatg 147480
ccatttactt aatatggtcg tcttggaagt tttattataa gttaaaatat catggttgtc 147540
caatttccat ctaatatact ttgtcggatt atctatagta cacggaataa tgatggtatt 147600
attacatgct gtatactcta tagtctttgt agatgttata atcataaaag tacagaggta 147660
tatcaacgat attctaactc ttgacatttt ttatttattt aaaatgatac ctttgttatt 147720
tattttattc tattttgcta acggtatcga atggcataag tttgaaacga gtgaagaaat 147780
aatttctact tacttattag acgacgtatt atacacgggt gttaatgggg cggtatacac 147840
attttcaaat aataaactaa acaaaactgg tttagctaat actaattata tcacaacatc 147900
tataaaagta gaggatgcgg ataaggatac attagtatgc ggaaccaata acggaaatcc 147960
caaatgttgg aaaatagacg gttcagacga cccaaaacat agaggtagag gatacgctcc 148020
ttatcaaaat agcaaagtaa cgataatcag tcacaacgga tgtgtactat ctgacataaa 148080
catatcaaaa gaaggaatta aacgatggag aagatttgac ggaccatgtg gttatgattt 148140
atacacggcg gataacgtaa ttccaaaaga tggtttacga ggagcattcg tcgataaaga 148200
tggtacttat gacaaagttt acattctttt cactgatact atcggctcaa agagaattgt 148260
caaaattccg tatatagcac aaatgtgcct aaacgacgaa ggtggtccat catcattgtc 148320
tagtcataga tggtcgacgt ttctcaaagt cgaattagaa tgtgatatcg acggaagaag 148380
ttatagacaa attattcatt ctagaactat aaaaacagat aatgatacga tactatatgt 148440
attcttcgat agtccgcatt atgtacctat tctatgaata ccattaaaca atctttttct 148500
acgtcaaaat tggaaggata tacaaagcaa ttgccgtctc cagctcctgg tatatgtcta 148560
ccagctggaa aagttgttcc acataccacg tttgaagtca tagaaaaata taatgtacta 148620
gatgatatta taaagccttt atctaaccaa cctatcttcg aaggaccgtc tggtgttaaa 148680
tggttcgata taaaggagaa ggaaaatgaa catcgggaat atagaatata cttcataaaa 148740
gaaaattcta tatattcgtt cgatacaaaa tctaaacaaa ctcgtagctc gcaagtcgat 148800
gcgcgactat tttcagtaat ggtaacttcg aaaccgttat ttatagcaga tatagggata 148860
ggagtaggaa tgccacaaat gaaaaaaata cttaaaatgt aatcttaatc gagtacacca 148920
cacgacaatg aacaaacata agacagatta tgctggttat gcttgctgcg taatatgcgg 148980
tctaattgtt ggaattattt ttacagcgac actattaaaa gttgtagaac gtaaattagt 149040
tcatacacca tcaatagata aaacgataaa agatgcatat attagagaag attgtcctac 149100
tgactggata agctataata ataaatgtat ccatttatct actgatcgaa aaacctggga 149160
ggaaggacgt aatgcatgca aagctctaaa tccaaattcg gatctaatta agatagagac 149220
tccaaacgag ttaagttttt taagaagcat tagacgcgga tattgggtag gagaatccga 149280
aatattaaac cagacaaccc catataattt tatagctaag aatgccacga agaatggaac 149340
taaaaaacgg aaatatattt gtagcacaac gaatactccc aaactgcatt cgtgttacac 149400
tatataacaa ttacactaca tttttatcat accactactt cggttagatg ttttagaaaa 149460
aaataaatat cgccgtaccg ttcttgtttt tataaaaata acaattaaca attatcaaat 149520
tttttcttta atattttacg tggttgacca ttcttggtgg taaaataatc tcttagtgtt 149580
ggaatggaat gctgtttaat gtttccacac tcatcgtata ttttgacgta tgtagtcaca 149640
tcgtttacgc aatagtcaga ctgtagttct atcatgcttc ctacattaga aggaggaaca 149700
gttttaaagt ctcttggttt taatctatta ccgttagttt tcatgaaatc ctttgtttta 149760
tccacttcac attttaaata aatgtccact atacattctt ctgttaattt tactagatcg 149820
tcatgggtca tagaatttat aggttccgta gtccatggat ccaaactagc aaacttcgcg 149880
tatacggtat cgcgattagt gtatacacca actgtatgaa aattaagaaa acagtttaat 149940
agatcaacag aaatatttaa tcctccgttt gatacagatg caccatattt atggattttg 150000
gattcacacg ttgtttgtct gaggggttcg tctagcgttg cttctacata aacttctatt 150060
cccatatatt ctttattgtc agaatcgcat accgatttat catcatacac tgtttgaaaa 150120
ctaaatggta tacacatcaa aataacaaat actaacgagt acattctgca atattgttat 150180
cgtaattgga aaaatagtgt tcgagtgagt tggattatgt gagtattgga ttgtatattt 150240
tattttatat tttgtaataa gaataaaatg ctaatgtcaa gtttattcca atagatgtct 150300
tattaaaaac atatataata aataacaatg gctgaatggc ataaaattat cgaggatatc 150360
tcaaaaaata ataagttcga ggatgccgcc atcgttgatt acaagactac aaagaatgtt 150420
ctagctgcta ttcctaacag aacatttgcc aagattaatc cgggtgaaat tattcctctc 150480
atcactaatc gtaatattct aaaacctctt attggtcaga aatattgtat tgtatatact 150540
aactctctaa tggatgagaa cacgtatgct atggagttgc ttactgggta cgcccctgta 150600
tctccgatcg ttatagcgag aactcatacc gcacttatat ttttgatggg taagccaaca 150660
acatccagac gtgacgtgta tagaacgtgt agagatcacg ctacccgtgt acgcgcaact 150720
ggtaattaaa ataaaaagta atattcatat gtagtgtcaa ttttaaatga tgatgatgaa 150780
atggataata tccatattga cgatgtcaat aatgccggta ttggcataca gctcatcgat 150840
ttttagattt cattcagagg atgtggaatt atgttatggg catttgtatt ttgataggat 150900
ctataatgta gtaaatataa aatataatcc gcatattcca tatagatata attttattaa 150960
tcgcacgtta accgtagatg aactagacga taatgtcttt tttacacatg gttatttttt 151020
aaaacacaaa tatggttcac ttaatcctag tttgattgtc tcattatcag gaaacttaaa 151080
atataatgat atacaatgct cagtaaatgt atcgtgtctc attaaaaatt tggcaacgag 151140
tacatctact atattaacat ctaaacataa gacttattct ctacatcggt ccacgtgtat 151200
tactataata ggatacgatt ctattatatg gtataaagat ataaatgaca agtataatgg 151260
catctatgat tttactgcaa tatgtatgct aatagcgtct acattgatag tgaccatata 151320
cgtgtttaaa aaaataaaaa tgaactctta attatgctat gctattagaa atggataaaa 151380
tcaaaattac ggttgattca aaaattggta atgttgttac catatcgtat aacttggaaa 151440
agataactat tgatgtcaca cctaaaaaga aaaaagaaaa ggatgtatta ttagcgcaat 151500
cagttgctgt cgaagaggca aaagatgtca aggtagaaga aaaaaatatt atcgatattg 151560
aagatgacga tgatatggat gtagaaagcg cataatacga tctataaaaa taagtatata 151620
aatacttttt atttactgta ctcttactgt gtagtggtga taccctactc gattattttt 151680
ttaaaaaaat acttattctg attcttctag ccatttccgt gttcgttcga atgccacatc 151740
gacgttaaag ataggggagt agttgaaatc tagttctgca ttgttggtac gcacctcaaa 151800
tgtagtgttg gatatcttca acgtatagtt gttgagtagt gatggttttc taaatagaat 151860
tctcttcata tcattcttgc acgcgtacat ttttagcatc catcttggaa ttctagatcc 151920
ttgttctatt cccaatggtt tcatcaatag aagattaaac atatcgtacg aacacgatgg 151980
agagtaatcg tagcaaaagt aagcatttcc tttaatctca gatcccggat actggatata 152040
ttttgcagcc aacacgtgca tccatgcaac atttcctaca tatacccggc tatgcaccgc 152100
gtcatcatcg actgtacgat acataatgtt accgtgttgc ttacattgct cgtaaaagac 152160
tttcgtcaat ttgtctcctt ctccgtaaat tccagtgggt cttaggcaac aagtatacaa 152220
ttttgctcca ttcatgatta cggaattatt ggctttcata accagttgct cggccatacg 152280
tttacttttt gcgtatacat gtcctggtga tatatcataa agggtatgct catggccgat 152340
gaatggatca ccgtgtttat ttggtcctat tgcttccatg ctactagtat agatcaaata 152400
cttgattcct aggtccacac aagctgccaa tatagtctgt gttccataat agtttacttt 152460
catgatttca ttatcggtgt attttccaaa tacatccact agagcagccg tatgaataat 152520
cagatttacc ccatctagcg cttctctcac cttatcaaag tcgtttatat cacattgtat 152580
atagtttata accttaactt tcgaggttat tggttgtgga tcttctacaa tatctatgac 152640
tctgatttct tgaacatcat ctgcactaat taacagtttt actatatacc tgcctagaaa 152700
tccggcacca ccagtaaccg cgtacacggc cattgctgcc actcataata tcagactact 152760
tattctattt tactaaataa tggctgtttg tataatagac cacgataata tcagaggagt 152820
tatttacttt gaaccagtcc atggaaaaga taaagtttta ggatcagtta ttggattaaa 152880
atccggaacg tatagtttga taattcatcg ttacggagat attagtcaag gatgtgattc 152940
cataggcagt ccagaaatat ttatcggtaa catctttgta aacagatatg gtgtagcata 153000
tgtttattta gatacagatg taaatatatc tacaattatt ggaaaggcgt tatctatttc 153060
aaaaaatgat cagagattag cgtgtggagt tattggtatt tcttacataa atgaaaagat 153120
aatacatttt cttacaatta acgagaatgg cgtttgatat atcagttaat gcgtctaaaa 153180
caataaatgc attagtttac ttttctactc agcaaaataa attagtcata cgtaatgaag 153240
ttaatgatac acactacact gtcgaatttg atagggacaa agtagttgac acgtttattt 153300
catataatag acataatgac accatagaga taagaggggt gcttccagag gaaactaata 153360
ttggttgcgc ggttaatacg ccggttagta tgacttactt gtataataag tatagtttta 153420
aactgatttt agcagaatat ataagacaca gaaatactat atccggcaat atttattcgg 153480
cattgatgac actagatgat ttggctatta aacagtatgg agacattgat ctattattta 153540
atgagaaact taaagtagac tccgattcgg gactatttga ctttgtcaac tttgtaaagg 153600
atatgatatg ttgtgattct agaatagtag tagctctatc tagtctagta tctaaacatt 153660
gggaattgac aaataaaaag tataggtgta tggcattagc cgaacatata tctgatagta 153720
ttccaatatc tgagctatct agactacgat acaatctatg taagtatcta cgcggacaca 153780
ctgagagcat agaggataaa tttgattatt ttgaagacga tgattcgtct acatgttctg 153840
ccgtaaccga cagggaaacg gatgtataat tttttttata gcgtgaagga tatgataaaa 153900
aatataattg ttgtatttat cccattccaa tcaccttata tgattctgta acacaatgaa 153960
ggagtctcat agatgtatag aggtcagata ctggtttgat aaactgttta ttccacatga 154020
gtatgtttga ctttatggtt agacccgcat actttaacaa atcactgaaa attggagtta 154080
ggtattgacc tctcagaatc agttgccgtt ctggaacatt aaatgtattt tttatgatat 154140
actccaacgc atttatgtgg gcatacaaca agtcattact aatggagtat tccaagagtt 154200
ttagttgtct agtatttaac aagagaagag atttcaacag actgtttatg aactcgaatg 154260
ccgcctcatt gtcgcttata ttgatgatgt cgaattctcc caatatcatc accgatgagt 154320
agctcatctt gttatcggga tccaagtttt ctaaagatgt cattaaaccc tcgatcatga 154380
atggatttat catcatcgtt tttatgttgg acatgagctt agtccgtttg tccacatcta 154440
tagacgacga tttctgaatt attttatata tccctctctt taactccagg aacttgtcag 154500
gatggtctac tttaatatgt tctcgtctaa gagatgaaaa tctttggatg gttgcacgcg 154560
acttttctct aaaggatgac gttgcccaag atcctctctt aaatgaatcc atcttatcct 154620
tggacaagat ggacagtcta ttttccttag atggtttaat atttttgtta cccatgatct 154680
ataaaggtag acctaatcgt ctcggatgac ctatatattt attttcagtt ttattatacg 154740
cataaattgt aaaaaatatg ttaggtttac aaaaatgtct cgtggggcat taatcgtttt 154800
tgaaggattg gacaaatctg gaaaaacaac acaatgtatg aacatcatgg aatctatacc 154860
ggcaaacacg ataaaatatc ttaactttcc tcagagatcc actgtcactg gaaagatgat 154920
agatgactat ctaactcgta aaaaaaccta taatgatcat atagttaatc tattattttg 154980
tgcaaataga tgggagtttg catcttttat acaagaacaa ctagaacagg gaattacttt 155040
aatagttgat agatacgcgt tctctggagt agcgtatgcc gccgctaaag gcgcgtcaat 155100
gactctcagt aagagttatg aatctggatt gcctaaaccc gacttagtta tattcttgga 155160
atctggtagc aaagaaatta atagaaacgt cggcgaggaa atttatgaag atgttacatt 155220
ccaacaaaag gtattacaag aatataaaaa aatgattgaa gaaggagata ttcattggca 155280
aattatttct tctgaattcg aggaagatgt aaagaaggag ttgattaaga atatagttat 155340
agaggctata cacacggtta ctggaccagt ggggcaactg tggatgtaat agtgaaatta 155400
cattttttat aaatagatgt tagtacagtg ttataaatgg atgaagcata ttactctggc 155460
aacttggaat cagtactcgg atacgtgtcc gatatgcata ccgaactcgc atcaatatct 155520
caattagtta ttgccaagat agaaactata gataatgata tattaaacaa ggacattgta 155580
aattttatca tgtgtagatc aaacttggat aatccattta tctctttcct agatactgta 155640
tatactatta tagatcaaga gaactatcag accgaattga ttaattcatt agacgacaat 155700
gaaattatcg attgtatagt taataagttt atgagctttt ataaggataa cctagaaaat 155760
atagtagatg ctatcattac tctaaaatat ataatgaata atccagattt taaaactacg 155820
tatgccgaag tactcggttc cagaatagcc gatatagata ttaaacaagt gatacgtgag 155880
aatatactac aattgtctaa tgatatccgc gaacgatatt tgtgaaaaat attaaaaaaa 155940
aatacttttt ttattaaatg acgtcgcttc gcgaatttag aaaattatgc tgtgatatat 156000
atcacgcatc aggatataaa gaaaaatcta aattaattag agactttata acagataggg 156060
atgataaata tttgatcatt aagctattgc ttcccggatt agacgataga atttataaca 156120
tgaacgataa acaaattata aaattatata gtataatatt taaacaatct caggaagata 156180
tgctacaaga tttaggatac ggatatatag gagacactat taggactttc ttcaaagaga 156240
acacagaaat ccgtccacga gataaaagca ttttaacttt agaagacgtg gatagtttct 156300
taactacgtt atcatccgta actaaagaat cgcatcaaat aaaattattg actgatatcg 156360
catccgtttg tacatgtaat gatttaaaat gtgtagtcat gcttattgat aaagatctaa 156420
aaattaaagc gggtcctcgg tacgtactta acgctattag tcctaatgcc tatgatgtgt 156480
ttagaaaatc taataacttg aaagagataa tagaaaatgc atctaaacaa aatctagact 156540
ctatatctat ttctgttatg actccaatta atcccatgtt agcggaatcg tgtgattctg 156600
tcaataaggc gtttaaaaaa tttccatcag gaatgtttgc ggaagtcaaa tacgatggtg 156660
aaagagtaca agttcataaa aataataacg agtttgcctt ctttagtaga aacatgaaac 156720
cagtactctc tcataaagtg gattatctca aagaatacat accgaaagca tttaaaaaag 156780
ctacgtctat cgtattggat tctgaaattg ttcttgtaga cgaacataat gtaccgctcc 156840
cgtttggaag tttaggaata cacaaaaaga aagaatataa aaactctaac atgtgtttgt 156900
tcgtgtttga ctgtttgtac tttgatggat tcgatatgac ggacattcca ttgtacgaac 156960
gaagatcttt tctcaaagat gttatggttg aaatacccaa tagaatagta ttctcagagt 157020
tgacgaatat tagtaacgag tctcagttaa ctgacgtatt ggatgatgca ctaacgagaa 157080
aattagaagg attggtctta aaagatatta atggagtata cgaaccggga aagagaagat 157140
ggttaaaaat aaagcgagac tatttgaacg agggttccat ggcagattct gccgatttag 157200
tagtactagg tgcttactat ggtaaaggag caaagggtgg tatcatggca gtctttctaa 157260
tgggttgtta cgacgatgaa tccggtaaat ggaagacggt taccaagtgt tcaggacacg 157320
atgataatac gttaagggtt ttgcaagacc aattaacgat ggttaaaatt aacaaggatc 157380
ccaaaaaaat tccagagtgg ttggtagtta ataaaatcta tattcccgat tttgtagtag 157440
aggatccgaa acaatctcag atatgggaaa tttcaggagc agagtttaca tcttccaagt 157500
cccataccgc aaatggaata tccattagat ttcctagatt tactaggatt agagaagata 157560
aaacgtggaa agaatctact catctaaacg atttagtaaa cttgactaaa tcttaatagt 157620
tacatacaaa ctgaaaatta aaataacact atttagttgg tggtcgccat ggatggtgtt 157680
attgtatact gtctaaacgc gttagtaaaa catggcgagg aaataaatca tataaaaaat 157740
gatttcatga ttaaaccatg ttgtgaaaga gtttgtgaaa aagtcaagaa cgttcacatt 157800
ggcggacaat ctaaaaacaa tacagtgatt gcagatttgc catatatgga taatgcggta 157860
tccgatgtat gcaattcact gtataaaaag aatgtatcaa gaatatccag atttgctaat 157920
ttgataaaga tagatgacga tgacaagact cctactggtg tatataatta ttttaaacct 157980
aaagatgtta ttcctgttat catatctata ggaaaggata aagatgtctg tgaactatta 158040
atctcatcag acatatcgtg tgcatgcgtg gagttaaatt catatcacgt agccattctt 158100
cccatggatg tttccttttt taccaaagga aatgcatcat tgattattct cctgtttgat 158160
ttctctatcg atgcagcacc tctcttaaga agtgtaaccg ataataatgt tattatatct 158220
agacaccagc gtctacatga cgagcttccg agttccaatt ggttcaagtt ttacataagt 158280
ataaagtccg actattgttc tatattatat atggttgttg atggatctgt gatgcatgcg 158340
atagctgata atagaactca cgcaattatt agcaaaaata tattagacaa tactacgatt 158400
aacgatgagt gtagatgctg ttattttgaa ccacagatta ggattcttga tagagatgag 158460
atgctcaatg gatcatcgtg tgatatgaac agacattgta ttatgatgaa tttacctgat 158520
gtaggcaaat ttggatctag tatgttgggg aaatatgaac ctgacatgat taagattgct 158580
ctttcggtgg ctggtaattt aataagaaat cgagactaca ttcccgggag acgaggatat 158640
agctactacg tttacggtat agcctctaga taattttttt aagcacgaaa taaaaaacat 158700
aattttaaac caatctattt catactattt tgtgtgatca ccatggacat aaagatagat 158760
attagtattt ctggtgataa atttacggtg actactagga gggaaaatga agaaagaaaa 158820
aaatatctac ctctccaaaa agaaaaaact actgatgtta tcaaacctga ttatcttgag 158880
tacgatgact tgttagatag agatgagatg tttactattc tagaggaata ttttatgtac 158940
agaggtctat taggcctcag aataaaatat ggacgactct ttaacgaaat taaaaaattc 159000
gacaatgatg cggaagaaca attcggtact atagaagaac tcaagcagaa acttagatta 159060
aattctgaag agggagcaga taactttata gattatataa aggtacaaaa acaggatatc 159120
gtcaaactta ctgtatacga ttgcatatct atgataggat tgtgtgcatg cgtggtagat 159180
gtttggagaa atgagaaact gttttctaga tggaaatatt gtttacgagc tattaaactg 159240
tttattaatg atcacatgct tgataagata aaatctatac tgcagaatag actagtatat 159300
gtggaaatgt catagaaagt taaaagttaa tgagagcaaa aatatataag gttgtattcc 159360
atatttgtta ttttttctgt aatagttaga aaaatacatt cgatggtcta tctaccagat 159420
tattatgtgt tataaggtac tttttctcat aataaactag agtatgagta agatagtgtt 159480
tttcaaaaca tataaatcta aaattgatgg atgagatata cagctattaa tttcgaaaat 159540
atattttaat ctgataactt taaacatgga tttttgatgg tggtttaacg ttttaaaaaa 159600
agattttgtt attgtagtat atgataatat taaaagatgg atataaagaa tttgctgact 159660
gcatgtacta ttttttacat tactacattg gctacggcag atatacctac tccgccacca 159720
acgggtcatg tgacaaggga gaatatcttg ataagaggca taatcaatgt tgtaatcggt 159780
gtccacctgg agaatttgcc aaggttagat gtaatggtaa cgataacaca aaatgtgaac 159840
gctgcccacc tcatacatat accacaatcc caattattct aatggatgtc atcaatgtag 159900
aaaatgccca accggatcat ttgataaggt aaagtgtacc ggaacacaga acagtaaatg 159960
ttcgtgtctt cctggttggt attgtgctac tgattcttca cagactgaag attgttgaaa 160020
ttgtgtacca aaaaggagat gtccatgcgg atactttggt ggaatagatg aacaaggaaa 160080
tcctatttgt aaatcgtgtt gtgttggtga atattgcgac tacctacgta attatagact 160140
tgatccattt cctccatgca aactatctaa atgtaattaa ttatgatttt gatgataatg 160200
ttaccataca ttatatcgct acttggttag tgtattattc agtatgaaga cctattaata 160260
attacttatc ttttgacgat cttgttataa ttataatata aaaatactta tggcatagta 160320
actcataatt gctgacgcga taaattcgta ataatctgtt ttgttcaaat ttttataagg 160380
aatctacagg cataaaaata aaaatataat ttataatata ctcttacagc gcgccatcat 160440
gaataacagc agtgaattga ttgctgttat taatggattt agaaatagtg gacgattttg 160500
tgatattagt atagttatta atgatgaaag gataaacgct cataaactca tcctatctgg 160560
agcctccgaa tatttttcca ttctgttttc caataatttt atcgattcta atgaatacga 160620
agttaatcta agtcatttag attatcaaag cgttaacgat ttgatcgatt acatttatgg 160680
gatacctttg agcctaacta acgataacgt gaaatatatt ctttcaaccg ctgatttttt 160740
acaaattgga tctgctatta cggagtgtga aaattacata cttaaaaatc tttgttctaa 160800
aaactgtatc gatttctaca tatacgctga taaatataat aacaagaaaa tagaatcagc 160860
gtcgtttaac acaatattac aaaatatttt gagactcatc aacgatgaaa actttaaata 160920
cttaacagag gaatcaatga taaaaatttt aagcgatgat atgttaaata taaaaaatga 160980
ggattttgca ccactaattc tcattaaatg gttagagagt actcaacaat catgcaccgt 161040
cgagttactt agatgcctca gaatatcatt gctttcccca caagttataa aatcacttta 161100
tagtcatcaa ctggttagtt caatctacga atgtataaca ttcttaaaca atatagcatt 161160
cttggatgaa tcatttccta gataccatag catcgagttg atatctatcg gtataagtaa 161220
ttcgcatgat aagatttcca taaactgcta caatcataaa aaaaatacat gggaaatgat 161280
atcttcacgt agatataggt gtagtttcgc agtggccgtc ctggataata ttatctatat 161340
gatgggtgga tatgatcagt ccccgtatag aagttcaaag gttatagcgt acaatacatg 161400
tacaaattct tggatatatg atataccaga gctaaaatat cctcgttcta attgtggggg 161460
actggctgat gacgaataca tttattgtat aggcggcata cgcgatcagg attcatcgtt 161520
gacatctagt attgataaat ggaagccatc aaaaccatat tggcagaagt atgctaaaat 161580
gcgcgaacca aaatgtgata tgggggttgc gatgttaaac ggattaatat atgtcatggg 161640
tggaatcgtt aaaggtgaca cgtgtaccga cgcactagag agtttatcag aagatggatg 161700
gatgaagcat caacgtcttc caataaaaat gtccaatatg tcgacgattg ttcatgatgg 161760
caagatttat atatctggag gttacaacaa tagtagtgta gttaatgtaa tatcgaatct 161820
agtccttagc tataatccga tatatgatga atggaccaaa ttatcatcat taaacattcc 161880
tagaattaat cccgctctat ggtcagcgca taataaatta tatgtaggag gaggaatatc 161940
tgatgatgtt cgaactaata catctgaaac atacgataaa gaaaaagatt gttggacatt 162000
ggataatggt cacgtgttac cacgcaatta tataatgtat aaatgcgaac cgattaaaca 162060
taaatatcca ttggaaaaaa cacagtacac gaatgatttt ctaaagtatt tggaaagttt 162120
tataggtagt tgatagaaca aaatacataa ttttgtaaaa ataaatcact ttttatacta 162180
atatgacacg attaccaata cttttgttac taatatcatt agtatacgct acaccttttc 162240
ctcagacatc taaaaaaata ggtgatgatg caactctatc atgtaatcga aataatacaa 162300
atgactacgt tgttatgagt gcttggtata aggagcccaa ttccattatt cttttagctg 162360
ctaaaagcga cgtcttgtat tttgataatt ataccaagga taaaatatct tacgactctc 162420
catacgatga tctagttaca actatcacaa ttaaatcatt gactgctaga gatgccggta 162480
cttatgtatg tgcattcttt atgacatcaa ctacaaatga cactgataaa gtagattatg 162540
aagaatactc cacagagttg attgtaaata cagatagtga atcgactata gacataatac 162600
tatctggatc tacacattca ccggaaacta gttctaagaa acctgattat atagataatt 162660
ctaattgctc gtcggtattc gaaatcgcga ctccggaacc aattactgat aatgtagaag 162720
atcatacaga caccgtcaca tacactagtg atagcattaa tacagtaagt gcatcatctg 162780
gagaatccac aacagacgag actccggaac caattactga taaagaagat catacagtta 162840
cagacactgt ctcatacact acagtaagta catcatctgg aattgtcact actaaatcaa 162900
ccaccgatga tgcggatctt tatgatacgt acaatgataa tgatacagta ccaccaacta 162960
ctgtaggcgg tagtacaacc tctattagca attataaaac caaggacttt gtagaaatat 163020
ttggtattac cgcattaatt atattgtcgg ccgtggcaat tttctgtatt acatattata 163080
tatataataa acgttcacgt aaatacaaaa cagagaacaa agtctagatt tttgacttac 163140
ataaatgtct gggatagtaa aatctatcat attgagcgga ccatctggtt taggaaagac 163200
agccatagcc aaaagactat gggaatatat ttggatttgt ggtgtcccat accactagat 163260
ttcctcgtcc tatggaacga gaaggtgttg attaccatta cgttaacaga gaggccatct 163320
ggaagggaat agccgccgga aactttctag aacatactga gtttttagga aatatttacg 163380
gaacttctaa aacagctgtg aatacagcgg ctattaataa tcgtatttgt gtgatggatc 163440
taaacatcga cggtgttaga agtcttaaaa atacgtacct aatgccttac tcggtgtata 163500
taagacctac ctctcttaaa atggttgaga ccaagcttcg ttgtagaaac actgaagcta 163560
acgatgagat tcatcgtcgc gtgatattgg caaaaacgga tatggatgag gccaacgaag 163620
caggtctatt cgacactatt atcattgaag atgatgtgaa tttagcatat agtaagttaa 163680
ttcagatact acaggaccgt attagaatgt attttaacac taattagaga cttaagactt 163740
aaaacttgat aattaataat ataactcgtt tttatatgtg gctatttcaa cgtctaatgt 163800
attagttaaa tattaaaact taccacgtaa aacttaaaat ttaaaatgat atttcattga 163860
cagatagatc acacattatg aactttcaag gacttgtgtt aactgacaat tgcaaaaatc 163920
aatgggtcgt tggaccatta ataggaaaag gtggattcgg tagtatttat actactaatg 163980
acaataatta tgtagtaaaa atagagccca aagctaacgg atcattattt accgaacagg 164040
cattttatac tagagtactt aaaccatccg ttatcgaaga atggaaaaaa tctcacaata 164100
taaagcacgt aggtcttatc acgtgcaagg catttggtct atacaaatcc attaatgtgg 164160
aatatcgatt cttggtaatt aatagattag gtgcagatct agatgcggtg atcagagcca 164220
ataataatag attaccaaaa aggtcggtga tgttgatcgg aatcgaaatc ttaaatacca 164280
tacaatttat gcacgagcaa ggatattctc acggagatat taaagcgagt aatatagtct 164340
tggatcaaat agataagaat aaattatatc tagtggatta cggattggtt tctaaattca 164400
tgtctaatgg agaacatgtt ccatttataa gaaatccaaa taaaatggat aacggtactc 164460
tagaatttac acctatagat tcgcataaag gatacgttgt atctagacgt ggagatctag 164520
aaacacttgg atattgtatg attagatggt tgggaggtat cttgccatgg actaagatat 164580
ctgaaacaaa gaattgtgca ttagtaagtg ccacaaaaca gaaatatgtt aacaatactg 164640
cgactttgtt aatgaccagt ttgcaatatg cacctagaga attgctgcaa tatattacca 164700
tggtaaactc tttgacatat tttgaggaac ccaattatga cgagtttcgg cacatattaa 164760
tgcagggtgt atattattaa gtgtggtgtt tggtcgatgt aaaatttttg tcgataaaaa 164820
ttaaaaaata acttaattta ttattgatct cgtgtgtaca accgaaatca tggcgatgtt 164880
ttacgcacac gctctcggtg ggtacgacga gaatcttcat gcctttcctg gaatatcatc 164940
gactgttgcc aatgatgtca ggaaatattc tgttgtgtca gtttataata acaagtatga 165000
cattgtaaaa gacaaatata tgtggtgtta cagtcaggtg aacaagagat atattggagc 165060
actgctgcct atgtttgagt gcaatgaata tctacaaatt ggagatccga tccatgatca 165120
agaaggaaat caaatctcta tcatcacata tcgccacaaa aactactatg ctctaagcgg 165180
aatcgggtac gagagtctag acttgtgttt ggaaggagta gggattcatc atcacgtact 165240
tgaaacagga aacgctgtat atggaaaagt tcaacatgat tattctacta tcaaagagaa 165300
ggccaaagaa atgaatgcac ttagtccagg acctatcatt gattaccacg tctggatagg 165360
agattgtatc tgtcaagtta ctgctgtgga cgtacatgga aaggaaatta tgagaatgag 165420
attcaaaaag ggtgcggtgc ttccgatccc aaatctggta aaagttaaac ttggggagaa 165480
tgatacagaa aatctttctt ctactatatc ggcggcacca tcgaggtaac cacctctctg 165540
gaagacagcg tgaataatgt actcatgaaa cgtttggaaa ctatacgcca tatgtggtct 165600
gtcgtatatg atcattttga tattgtgaat ggtaaagaat gctgttatgt gcatacgcat 165660
ttgtctaatc aaaatcttat accgagtact gtaaaaacaa atttgtacat gaagactatg 165720
ggatcatgca ttcaaatgga ttccatggaa gctctagagt atcttagcga actgaaggaa 165780
tcaggtggat ggagtcccag accagaaatg caggaatttg aatatccaga tggagtggaa 165840
gacactgaat caattgagag attggtagag gagttcttca atagatcaga acttcaggct 165900
ggtgaatcag tcaaatttgg taattctatt aatgttaaac atacatctgt ttcagctaag 165960
caactaagaa cacgtatacg gcagcagctt cctttatact ctcatctttt accaacacaa 166020
agggtggata tttgttcatt ggagttgata ataatacaca caaagtaatt ggattcacgg 166080
tgggtcatga ctacctcaga ctggtagaga atgatataga aaagcatatc aaaagacttc 166140
gtgttgtgca tttctgtgag aagaaagagg acatcaagta cacgtgtcga ttcatcaagg 166200
tatataaacc tggggatgag gctacctcga catacgtgtg cgctatcaaa gtggaaagat 166260
gctgttgtgc tgtgtttgca gattggccag aatcatggta tatggatact aatggtatca 166320
agaagtattc tccagatgaa tgggtgtcac atataaaatt ttaattaatg taatagagaa 166380
caaataataa ggttgtaata tcatatagac aataactaac aattaattag taactgttat 166440
ctctttttta actaaccaac taactatata cctattaata catcgtaatt atagttctta 166500
acatctatta atcattaatt cgcttcttta attttttata aactaacatt gttaattgaa 166560
aagggataac atgttacaga atataaatta tatatggatt tttttaaaaa ggaaatactt 166620
gactggagta tatatttatc tcttcattat atagcacgcg tgttttccaa tttttccaca 166680
tcccatataa tacaggatta taatctcgtt cgaacatacg agaaagtgga taaaacaata 166740
gttgattttt tatctaggtt gccaaattta ttccatattt tagaatatgg ggaaaatatt 166800
ctacatattt attctatgga tgatgctaat acgaatatta taattttttt tctagataga 166860
gtattaaata ttaataagaa cgggtcattt atacacaatc tcaggttatc atcatccatt 166920
aatataaaag aatatgtata tcaattagtt aataatgatc atccagataa taggataaga 166980
ctaatgcttg aaaatggacg tagaacaaga cattttttgt cctatatatc agatacagtt 167040
aatatctata tatgtatttt aataaatcat ggattttata tagatgccga agacagttac 167100
ggttgtacat tattacatag atgtatatat cactataaga aatcagaatc agaatcatac 167160
aatgaattaa ttaagatatt gttaaataat ggatcagatg tagataaaaa agatacgtac 167220
ggaaacacac cttttatcct attatgtaaa cacgatatca acaacgtgga attgtttgag 167280
atatgtttag agaatgctaa tatagactct gtagacttta atagatatac acctcttcat 167340
tatgtctcat gtcgtaataa atatgatttt gtaaagttat taatttctaa aggagcaaat 167400
gttaatgcgc gtaatagatt cggaactact ccattttatt gtggaattat acacggtatc 167460
tcgcttataa aactatattt ggaatcagac acagagttag aaatagataa tgaacatata 167520
gttcgtcatt taataatttt tgatgctgtt gaatctttag attatctatt atccagagga 167580
gttattgata ttaactatcg tactatatac aacgaaacat ctatttacga cgctgtcagt 167640
tataatgcgt ataatacgtt ggtctatcta ttaaacagaa atggtgattt tgagacgatt 167700
actactagtg gatgtacatg tatttcggaa gcagtcgcaa acaacaacaa aataataatg 167760
gaagtactat tgtctaaacg accatctttg aaaattatga tacagtctat gatagcaatt 167820
actaaacata aacagcataa tgcagattta ttgaaaatgt gtataaaata tactgcgtgt 167880
atgaccgatt atgatactct tatagatgta cagtcgctac agcaatataa atggtatatt 167940
ttaaaatgtt tcgatgaaat agatatcatg aagagatgtt atataaaaaa taaaactgta 168000
ttccaattag ttttttgtat caaagacatt aatactttaa tgagatacgg taaacatcct 168060
tctttcgtga aatgcactag tctcgacgta tacggaagtc gtgtacgtaa tatcatagca 168120
tctattagat atcgtcagag attaattagt ctattatcca agaagctgga tcctggagat 168180
aaatggtcgt gttttcctaa cgaaataaaa tataaaatat tggaaaactt taacgataac 168240
gaactatcca catatctaaa aatcttataa acactattaa aatataaaat ctaagtagga 168300
taaaatcaca ctacatcatt gtttcctttt agtgctcgac agtgtatact atttttaaca 168360
ctcataaata aaaatgaaaa cgatttccgt tgttacgttg ttatgcgtac tacctgctgt 168420
tgtttattca acatgtactg tacccactat gaataacgct aaattaacgt ctaccgaaac 168480
atcgtttaat gataaacaga aagttacgtt tacatgtgat cagggatatc attcttcgga 168540
tccaaatgct gtctgcgaaa cagataaatg gaaatacgaa aatccatgca aaaaaatgtg 168600
cacagtttct gattacatct ctgaattata taataaaccg ctatacgaag tgaattccac 168660
catgacacta agttgcaacg gcgaaacaaa atattttcgt tgcgaagaaa aaaatggaaa 168720
tacttcttgg aatgatactg ttacgtgtcc taatgcggaa tgtcaacctc ttcaattaga 168780
acacggatcg tgtcaaccag ttaaagaaaa atactcattt ggggaatata tgactatcaa 168840
ctgtgatgtt ggatatgagg ttattggtgc ttcgtacata agttgtacag ctaattcttg 168900
gaatgttatt ccatcatgtc aacaaaaatg tgatatgccg tctctatcta atggattaat 168960
ttccggatct acattttcta tcggtggcgt tatacatctt agttgtaaaa gtggttttac 169020
actaacgggg tctccatcat ccacatgtat cgacggtaaa tggaatcccg tactcccaat 169080
atgtgtacga actaacgaag aatttgatcc agtggatgat ggtcccgacg atgagacaga 169140
tttgagcaaa ctctcgaaag acgttgtaca atatgaacaa gaaatagaat cgttagaagc 169200
aacttatcat ataatcatag tggcgttaac aattatgggc gtcatatttt taatctccgt 169260
tatagtatta gtttgttcct gtgacaaaaa taatgaccaa tataagttcc ataaattgct 169320
accgtaaata taaatccgtt aaaataatga ataattaata acgaacaagt atcaaaagat 169380
taaagaatta tagctagaat caattgagat gtcttcttca gtggatgttg atatctacga 169440
tgccgttaga gcatttttac tcaggcacta ttataacaag agatttattg tgtatggaag 169500
aagtaacgcc atattacata atatatacag gctatttaca agatgcgccg ttataccgtt 169560
cgatgatata gtacgtacta tgccaaatga atcacgtgtt aaacaatggg tgatggatac 169620
acttaatggt ataatgatga atgaacgcga tgtttctgta agcgttggca ccggaatact 169680
attcatggaa atgtttttcg attacaataa aaatagtatc aacaatcaac taatgtatga 169740
tataattaat agcgtatcta taattctagc taatgagaga tatagaagcg cttttaacga 169800
cgatggtata tacatccgta gaaatatgat taacaagttg tacggatacg catctctaac 169860
tactattggc acgatcgctg gaggtgtttg ttattatctg ttgatgcatc tagttagttt 169920
gtataaataa ttatttcaat atactagtta aaattttaag attttaaatg tataaaaaac 169980
taataacgtt tttatttgta ataggtgcat tagcatccta ttcgaataat gagtacactc 170040
cgtttaataa actgagtgta aaactctata tagatggagt agataatata gaaaattcat 170100
atactgatga taataatgaa ttggtgttaa attttaaaga gtacacaatt tctattatta 170160
cagagtcatg cgacgtcgga tttgattcca tagatataga tgttataaac gactataaaa 170220
ttattgatat gtataccatt gactcgtcta ctattcaacg cagaggtcac acgtgtagaa 170280
tatctaccaa attatcatgc cattatgata agtaccctta tattcacaaa tatgatggtg 170340
atgagcgaca atattctatt actgcagagg gaaaatgcta taaaggaata aaatatgaaa 170400
taagtatgat caacgatgat actctattga gaaaacatac tcttaaaatt ggatctactt 170460
atatatttga tcgtcatgga catagtaata catattattc aaaatatgat ttttaaaaat 170520
ttaaaatata ttatcacttc agtgacagta gtcaaataac aaacaacacc atgagatata 170580
ttataattct cgcagttttg ttcattaata gtatacacgc taaaataact agttataagt 170640
ttgaatccgt caattttgat tccaaaattg aatggactgg ggatggtcta tacaatatat 170700
cccttaaaaa ttatggcatc aagacgtggc aaacaatgta tacaaatgta ccagaaggaa 170760
catacgacat atccgcattt ccaaagaatg atttcgtatc tttctgggtt aaatttgaac 170820
aaggcgatta taaagtggaa gagtattgta cgggactatg cgtcgaagta aaaattggac 170880
caccgactgt aacattgact gaatacgacg accatatcaa tttgtacatc gagcatccgt 170940
atgctactag aggtagcaaa aagattccta tttacaaacg cggtgacatg tgtgatatct 171000
acttgttgta tacggctaac ttcacattcg gagattctaa agaaccagta ccatatgata 171060
tcgatgacta cgattgcacg tctacaggtt gcagcataga ctttgtcaca acagaaaaag 171120
tgtgcgtgac agcacaggga gccacagaag ggtttctcga aaaaattact ccatggagtt 171180
cgaaagtatg tctgacacct aaaaagagtg tatatacatg cgcaattaga tccaaagaag 171240
atgttcccaa tttcaaggac aaaatggcca gagttatcaa gagaaaattt aataaacagt 171300
ctcaatctta tttaactaaa tttctcggta gcacatcaaa tgatgttacc acttttctta 171360
gcatgcttaa cttgactaaa tattcataac taatttttat taatgataca aaaacgaaat 171420
aaaactgcat attatacact ggttaacgcc cttataggct ctaaccattt tcaagatgag 171480
gtccctgatt atagtccttc tgttcccctc tatcatctac tccatgtcta ttagacaatg 171540
tgagaagact gaagaggaaa catggggatt gaaaataggg ttgtgtataa ttgccaaaga 171600
tttctatccc gaaagaactg attgcagtgt tcatctccca actgcaagtg aaggattgat 171660
aactgaaggc aatggattca gggatatacg aaacaccgat aaattataaa aaaagcaatg 171720
tgtccgctgt ttccgttaat aatactattt tcgtaactgg cggattattc ataaataact 171780
ctaatagcac gatcgtggtt aacaatatgg aaaaacttga catttataaa gacaaacaat 171840
ggtcgattat agaaatgcct atggctaggg tatatcacgg catcgactcg acatttggaa 171900
tgttatattt tgccggaggt ctatccgtta ccgaacaata tggtaattta gagaaaaaca 171960
acgagatatc ttgttacaat cctagaacga ataagtggtt tgatatttca tatactattt 172020
ataagatatc catatcatca ttgtgtaaac taaataacgt cttctatgta tttagtaagg 172080
acattggata tgtggaaaag tatgatggtg catggaagtt agtacatgat cgtctccccg 172140
ctataaaggc attatcaact tctccttatt gattgaaaat gaaaatataa atagttttta 172200
tgtatagcag tattacccta tagttttatt gcttactact aacatggata cagatgttac 172260
aaatgtagaa gatatcataa atgaaataga tagagagaaa gaagaaatac taaaaaatgt 172320
agaaattgaa aataataaaa acattaacaa gaatcatcca agtggatata ttagagaagc 172380
actcgttatt aataccagta gtaatagtga ttccattgat aaagaagtta tagaatgtat 172440
ctgtcacgat gtaggaatat agatcatatc tactaatttt tataatcgat acaaaacata 172500
aaaaacaact cgttattaca tagcaggcat ggaatccttc aagtattgtt ttgataacga 172560
tggcaagaaa tggattatcg gaaatacttt atattctggt aattcaatac tatataaggt 172620
cagaaaaaat ttcactagtt cgttctacaa ttacgtaatg aagatagatc acaaatcaca 172680
caagccattg ttgtctgaaa tacgattcta tatatctgta ttggatcctt tgactatcga 172740
caactggaca cgggaacgtg gtataaagta tttggctatt ccagatctgt atggaattgg 172800
agaaaccgat gattatatgt tcttcgttat aaagaatttg ggaagagtat tcgccccaaa 172860
ggatactgaa tcagtcttcg aagcatgcgt cactatgata aacacgttag agtttataca 172920
ctctcaagga tttacccatg gaaaaataga accgaggaat atactgatta gaaataaacg 172980
tctttcacta attgactatt ctagaactaa caaactatac aagagtggaa actcacatat 173040
agattacaac gaggacatga taacttcagg aaatatcaat tatatgtgtg tagacaatca 173100
tcttggagca acagtttcaa gacgaggaga tttagaaatg ttgggatatt gcatgataga 173160
atggttcggt ggcaaacttc catggaaaaa cgaaagtagt ataaaagtaa taaaacaaaa 173220
aaaagaatat aaaaaattta tagctacttt ctttgaggac tgttttcctg aaggaaatga 173280
acctctggaa ttagttagat atatagaatt agtatacacg ttagattatt ctcaaactcc 173340
taattatgac agactacgta aactgtttat acaagattga aattatattc ttttttttat 173400
agagtgtggt agtgttacgg atatttaata ttagactatc tctatcgcgc tacacgacca 173460
atatcgatta ctatggatat cttcagggaa atcgcatctt ctatgaaagg agagaatgta 173520
ttcatttctc cagcgtcaat ctcgtcagta ttgacaatac tgtattatgg agctaatgga 173580
tccactgctg aacagctatc aaaatatgta gaaaaggagg agaacatgga taaggttagc 173640
gctcaaaata tctcattcaa atccataaat aaagtatatg ggcgatattc tgccgtgttt 173700
aaagattcct ttttgagaaa aattggcgat aagtttcaaa ctgttgactt cactgattgt 173760
cgcactatag atgcaatcaa caagtgtgta gatatcttta ctgaggggaa aatcaatcca 173820
ctattggatg aaccattgtc tcctgatacc tgtctcctag caattagtgc cgtatacttt 173880
aaagcaaaat ggttgacgcc attcgaaaag gaatttacca gtgattatcc cttttacgta 173940
tctccgacgg aaatggtaga tgtaagtatg atgtctatgt acggcaaggc atttaatcac 174000
gcatctgtaa aggaatcatt cggcaacttt tcaatcatag aactgccata tgttggagat 174060
actagtatga tggtcattct tccagacaag attgatggat tagaatccat agaacaaaat 174120
ctaacagata caaattttaa gaaatggtgt aactctctgg aagctacgtt tatcgatgtt 174180
cacattccca agtttaaggt aacaggctcg tataatctgg tggatactct agtaaagtca 174240
ggactgacag aggtgttcgg ttcaactgga gattatagca atatgtgtaa ttcagatgtg 174300
agtgtcgacg ctatgatcca caaaacgtat atagatgtca atgaagagta tacagaagca 174360
gctgcagcaa cttgtgcact ggtgtcagac tgtgcatcaa caattacaaa tgagttctgt 174420
gtagatcatc cgttcatcta tgtgattagg catgttgatg gaaaaattct tttcgttggt 174480
agatattgct ctccgacaac taattgttaa ccattttttt taaaaaatag aaaaaacatg 174540
tggtattagt gcaggtcgtt attcttccaa ttgcaattgg taagatgacg gccaacttta 174600
gtacccacgt cttttcacca cagcactgtg gatgtgacag actgaccagt attgatgacg 174660
tcagacaatg tttgactgaa tatatttatt ggtcgtccta tgcataccgc aacaggcaat 174720
gcgctggaca attgtattcc acactcctct cttttagaga tgatgcggaa ttagtgttca 174780
tcgacattcg cgagctggta aaaaatatgc cgtgggatga tgtcaaagat tgtgcagaaa 174840
tcatccgttg ttatataccg gatgagcaaa aaaccatcag agagatttcg gccatcatcg 174900
gactttgtgc atatgctgct acttactggg gaggtgaaga ccatcccact agtaacagtc 174960
tgaacgcatt gtttgtgatg cttgagatgc tcaattacgt ggattataac atcatattcc 175020
ggcgtatgaa ttgatgagtt gtacatcttg acattttctt ctttcttctc ttctcccttt 175080
cccagaaaca aacttttttt acccactata aaataaaatg agtatactac ctgttatatt 175140
tctttctata tttttttatt cttcattcgt tcagactttt aacgcgcctg aatgtatcga 175200
caaagggcaa tattttgcat cattcatgga gttagaaaac gagccagtaa tcttaccatg 175260
tcctcaaata aatacgctat catccggata taatatatta gatattttat gggaaaaacg 175320
aggagcggat aatgatagaa ttataccgat agataatggt agcaatatgc taattctgaa 175380
cccgacacaa tcagactctg gtatttatat atgcattacc acgaacgaaa cctactgtga 175440
catgatgtcg ttaaatttga caatcgtgtc tgtctcagaa tcaaatatag atcttatctc 175500
gtatccacaa atagtaaatg agagatctac tggcgaaatg gtatgtccca atattaatgc 175560
atttattgct agtaacgtaa acgcagatat tatatggagc gggcatcgac gccttagaaa 175620
taagagactt aaacaacgga cacctggaat tattaccata gaagatgtta gaaaaaatga 175680
tgctggttat tatacatgtg ttttagaata tatatacggt ggcaaaacat ataacgtaac 175740
cagaattgta aaattagagg tacgggataa aataatacct tctactatgc aattaccaga 175800
tggcattgta acttcaatag gtagtaattt gactattgca tgcagagtat cgttgagacc 175860
tcccacaacg gatgcagacg tcttttggat aagtaatggt atgtattacg aagaagatga 175920
tggggacgga aacggtagaa taagtgtagc aaataaaatc tatatgaccg ataagagacg 175980
tgttattaca tcccggttaa acattaatcc tgtcaaggaa gaagatgcta caacgtttac 176040
gtgtatggcg tttactattc ctagcatcag taaaacagtt actgttagta taacgtgaat 176100
gtatgttgtt acatttccat gtcaattgag tttataagaa tttttataca ttatcttcca 176160
acaagcaatt gacgaacgta ttgctatgat taactcccac gatactatgc atattattaa 176220
tcattaactt gcagactata cctagagcta ttttgacata ctcgtgttct tgtgtaattg 176280
cagtatctat attattaaag tacgtaaatc tagctatagt tttattattt aattttagat 176340
aatataccgt ctccttattt ttaaaaattg ccacatcctt tattaaatca tgaatgggaa 176400
tttctatgtc atagttaata tattgtgaac aacaagagca gatatctata ggaaagggtg 176460
gaatgcgata cattgatcta tgtagtttta aaacacacgc aaactttgaa gaatttatat 176520
aaatcattcc atcgatacat ccttctatgt tgagatgtat atatccagga attcgtttat 176580
taatatcggg aaatgtataa actaaaacat tgcccggaag cggagcttct accggagtta 176640
tatcagtttt taacttacaa aatgtaacca atacctttgc atgacttgtt ttgttcggca 176700
acgttagttt aaacttgacg aatggattaa ttacaatagc atgatccgcg catctattaa 176760
gtttttttac tttaacgccc ttgtatgttt ttacagagac tttatctaaa tttctagtgc 176820
ttgtatgtgt tataaatata acgggatata gaactgaatc acctacctta gatacccaat 176880
tacattttat cagatccaga taataaacaa attttgtcgc cctaactaat tctatattgt 176940
tatatatttt acaattggtt atgatatcat gtaataactt ggaatctaac gcacatcgtc 177000
gtacgtttat acaattgtga tttagtgtag tatatctaca catgtatttt tccgcgctat 177060
agtattctgg actagtgata aaactatcgt tatatctgtc ttcaatgaac tcatcgagat 177120
attgctctct gtcatattca tacacctgca taaactttct agacatctta caatccgtgt 177180
tattttagga tcatatttac atatttacgg gtatatcaaa gatgttagat tagttaatgg 177240
gaatcgtcta taataatgaa tattaaacaa ttatatgagg acttttacca caaagcatca 177300
taaaaatgag tcgtcgtctg atttatgttt taaatatcaa ccgcgaatca actcataaaa 177360
tacaagagaa tgaaatatat acatatttta gtcattgcaa tatagaccat acttctacag 177420
aacttgattt tgtagttaaa aactatgatc taaacagacg acaacctgta actgggtata 177480
ctgcactaca ctgctatttg tataataatt actttacaaa cgatgtactg aagatattat 177540
taaatcatgg agtggatgta acgatgaaaa ccagtagcgg acgtatgcct gtttatatat 177600
tgcttactag atgttgcaat atttcacatg atgtagtgat agatatgata gacaaagata 177660
aaaaccactt attacataga gactattcca acctattact agagtatata aaatctcgtt 177720
acatgttatt aaaggaagag gatatcgatg agaacatagt atccacttta ttagataagg 177780
gaatcgatcc taactttaaa caagacggat atacagcgtt acattattat tatttgtgtc 177840
tcgcacacgt ttataaacca ggtgagtgta gaaaaccgat aacgataaaa aaggccaagc 177900
gaattatttc tttgtttata caacatggag ctaatctaaa cgcgttagat aattgtggta 177960
atacaccatt ccatttgtat cttagtattg aaatgtgtaa taatattcat atgactaaaa 178020
tgctgttgac ttttaatccg aatttcgaaa tatgtaataa tcatggatta acgcctatac 178080
tatgttatat aacttccgac tacatacaac acgatattct tgttatgtta atacatcact 178140
atgaaacaaa tgttggagaa atgccgatag atgagcgtcg tataatcgta ttcgagttta 178200
tcaaaacata ttctacacgt cctgcagatt cgataactta tttgatgaat aggtttaaaa 178260
atatagatat ttatacccgc tatgaaggaa agacattatt acacgtagca tgtgaatata 178320
ataatacaca cgtaatagat tatcttatac gtatcaacgg agatataaat gcgttaaccg 178380
acaataacaa acacgctaca caactcatta tagataacaa agaaaattcc ccatatacca 178440
ttaattgttt actgtatata cttagatata ttgtagataa gaatgtgata agatcgttgg 178500
tggatcaact tccatctcta cctatcttcg atataaaatc atttgagaaa ttcatatcct 178560
actgtatact tttagatgac acattttaca atagacacgt taggaatcgc gattctaaaa 178620
cgtatcgata cgcattttca aaatacatgt cgtttgataa atacgatggt ataataacta 178680
aatgtcataa agaaacaata ttgctcaaac tatccactgt tctagacact acactatatg 178740
cagttttaag atgccataat tcgaaaaagt taagaagata cctcaccgag ttaaaaaaat 178800
ataataacga taagtccttt aaaatatatt ctaatattat gaatgagaga taccttaatg 178860
tatattataa agatatgtac gtgtcaaagg tatatgataa actatttcct gttttcacag 178920
ataaaaattg tctactaaca ttactacctt cagaaattat atacgaaata ttatacatgc 178980
tgacaattaa cgatctttat aatatatcgt atccacctac caaagtatag ttgtattttt 179040
ctcatgcgat gtgtgtaaaa aaactgatat tatataaata ttttagtgcc gtataataaa 179100
gatgacgatg aaaatgatgg tacatatata tttcgtatca ttattgttat tgctattcca 179160
cagttacgcc atagacatcg aaaatgaaat cacagaattc ttcaataaaa tgagagatac 179220
tctaccagct aaagactcta aatggttgaa tccagcatgt atgttcggag gcacaatgaa 179280
tgatatagcc gctctaggag agccattcag cgcaaagtgt cctcctattg aagacagtct 179340
tttatcgcac agatataaag actatgtggt taaatgggaa aggctagaaa aaaatagacg 179400
gcgacaggtt tctaataaac gtgttaaaca tggtgattta tggatagcca actatacatc 179460
taaattcagt aaccgtaggt atttgtgcac cgtaactaca aagaatggtg actgtgttca 179520
gggtatagtt agatctcata ttagaaaacc tccttcatgc attccaaaaa catatgaact 179580
aggtactcat gataagtatg gcatagactt atactgtgga attctttacg caaaacatta 179640
taataatata acttggtata aagataataa ggaaattaat atcgacgaca ttaagtattc 179700
acaaacggga aaggaattaa ttattcataa tccagagtta gaagatagcg gaagatacga 179760
ctgttacgtt cattacgacg acgttagaat caagaatgat atcgtagtat caagatgtaa 179820
aatacttacg gttataccgt cacaagacca caggtttaaa ctaatactag atccaaaaat 179880
caacgtaacg ataggagaac ctgccaatat aacatgcact gctgtgtcaa cgtcattatt 179940
gattgacgat gtactgattg aatgggaaaa tccatccgga tggcttatag gattcgattt 180000
tgatgtatac tctgttttaa ctagtagagg cggtattacc gaggcgacct tgtactttga 180060
aaatgttact gaagaatata taggtaatac atataaatgt cgtggacaca actattattt 180120
tgaaaaaacc cttacaacta cagtagtatt ggagtaaata tacaatgcat ttttatatac 180180
attactgaat aattattatt attatttata tcgtatttgt gctataacgc gactatctag 180240
gtatttgtat ctcaccgata gagaacatat aaatgtagac tctattaaac agttgtgtaa 180300
aatatcagat cctaatgcat gttatagatg tggatgtacg gctttacatg agtactttta 180360
taattataga tcagtcaacg gaaaatacaa gtatagatac aacggttact atcaatatta 180420
tttatctagc gattatgaaa attataatga atattattat gatgattatg atagaactgg 180480
tatgaacagt gagagtgata atatatcaat caaaacagaa tatgaattct atgatgaaac 180540
acaagatcaa agtacacaac tagtaggtta cgacattaaa ctcaaaacca atgaggatga 180600
ttttatggct atgatagatc agtgggtgtc catgattata tagatgaatc aattaataaa 180660
gtagtatatg gaagagagtc tcacgtaaga tggcgggata tatggcaaga acataatgat 180720
ggcgtataca gtataggaaa ggagtgcata gataatatat acgaagacaa ccataccgta 180780
gacgaattct acaagataga cagcgtatca gatgtagatg acgcggaaca catatctccg 180840
ataactaatg atgtatctac acaaacatgg gaaaagaaat cagagttaga tagatacatg 180900
gaaatgtatc ctcgtcatag atatagtaag cattctgtct ttaagggatt ttctgacaaa 180960
gttagaaaaa atgatttaga catgaatgtg gtaaaagaat tactttctaa cggtgcatct 181020
ctaacaatta aggatagcag taataaggat ccaataaccg tttattttcg aagaacgata 181080
atgaatttag aaatgattga tgaacgaaag tatatagtac actcctatct aaaaaattat 181140
aaaaatttcg attatccatt tttcaggaag ttagttttga ctaataaaca ttgtctcaac 181200
aattattata atataagcga cagcaaatat ggaacaccgc tacatatatt ggcgtctaat 181260
aaaaaattaa taactcctaa ttacatgaag ttattagtgt ataacggaaa tgatataaac 181320
gcacgaggtg aagatacaca aatgcgaact ccattacaca aatatttgtg taaatttgta 181380
tatcataata ttgaatatgg tatccgatac tataatgaaa agattataga cgcatttata 181440
gagttaggag ccgatctaac tattccaaat gacgatggaa tgataccagt agtttactgt 181500
atacactcaa atgccgaata tggttataac aatattacta acataaagat aatacgtaaa 181560
ctacttaatc ttagtagacg tgcgtcacat aatctattta gagatcgagt catgcacgat 181620
tatataagta atacatatat tgatcttgag tgtttagata ttattagatc gttggatgga 181680
ttcgatatca atggttactt tgaaggacgt acaccacttc attgcgctat acaacataac 181740
ttcactcaga ttgctaagta cttattagat cgaggagctg atatagtcgt acccaacaca 181800
ttgattatac atcagtacat acagtaaata gcatagatat ggaggaggat acaaatattt 181860
caaataaagt tataaggtac aacactgtca ataatatatg ggaaacatta cctaacttct 181920
ggactggaac tataaatcca ggcgtggtct cgcataaaga tgatatatat gttgtatgcg 181980
acatcaaaga tgaaaaaaat gttaaaactt gtatatttag atataacacg aatacgtata 182040
acggatggga attggtcacg acgacagaaa gcagattatc agctctgcat actattcttt 182100
ataacaatac cataatgatg ttacattgtt atgaatcgta tatgttacaa gatacattta 182160
atgtgtacac tcgcgaatgg aatcatatgt gtcatcaaca ttcgaatagt tatatcatgt 182220
acaatatact acccatctac taaatataat agaataaaat aaatgagtat gatcatttta 182280
gataacgatt gattttatca ttaccgcttc attcttatat tctttgctta cggaacctat 182340
atttagaaac atctactaac gattttttat gcttgcatta ttaatggtat gtaatatgat 182400
tgattgtgta cgcaatacca atttgttaag tatgaatacg gggtacaaac ataaactgaa 182460
gtttaacatt atttatttat gatatatatc gttattgttt ggtctatacc atggatatct 182520
ttaaagaact aatcttaaaa cacacggatg aaaatgtttt gatttctcca gtttctattt 182580
tatctacttt atctattcta aatcatggag cagctggttc tacagctgaa caactatcaa 182640
aatatataga gaatatgaat gagaatacac ccgatgacaa taatgacatg gacgtagata 182700
ttccgtattg tgcgacacta gctaccgcaa ataaaatata cggtagcgat agtatcgagt 182760
tccacgcctc cttcctacaa aaaataaaag acgattttca aactgtaaac tttaataatg 182820
ctaaccaaac aaaggaacta atcaacgaat gggttaagac aatgacaaat ggtaaaatta 182880
attccttatt gactagtccg ctatccatta atactcgtat gacagttgtt agcgccgtcc 182940
attttaaagc aatgtggaaa tatccatttt ctaaacatct tacatataca gacaagtttt 183000
atatttctaa gaatatagtt accagtgttg atatgatggt gagcactgag aataacttgc 183060
aatatgtaca tattaatgaa ttattcggag gattctctat tatcgatatt ccatacgagg 183120
gaaactctag tatggtaatt atactaccgg acgacataga aggtatatat aacatagaaa 183180
aaaatataac agatgaaaaa tttaaaaaat ggtgtggtat gttatctact aaaagtatag 183240
acttgtatat gccaaagttt aaagtggaaa tgacagaacc gtataatctg gtaccgattt 183300
tagaaaattt aggacttact aatatattcg gatattatgc agattttagc aagatgtgta 183360
atgaaactat cactgtagaa aaatttctac atacgacgtt tatagatgtt aatgaggagt 183420
atacagaagc atcggccgtt acaggagtat ttatgactaa cttttcgatg gtatatcgta 183480
cgaaggtcta cataaaccat ccattcatgt acatgattaa agacaacaca ggacgtatac 183540
tttttatagg gaaatactgc tatccgcaat aaatataaac aaatagactt ttatcacgtt 183600
tatctatgtc taaatattac aaatagtaat agtataaact aaagctgata atacttaaaa 183660
aaataataat atcatttaca attaatagta taaactaaaa attaaacaaa tcgttattat 183720
aagtaatatc aaaatgatga tatacggatt aatagcgtgt cttatattcg tgacttcatc 183780
catcgctagt ccactttata ttcccgttat tccacccatt tcggaagata aatcgttcaa 183840
tagtgtagag gtattagttt ccttgtttag agatgaccaa aaagactata cggtaacttc 183900
tcagttcaat aactacacta tcgataccaa agactggact atcggcgtac tatccacacc 183960
tgatggtttg gatataccat tgactaatat aacttattgg tcacggttta ctataggtcg 184020
tgcattgttc aaatcagagt ctgaggatat tttccaaaag aaaatgagta ttctaggtgt 184080
ttctatagaa tgtaagaagt cgtcgacatt acttactttt ttgaccgtgc gtaaaatgac 184140
tcgagtattt aataaatttc cagatatggc ttattatcga ggagactgtt taaaagccgt 184200
ttatgtaaca atgacttata aaaatactaa aactggagag actgattaca cgtacctctc 184260
taatgggggg ttgcctgcat actatcgtaa tggggtcgat ggttgattat tgattagtat 184320
attccttatt ctttttattc acacaaaaag aacattttta taaacatgaa accactgtct 184380
aaatgtaatt atgatcttga tttatagatg aagatcagcc tttagaggat tttaaccagt 184440
atgtttaata tgaaaaaaat aaacataaca tattttgaga ttaagcgcta ttgtgcaaga 184500
ttatattaga atcaaattaa tctttcatac gagaaaaata acgacatacg tcgtcaacaa 184560
attaaacttt ttatttatta gttaactagc ttatagaact tgctcattgt tatgtttcta 184620
aaacgggtac gacatatagg acaattatcc gacgcaccgg tttctcttcg tgttttatgc 184680
catatattga tgcatgttat gcaaaatata tgagtacacg aatccaataa accaaagtat 184740
ctatcgtttt gagtaaacaa cttcatagca aattccacat tctttttctt tacttactct 184800
atacacgtcc tcgtatttat ccagtatttt gatgatatcc aactcagaaa tggttgttgt 184860
attattgggt gtattgggag tataggtatt attagctatg taccaattta ccaaccctct 184920
taatattgat tgaacaatca catcggttat ccaatcaata accacattaa taactaaatt 184980
gtagtgtata tatagaccat atatgtttct atttttttga cagttacgta tagtttcagt 185040
aagttttgat tgttgtattc ctgtatctct agataagtta gtcatatagt cccttccggc 185100
gatacgtttt ttccaagccc gaaattgatt agccaaatgt gtatttattt ttgtgatatt 185160
gatataatat gtaatgttat taatatttcg gataatgcat actgttagtc ttatatcatt 185220
tggttcatct atgtattgta atattgttac atgatctata gatgatgtat tgattttggc 185280
aggatcgaat tccatatccg cgactaaaca gtgaaaaaaa tgtaaatact ttttaaattt 185340
taaattagta aaactttttt ttatttttta tgattccaaa aatactgaat acaaagtcct 185400
aaattataaa tatggagatc atactaccac aacttattat tatgcatact cagccggtgt 185460
aatagataga tatatataat tctattacac cggcagacaa ttaccgatcg gtatttgtcg 185520
ttaccaacat accgtataat atgtaatata caattccata acccattgac agttgttata 185580
catcaaaatt gcaattcttt tgattacgat gttataagaa tgtagttaat tgatgtatga 185640
tgttaatgtg tcctctttcc tcttataaca tcgtaatcaa aaactttttt ataatatata 185700
cctaataatg tgtcttaata gttctcgtga ttcgtcaaac aatcattctt ataaaatata 185760
ataaagcaac gtaaaacaca taaaaataag cgtaactaat aagacaatgg atatttacga 185820
cgataaaggt ctacagacta ttaaactgtt taataatgaa tttgattgta taaggaatga 185880
catcagagaa ttatttaaac atgtaactga ttccgatagt atacaacttc cgatggaaga 185940
caattctgat attatagaaa atatcagaaa aatactatat agacgattaa aaaatgtaga 186000
atgtgttgac atcgatagta caataacttt tatgaaatac gatccaaatg atgataataa 186060
gcgtacgtgt tctaattggg tacccttaac taataactat atggaatatt gtctagtaat 186120
atatttggaa acaccgatat gtggaggcaa aataaaatta taccacccta caggaaatat 186180
aaagtcggat aaggatatta tgtttgcaaa gactctagac tttaaatcaa agaaagtgtt 186240
aactggacgt aaaacaattg ccgttctaga catatccgtt tcatataata gatcaatgac 186300
tactattcac tacaacgacg acgttgatat agatatacat actgataaaa atggaaaaga 186360
gttatgttat tgttatataa caatagatga tcattacttg gttgatgtgg aaactatagg 186420
agttatagtc aatagatctg gaaaatgtct gttagtaaat aaccatctag gtataggtat 186480
cgttaaagat aaacgtataa gcgatagttt tggagatgta tgtatggata caatatttga 186540
cttttctgaa gcacgagagt tattttcatt aactaatgat gataacagga atatagcatg 186600
ggacactgat aaactagacg atgatacaga tatatggact cccgtcacag aagatgatta 186660
caaatttctt tctagactag tattgtatgc aaaatctcaa tcggatactg tattcgacta 186720
ttatgttctt actggtgata cggaaccacc cactgtattc attttcaagg taactagatt 186780
ttactttaat atgccgaaat aaaaaatttt tgtataatat ctagaggtag aggtattgtt 186840
tagataaata caaataacat agatacatcg catacttagc atttttataa atatacataa 186900
gacatacact ttatacattt tttttgtaaa aatactcata aaaaaattta taaaaattat 186960
ggcacaacca tatcttgtat aggtagttta gttcgtcgag tgaacctata aacagataat 187020
agacaacacg taataataat aatgcctact aatacaagca taataccggg agatgggata 187080
tatgacgttg tagtgtttgg gttttctgaa cgttgatagt ctactaatac tacatgctga 187140
catctaatgc ctgtataacc atgagagcat ctacaataca taccgtcaat atctctagcg 187200
tggatacagt caccgtgtaa acaatatcca tctccctctg gaccgcataa tctgatagct 187260
ggaatatctg ttgtagcgtt tgtaatttct ggcgatgtcg tttcgatagc gttaccacta 187320
tcggcgaatg atctgattat catagcagcg aacaacaaca tcagatattt catcgacatt 187380
tttgatggat tttgtgttta tgctgtttct cagtgtgtgt ttatgacaag attgggaatt 187440
ttatattatt aattcagtaa tataaactaa taatatattg ttaattgtgt aaataatata 187500
aaaataacaa tacaatattg aatgtgttgc tgttaaaaat gatcataaac acggagttta 187560
ttttatatgt ctcgcataaa cattactaaa aaaatatatt gttctgtttt tctttcacat 187620
ctttaattat gaaaaagtaa atcattatga gatggacgag attgtacgca tcgttcgcga 187680
cagtatgtgg tacataccta acgtatttat ggacgacggt aagaatgaag gtcacgtttc 187740
tgtcaacaat gtctgtcata tgtatttcac gttctttgat gtggatacat cgtctcatct 187800
gtttaagcta gttattaaac actgcgatct gaataaacga ggtaactctc cattacattg 187860
ctatacgatg aatacacgat ttaatccatc tgtattaaag atattgttac accacggcat 187920
gcgtaacttt gatagcaagg atgaaaaagg acaccactat caatcgataa caagatcttt 187980
gatatactaa cggacaccat tgatgacttt agtaaatcat ccgatctatt gctgtgttat 188040
cttagatata aattcaatgg gagcttaaac tattacgttc tgtacaaagg atccgacgag 188100
gatgaactca cttctcttca ttactactgt aaacacatat ccacgttcta caaaagcaat 188160
tattacaagt taagtcacac taagatgcga gccgagaagc gattcatcta cgcgataata 188220
gattatggag caaacattaa cgcggttaca cacttacctt caacagtata ccaaacatag 188280
tcctcgtgtg gtgtatgctc ttttatctcg aggagccgat acgaggatac gtaataatct 188340
tgattgtaca cccatcatgg aacgattgtg caacaggtca tattctcata atgttactca 188400
attggcacga acaaaaggaa gaaggacaac atctacttta tctattcata aaacataatc 188460
aaggatacac tctcaatata ctacggtatc tactagatag gttcgacatt cagaaagacg 188520
aatactataa taccgccttt caaaattgta acaacaatgt tgcctcatac atcggatacg 188580
acatcaacct tccgactaaa gacggtattc gacttggtgt ttgaaaacag aaacatcata 188640
tacaaggcgg atgttgtgaa tgacatcatc caccacagac tgaaagtatc tctacctatg 188700
attaaatcgt tgttctacaa gatgtctctc cctacgacga ttactacgta aagaagataa 188760
tagcctactg cctattaagg gacgagtcat tcgcggaact acatagtaaa ttctgtttaa 188820
acgaggacta taaaagtgta tttatgaaaa atatatcatt cgataagata gattccatca 188880
tcgtgacata agtcgcctta aagagattcg aatctccgac accgacctgt atacggtatc 188940
acagctatct taaagccata cattcagaca gtcacatttc atttcccatg tacgacgatc 189000
tcatagaaca gtgccatcta tcgatggagc gtaaaagtaa actcgtcgac aaagcactca 189060
ataaattaga gtctaccatc ggtcaatcta gactatcgta tttgcctccg gaaattatgc 189120
gcaatatcat ctaaacagta tgttgtacga aaagaaccat tacaaatatt atccatgata 189180
gaaagaaaat atctatatga ttggagaagt aggaaacagg aacaagacga cgattactac 189240
attattaaat catgaagtcc gtattatact cgtatatatt gtttctctca tgtataataa 189300
taaacggaag agatatagca ccgcatgcac catccgatgg aaagtgtaaa gacaacgaat 189360
acaaacgcca taatttgtgt ccgggaacat acgcttccag attatgcgat agcaagacta 189420
acacacaatg tacgccgtgt ggttcgggta ccttcacatc tcgcaataat catttacccg 189480
cttgtctaag ttgtaacgga agacgcgacc gtgtaacacg actcacaata gaatctgtga 189540
atgctctccc ggatattatt gtcttctcaa aggatcatcc ggatgcaagg catgtgtttc 189600
ccaaacaaaa tgtggaatag gatacggagt atccggagac gtcatctgtt ctccgtgtgg 189660
tctcggaaca tattctcaca ccgtctcttc cgcagataaa tgcgaacccg tacccagtaa 189720
tacctttaac tatatcgatg tggaaattaa tctgtatcca gttaacgacc actaccggtc 189780
tcagcgaatc catctcaacg tcggaactaa ctattactat gaatcataaa gactgtaatc 189840
ccgtatttcg tgaggaatac ttctccgtcc ttaataaggt agcaacttca ggtttcttta 189900
caggagaaag gtgtgcactc tgaatttcga gattaaatgc aataacaaaa atttttcctc 189960
caaacagtta acgaaagcaa agaatgatga cggtatcatg ccgcattcgg agactgtcta 190020
tctagcgtcg acatctatat actatatagt aataccaata ctcaagacta cgaaactgat 190080
acaatctctt atcatgtggg taatgttctc gatgtcgata gccatatgcc cggtagttgc 190140
gatatacata aactgatcac taattccaaa cccacccgct ttttatagta agtttttcac 190200
ccataaataa taaatacaat aattaatttc tcgtaaaagt agaaaatata ttctaattta 190260
ttgcacggta aggaagtaga atcataaaga acagtactca atcaatagca atcatgaaac 190320
aatatatcgt cctggcatgc atgtgcctgc cagtcttcag caatcatcct catcctcctc 190380
ctcgtgtacg gaagaagaaa acaaacatca tatgggaatc gatgttatta tcaaagtcac 190440
aaagcaagac caaacaccga ccaatgataa gatttgccaa tccgtaacgg aaattacaga 190500
gtccgagtca gatccagatc ccgaggtgga atcagaagat gattccacat cagtcgagga 190560
tgtagatcct cctaccactt attactccat catcggtgga ggtctgagaa tgaactttgg 190620
attcaccaaa tgtcctcaga ttaaatccat ctcagaatcc gctgatggaa acacagtgaa 190680
tgctagattg tccagcgtgt ccccaggaca aggtaaggac tctcccgcga tcactcatga 190740
agaagctctg gctatgatca aagactgtga ggtgtctatc gacatcagat gtagcgaaga 190800
agagaaagac agcgacatca agacccatcc agtactcggg tctaacatct ctcataagaa 190860
agtgagttac gaagatatca tcggttcaac gatcgtcgat acaaaatgtg tcaagaatct 190920
agagtttagc gttcgtatcg gagacatgtg caaggaatca tctgaacttg aggtcaagga 190980
tggatttaag tatgtcgacg gatcggcatc tgaaggtgca accgatgata cttcactcat 191040
cgattcaaca aaactcaaag cgtgtgtctg aatcgataac tctattcatc tgaaattgga 191100
tgagtagggt taatcgaacg attcaggcac accacgaatt aaaaaagtgt accggacact 191160
atattccggt ttgcaaaaca aaaatgttct taactacatt cacaaaaagt tacctctcgc 191220
gacttcttct ttttctgtct caatagtgtg atacgattat gacactattc ctattcctat 191280
tcctatttcc tttcagggta tcacaaaaat attaaacctc tttctgatgg tctcataaaa 191340
aaagttttac aaaaatattt ttattctctt tctctctttg atggtctcat aaaaaaagtt 191400
ttacaaaaat atttttattc tctttctctc tttgatggtc tcataaaaaa agttttacaa 191460
aaatattttt attctctttc tctctttgat ggtctcataa aaaaagtttt acaaaaatat 191520
ttttattctc tttctctctt tgatggtctc ataaaaaaag ttttacaaaa atatttttat 191580
tctctttctc tctttgatgg tctcataaaa aaagttttac aaaaatattt ttattctctt 191640
tctctctttg atggtctcat aaaaaaagtt ttacaaaaat atttttattc tctttctctc 191700
tttgatggtc tcataaaaaa agttttacaa aaatattttt attctctttc tctctttgat 191760
ggtctcataa aaaatattaa acctctttct gatggtgtca ctaaaatatt tttattctca 191820
ttctcatttt ctctttctct cttcaatgga gtcataaaat atttttattc tctttctctc 191880
ttcgatggtc tcacaaaaat attaaacctc tttctgatgg tgtcactaaa atatttttat 191940
tctcattctc attttctctt tctctcttca atggagtcat aaaatatttt tattctcttt 192000
ctctcttcga tggtctcaca aaaatattaa acctctttct gatggagtcg taaaaaagtt 192060
ttatctcttt ctctcttcga tggtctcaca aaaatattaa acctctttct gatggagtcg 192120
taaaaaagtt ttatctcttt ctctcttcga tggtctcaca aaaatattaa acctctttct 192180
gatggagtcg taaaaaagtt ttatctcttt ctctcttcga tggtctcaca aaaatattaa 192240
acctctttct gatggagtcg taaaaaagtt ttatctcttt ctctcttcga tggtctcaca 192300
aaaatattaa acctctttct gatggagtcg taaaaaagtt ttatctcttt ctctcttcga 192360
tggtctcaca aaaatattaa acctctttct gatggagtcg taaaaaagtt ttatctcttt 192420
ctctcttcga tggtctcaca aaaatattaa acctctttct gatggagtcg taaaaaagtt 192480
ttatctcttt ctctcttcga tggtctcaca aaaatattaa acctctttct gatggagtcg 192540
taaaaaagtt ttatctcttt ctctcttcga tggtctcaca aaaatattaa acctctttct 192600
gatggagtcg taaaaaagtt ttatctcttt ctctcttcga tggtctcaca aaaatattaa 192660
acctctttct gatggagtcg taaaaaagtt ttatctcttt ctctcttcga tggtctcaca 192720
aaaatattaa acctctttct gatggagtcg taaaaaagtt ttatctcttt ctctcttcga 192780
tggtctcaca aaaatattaa acctctttct gatggagtcg taaaaaagtt ttatctcttt 192840
ctctcttcga tggtctcaca aaaatattaa acctctttct gatggagtcg taaaaaagtt 192900
ttatctcttt ctctcttcga tggtctcaca aaaatattaa acctctttct gatggagtcg 192960
taaaaaagtt ttatctcttt ctctcttcga tggtctcaca aaaatattaa acctctttct 193020
gatggagtcg taaaaaagtt ttatctcttt ctctcttcga tggtctcaca aaaatattaa 193080
acctctttct gatggagtcg taaaaaagtt ttatctcttt ctctcttcga tggtctcaca 193140
aaaatattaa acctctttct gatggagtcg taaaaaagtt ttatctcttt ctctcttcga 193200
tggtctcaca aaaatattaa acctctttct gatggagtcg taaaaaagtt ttatctcttt 193260
ctctcttcga tggtctcact aaaatatttt ttattctctt tctgatgcat caactatttc 193320
ttaaacaata acgtccaaca acatatactc gtcgagctta tcaacatccc ctatgcccat 193380
ctaggttacc agacaattgt atatcataaa ataatgttta taatttacac gttaaaatca 193440
tataataaaa cgtagatcgt ataatatttt ttggtatata aatgatctag taaaatccat 193500
gtaggggata ctgctcacat tttttctttg gtacaaaatt tcacacaagt ttttatacag 193560
acaaattctt gtccatatat tttaaaacat tgacttttgt actaagaaaa atatctagat 193620
caactatctc tttctctttc tctcttcgat ggtctcacaa aaatattaaa cctctttctg 193680
atggagtcgt aaaaaagttt tatctctttc tctcttcgat ggtctcacaa aaatattaaa 193740
cctctttctg atggagtcgt aaaaaagttt tatctctttc tctcttcgat ggtctcacaa 193800
aaatattaaa cctctttctg atggagtcgt aaaaaagttt tatctctttc tctcttcgat 193860
ggtctcacaa aaatattaaa cctctttctg atggagtcgt aaaaaagttt tatctctttc 193920
tctcttcgat ggtctcacaa aaatattaaa cctctttctg atggagtcgt aaaaaagttt 193980
tatctctttc tctcttcgat ggtctcacaa aaatattaaa cctctttctg atggagtcgt 194040
aaaaaagttt tatctctttc tccttcgatg gtctcacaaa aatattaaac ctctttctga 194100
tggagtcgta aaaaagtttt atctctttct ctcttcgatg gtctcacaaa aatattaaac 194160
ctctttctga tggagtcgta aaaaagtttt atctctttct ctcttcgatg gtctcacaaa 194220
aatattaaac ctctttctga tggagtcgta aaaaagtttt atctctttct ccttcgatgg 194280
tctcacaaaa atattaaacc tctttctgat ggagtcgtaa aaaagtttta tctctttctc 194340
cttcgatggt ctcacaaaaa tattaaacct ctttctgatg gagtcgtaaa aaagttttat 194400
ctctttctct cttcgatggt ctcacaaaaa tattaaacct ctttctgatg gagtcgtaaa 194460
aaagttttat ctctttctct cttcgatggt ctcacaaaaa tattaaacct ctttctgatg 194520
gtctctataa agcgatcgat ctttcttaca ctctagagtt tcctacagtc atgggtcaca 194580
catttttttc tagacactaa ataaaattag taaaattaaa ttaattataa aattatatat 194640
ataatttact aactttagtt agataaatta ataatatata agttttagta cattaatatt 194700
atattttaaa t 194711
<210> 2
<211> 177923
<212> DNA
<213> 牛痘病毒
<400> 2
gtaagattaa attaattata aaattatgta tataatatta attataaaat tatgtatatg 60
atttactaac tttagttaga taaattaata atacataaat tttagtatat taatattata 120
aattaataat acataaattt tagtatatta atattatatt ttaaatattt atttagtgtc 180
tagaaaaaaa tgtgtgacca acgaccgtag gaaactctag agggtaagaa aaatcaatcg 240
ctttatagag accatcagaa agaggtttaa tatttttgtg agaccatcga aggagaaaga 300
gataaaactt ttttacgact ccatcagaaa gaggtttaat atttttgtga gaccatcgaa 360
gagagaaaga gataaaactt ttttacgact ccatcagaaa gaggtttaat atttttgtga 420
gaccatcgaa gagagaaaga gataaaactt ttttacgact ccatcagaaa gaggtttaat 480
atttttgtga gaccatcgaa ggagaaagag ataaaacttt tttacgactc catcagaaag 540
aggtttaata tttttgtgag accatcgaag gagaaagaga taaaactttt ttacgactcc 600
atcagaaaga ggtttaatat ttttgtgaga ccatcgaagg agaaagagat aaaacttttt 660
tacgactcca tcagaaagag gtttaatatt tttgtgagac catcgaagag agaaagagat 720
aaaacttttt tacgactcca tcagaaagag gtttaatatt tttgtgagac catcgaagga 780
gaaagagata aaactttttt acgactccat cagaaagagg tttaatattt ttgtgagacc 840
atcgaagaga gaaagagaat aaaaatattt tagtgacacc atcagaaaga ggtttaatat 900
ttttgtgaga ccatcgaaga gagaaagaga taaaactttt ttacgactcc atcagaaaga 960
ggtttaatat ttttgtgaga ccatcgaagg agaaagagat aaaacttttt tacgactcca 1020
tcagaaagag gtttaatatt tttgtgagac catcgaagag agaaagagat aaaacttttt 1080
tacgactcca tcagaaagag gtttaatatt tttgtgagac catcgaagag agaaagagat 1140
aaaacttttt tacgactcca tcagaaagac catcgaagag agaaagagaa agagatagtt 1200
agtctagata tttttcttag tacaaaagtc aatgttttaa aatatatgga caagaatttg 1260
tctgtataaa aacttgtgtg aaattttgta ccaaagaaaa aatgtgagca gtatccccta 1320
catggatttt actagatcat ttatatacca aaaaatatta tacgatctac gttttattat 1380
atgattttaa cgtgtaaatt ataaacatta ttttatgata tacaattgtc tggtaaccta 1440
gatgggcata ggggatgagt atatgttgtt ggacgttatt gtttaagaaa tagttgatgc 1500
atcagaaaga ggtttaatat ttttgtgaga ccatcgaaga gagaaagaga taaaactttt 1560
ttacgactcc atcagaaaga ggtttaatat ttttgtgaga ccatcgaaga gagaaagaga 1620
taaaactttt ttatgactcc attgaagaga gaatgagaat aaaaatattt tagtgacacc 1680
atcagaaaga ggtttaatat tttttatgag accatcaaag agagaaagag aataaaaata 1740
ttttatgact ccattgaaga gagaaagaga aaatgagaat aaaaatattt tagtgacacc 1800
atcagaaaga ggtttaatat tttttatgag accatcaaag agagaaagag aataaaaata 1860
tttttgtaaa acttttttta tgagaccatc aaagagagaa agagaataaa aatatttttg 1920
taaaactttt tttatgagac catcaaagag agaaagagaa taaaaatatt tttgtaaaac 1980
tttttttatg agaccatcaa agagagaaag agaataaaaa tatttttgta aaactttttt 2040
tatgagacca tcaaagagag aaagagaata aaaatatttt tgtaaaactt tttttatgag 2100
accatcaaag agagaaagag aataaaaata tttttgtaaa acttttttta tgagaccatc 2160
aaagagagaa agagaataaa aatatttttg taaaactttt tttatgagac catcaaagag 2220
agaaagagaa taaaaatatt ttatgactcc attgaagaga gaaagagaat aaaaatattt 2280
tagtgacacc atcagaaaga ggtttaatat ttttgtgaga ccatcgaaga gagaaagaga 2340
ataaaaatat tttatgactc cattgaagag agaaagagaa taaaaatatt ttagtgacac 2400
catcagaaag aggtttaata ttttttatga gaccatcaaa gagagaaaga gaataaaaat 2460
atttttgtaa aacttttttt atgagaccat caaagagaga aagagaataa aaatattttt 2520
gtaaaacttt ttttatgaga ccatcaaaga gagaaagaga ataaaaatat ttttgtaaaa 2580
ctttttttat gagaccatca aagagagaaa gagaataaaa atatttttgt aaaacttttt 2640
ttatgagacc atcaaagaga gaaagagaat aaaaatattt ttgtaaaact ttttttatga 2700
gaccatcaaa gagagaaaga gaataaaaat attttatgac tccattgaag agagaatgag 2760
aataaaaata ttttagtgac accatcagaa agaggtttaa tatttttgtg agaccatcga 2820
agagagaaag agaataaaaa tattttatga ctccattgaa gagagaaaga gaataaaaat 2880
attttagtga caccatcaga aagaggttta atatttttta tgagaccatc aaagagagaa 2940
agagaataaa aatatttttg taaaactttt tttatgagac catcaaagag agaaagagaa 3000
taaaaatatt tttgtaaaac tttttttatg agaccatcaa agagagaaag agaataaaaa 3060
tatttttgta aaactttttt tatgagacca tcaaagagag aaagagaata aaaatatttt 3120
tgtaaaactt tttttatgag accatcaaag agagaaagag aataaaaata tttttgtaaa 3180
acttttttta tgagaccatc aaagagagaa agagaataaa aatatttttg taaaactttt 3240
tttatgagac catcaaagag agaaagagaa taaaaatatt tttgtaaaac tttttttatg 3300
agaccatcaa agagagaaag agaataaaaa tattttatga ctccattgaa gagagaatga 3360
gaataaaaat attttagtga caccatcaga aagaggttta atatttttgt gagaccatcg 3420
aagagagaaa gagaataaaa atattttatg actccattga agagagaatg agaataaaaa 3480
tattttagtg acaccatcag aaagaggttt aatatttttt atgagaccat caaagagaga 3540
aagagaataa aaatattttt gtaaaacttt ttttatgaga ccatcaaaga gagaaagaga 3600
ataaaaatat ttttgtaaaa attataaaca ttattttatg atatacaatt gtctggtaac 3660
ctagatgggc ataggggatg ttgataagct cgacgagtat atgttgttgg acgttattgt 3720
ttaagaaata gttgatgcat cagaaagaga ataaaaaata ttttagtgag accatcgaag 3780
agagaaagag ataaaacttt tttacgactc catcagaaag aggtttaata tttttgtgag 3840
accatcgaag agagaaagag ataaaacttt tttacgactc catcagaaag aggtttaata 3900
tttttgtgag accatcgaag gagaaagaga taaaactttt ttacgactcc atcagaaaga 3960
ggtttaatat ttttgtgaga ccatcaaaga gagaaagaga ataaaaatat ttttgtaaaa 4020
ctttttttat gagaccatca aagagagaaa gagaataaaa atatttttgt aaaacttttt 4080
ttatgagacc atcaaagaga gaaagagaat aaaaatattt ttgtaaaact ttttttatga 4140
gaccatcaaa gagagaaaga gaataaaaat atttttgtaa aacttttttt atgagaccat 4200
caaagagaga aagagaataa aaatatttta tgactccatt gaagagagaa tgagaataaa 4260
aatattttag tgacaccatc agaaagaggt ttaatatttt tgtgagacca tcgaagagag 4320
aaagagaata aaaatatttt atgactccat tgaagagaga atgagaataa aaatatttta 4380
gtgacaccat cagaaagagg tttaatattt tttatgagac catcaaagag agaaagagaa 4440
taaaaatatt tttgtaaaac tttttttatg agaccatcaa agagagaaag agaataaaaa 4500
tatttttgta aaactttttt tatgagacca tcaaagagag aaagagaata aaaatatttt 4560
tgtaaaactt tttttatgag accatcaaag agagaaagag aataaaaata tttttgtaaa 4620
acttttttta tgagaccatc aaagagagaa agagaataaa aatattttat gactccattg 4680
aagagagaat gagaataaaa atattttagt gacaccatca gaaagaggtt taatattttt 4740
gtgagaccat cgaagagaga aagagaataa aaatatttta tgactccatt gaagagagaa 4800
agagaataaa aatattttag tgacaccatc agaaagaggt ttaatatttt ttatgagacc 4860
atcaaagaga gaaagagaat aaaaatattt ttgtaaaact ttttttatga gaccatcaaa 4920
gagagaaaga gaataaaaat attttatgac tccattgaag agagaatgag aataaaaata 4980
ttttagtgac accatcagaa agaggtttaa tatttttgtg agaccatcga agagagaaag 5040
agaataaaaa tattttatga ctccattgaa gagagaatga gaataaaaat attttagtga 5100
caccatcaga aagaggttta atatttttgt gagaccatcg aagagagaaa gagaataaaa 5160
atattttatg actccattga agagagaatg agaataaaaa tattttagtg acaccatcag 5220
aaagaggttt aatatttttt atgagaccat caaagagaga aagagaataa aaatattttt 5280
gtaaaacttt ttttatgaga ccatcaaaga gagaaagaga ataaaaatat ttttgtaaaa 5340
ctttttttat gagaccatca aagagagaaa gagaataaaa atatttttgt aaaacttttt 5400
ttatgagacc atcaaagaga gaaagagaat aaaaatattt ttgtgagacc atcaaagaga 5460
gaaagagaat aaaaatattt ttgtgagacc atcaaagaga gaaagagaat aaaaatattt 5520
ttgtgagacc atcaaagaga gaaagagaat aaaaatattt tatgactcca ttgaagagag 5580
aaagagaata aaaatatttt agtgacacca tcagaaagag gtttaatatt tttgtgagac 5640
catcgaagag agaaagagaa taaaaatatt ttatgactcc attgaagaga gaaagagaat 5700
aaaaatattt tagtgacacc atcagaaaga ggtttaatat tttttatgag accatcaaag 5760
agagaaagag aataaaaata ttttttatga gaccatcaaa gagagaaaga gaataaaaat 5820
attttatgag accatcaaag agagaaagag aataaaaata ttttttatga gaccatcaaa 5880
gagagaaaga gaataaaaat attttatgag accatcaaag agagaaagag aataaaaata 5940
ttttttatga gaccatcaaa gagagaaaga gaataaaaat atttttgtat gagaccatca 6000
gaaagaggtt taatattttt gtgataccct gaaaggaaat aggaatagtg tcataatcgt 6060
atcacactat tgagacagaa aaagaagaag tcgcgagagg taactttttg ttttgcaaac 6120
cggaatatag tgtccggtac acttttttaa ttcgtggtgt gcctgaatcg ttcgattaac 6180
cctactcatc caatttcaga tgaatagagt tatcgattca gacacacgct ttgagttttg 6240
ttgaatcgat gagtgaagta tcatcggttg caccttcaga tgccgatccg tcgacatact 6300
tgacctcaag ttcagatgat tccttgcaca tgtctccgat acgaacgcta aactctagat 6360
tcttgacaca ttttgtatcg acgatcgttg aaccgatgat atcttcgtaa ctcactttct 6420
tatgagagat gttagacccg agtactggat gggtcttgat gtcgctgtct ttctcttctt 6480
cgctacatct gatgtcgata gacacctcac agtctttcca tcagcggatt ctgagatgga 6540
tttaatctga ggacatttgg tgaatccaaa gttcattctc agacctccac cgatgatgga 6600
gtaataagtg gtaggaggat ctacatcctc gactgattcc acctcgggat ctggatctga 6660
ctcggactct gtaatttccg ttacggattg gcaaatctta tcatcggtcg gtgtttggtc 6720
ttgctttgtg actttgataa taacatcgat tcccatatga tgtttgtttt cttcttccgt 6780
acacgatgag gatgattgct gaagactggc aggcacatgc atgccagtac gatatattgt 6840
ttcatgattg ctattgattg agtactgttc tttatgattc tacttcctta ccgtgcaata 6900
aattagaata tattttctac ttttacgaga aattaattat tgtatttatg ggtgaaaaac 6960
ttactataaa aagcgggtgg gtttggaatt agtgatcagt ttatgtatat cgcaactacc 7020
gggcatatgg ctacattacc cacatgataa gagattgtat cagtttcgta gtcttgagta 7080
ttggtattac tatatagtat atagatgtcg acgctagagt tactgtctcc gaatgcggca 7140
tgatagtatc attctttgct ttcgttaact gtttggagga agaatctttg ttattgcatt 7200
taatctcgaa attcagagtg cacacctttc tcctgtaaag aaacctgaag tcgctacctt 7260
attaagaaga cgggatcgca gtctttatga ttcatagtaa tagttagttc cgacgttgag 7320
atggattcgc tgagaccggt agtggtcgtc cgagtacacg atgtgtcgtt aactggatac 7380
aggttaattt ccacatcgat atagttaaag gtatttctgg gtacgggttc gcatttatct 7440
gcggaagaga cggtgtgaga atatgttccg agaccacacg gagaacagat gacgtctccg 7500
gatactccgt atcctattcc acattttgtt tgggaaacac atgccttgca tccatgatcg 7560
ggagagcatt cacagattct attgtgagtc gtgttacacg atcgcgtcga cattgttgac 7620
agaaacgtga ccttcattct taccgtcgtc cataaatacg ttaggtatgt accacatact 7680
gtcgcgaacg atgcgtccat ctcataatga tttacttttt cataattaaa gatgtgaaag 7740
aaaaccgaac aatatatttt tttagtaatg tttatgcgag acatataaaa taaactccgt 7800
gtttatgatg ccggtaaatg tttttatcat cttggacgga atcgattttg taatatgcca 7860
tggaaacagg acattatcac tccatgataa attatttaat ggagtcgatc ctctcattgt 7920
tctttgcgta tctcaatctg tggcgtttgc ttcgtttaaa taatatatca aacatggaga 7980
cgcctgatat gtaggcattc ttcattctat taatgtctgc tctatagcgc tttagttcct 8040
tatgacgacc ggcgatatca tacttacttt agaaggaaaa tcatcatcta ggattaaggc 8100
gtatctgata caggcgaata atggttcagg atatagatag cgtatatctc tattaaatgc 8160
gtcaatcata gtctctagag tgggatggta actcagtaat aaatcaacta gcttctcttt 8220
ggtaactgct tttctggatg gccgtattga ttatcgagcg tgacactcgc tccatattcc 8280
aataaccgct ttgcaaattg tatattattg acatcgaccg cgtaatatag tagagttatc 8340
gatcatatct atatcatcca tgtacttgct tagtatatca aatacatctt cataacagtg 8400
atacccgcaa ttattaaatc tcgataatat cagaccgtac atacatagac ggccattgtt 8460
agatatgtga tttacagccg cgtgtccata ttttccacga taaaccttac gacgtttaca 8520
tcgacgagat tattattaac aaagttgttg tccgtcgtct tatccaacat gcattgaatg 8580
ataggtatac ttaccatatc gccgtaatgt aagtagttta tcagtatggc ttgtacgatg 8640
gattcatcct gttgtctaaa tctctttaga atgttatcga tgatgtagtg gttatattct 8700
ctggaatcgt acgaagtaat actacgcatt acgtcgacaa gagtatgacg tctctcaata 8760
agaagattaa cgatttccat gtctacatta tatggggtta ctctaaatcg cttgtttaga 8820
taatacgcct ctaatatagg gctgacgtcg tatactctac acgtgtccac atcctttatt 8880
aataatctct atatctatgg ttgagcaaga ccagtagtat tggatggaaa cattgttatc 8940
gatcaaacat ttaattacat ccttggatag agattctcta tgagacgata tatagtaatg 9000
aagagagttc ttacacatat cactgttgta catacaggta cgaaatacgt aaccggtgct 9060
gtaacattct gatttaagaa gccatagcaa tacttctggt ctcggattag gcgtcgttac 9120
gtatatatcc accaatccga gaccattgat tgcataattc gtattcttgg acggacgtat 9180
ccgtttatcc acaattaggt attttagcag acgtaagtcg aaatcattta tattcgactt 9240
gagttcgtta gaggaattcg aatagctgga tatcagtaga tgcacaatct gagattttac 9300
gtatctatgc ttactgtatg ctcctagcgg agttaatcct tcgttgtttc tacaaagtct 9360
ctcgactccg cgagagagta acagtcgaac aatcttaatg tctgtatcgc atttattgga 9420
gacgtaacaa tgtagcgcat tgtttcctcg tctatctata tgttttgata agttgtgaca 9480
cgtttcaatt tctagtttta tttttttgta cgtcacatct tcatccagta gacgacatag 9540
aatacatgtg caatccatag ctattctggt gctaattatt cctcataaga tgataaaaag 9600
tgtagtgaga gagcatgaag gagatttagt atttagcagt gcggatatga tccaagaggg 9660
tgagatagtc gttctcgttc agaatctttc gcagcataag tagtatgtcg atatacttat 9720
cgttgaagac tcttccagag acgatagctg attgagtaca aagtccaatg attgcacgaa 9780
gttcttcggc ggttttcatg gagtcatttc tgatgaaaca tttaatgatc taaatttcag 9840
tttatgtttg taccccgtat tcatacttaa caaattggta ttacatacca ttaataatgc 9900
aagcataaaa aatcgttagt agatgtttct aaatataggt tccgtaagca aagaatataa 9960
gaatgaagcg gtaatgataa aatcaatcgt tatctaaaat gatcatactc atttatttta 10020
ttctattata ttaacacata catttttaac agcaacacat tcaatattgt attgttattt 10080
ttatattatt tacacaatta acaatatatt attagtttat attactgaat taataatata 10140
aaattcccaa tcttgtcata aacacacact gagaaacagc ataaacacaa aatccatcaa 10200
aaatgttgat aaattatctg atgttgttgt tcgctgctat gataatcaga tcattcgccg 10260
atagtggtaa cgctatcgaa acgacatcgc cagaaattac aaacgctaca acagatattc 10320
cagctatcag attatgcggt ccagagggag atggatattg tttacacggt gactgtatcc 10380
acgctagaga tatcgacggt atgtattgta gatgctctca tggttataca ggcattagat 10440
gtcagcatgt agtattagta gactatcaac gttcagaaaa accaaacact acaacgtcat 10500
atatcccatc tcccggtatt atgcttgtat tagtaggcat tattattatt acgtgttgtc 10560
tattatctgt ttataggttc actcgacgaa ctaaactacc tatacaagat atggttgtgc 10620
cataattttt ataaattttt tttatgagta tttttacaaa aatgtataaa gtgtatgtct 10680
tatgtatatt tataaaaatg ctaaatatgc gatgtatcta tgttatttgt atttatctaa 10740
acaatacctc tacctctaga tattatacaa aaatttttta tttcggcata ttaaagtaaa 10800
atctagttac cttgaaaatg aatacagtgg gtggttccgt atcaccagta agaacataat 10860
agtcgaatac agtatccgat tgagattttg catacaatac tagtctagaa agaaatttgt 10920
aatcatcttc tgtgacggga gtccatatat ctgtatcatc gtcccatgct atattcctgt 10980
tatcatcatt agttaatgaa aataactctc gtgcttcaga aaagtcaaat attgtatcca 11040
tacatacatc tccaaaacta tcgcttatac gtttatcttt aacgatacct atacctagat 11100
ggttatttac taacagacat tttccagatc tattgactat aactcctata gtttccacat 11160
caaccaagta atgatcatct attgttatat aacaataaca taactctttt ccgtttttat 11220
cagtatgtat atctatatca acgtcgtcgt tgtagtgaat agtagtcatt gatctattat 11280
atgaaacgga tatgtctaga acggcaattg ttttacgtcc agttaacact ttcgttgatt 11340
taaagtctag agtctttgca aacataatat ccttatccga ctttatattt cctgtagggt 11400
ggtataattt tattttgcct ccacatatcg gtgtttccaa atatattact agacaatatt 11460
ccatatagtt attagttaag ggtacccaat tagaacacgt acgcttatta tcatcatttg 11520
gatcgtattt cataaaagtt attgtactat cgatgtcaac acattctaca ttttttaatc 11580
gtctatatag tatttttctg atattttcta taatatcaga attgtcttcc atcggaagtt 11640
gtatactatc ggaatcagtt acatgtttaa ataattctct gatgtcattc cttatacaat 11700
caaattcatt attaaacagt ttaatagtct gtagaccttt atcgtcgtaa atatccattg 11760
tcttattagt tacgcttatt tttatgtgtt tttacgttgc tttattatat tttataagaa 11820
tgattgtttg acgaatcacg agaactatta agacacatta ttaggtatat attataaaaa 11880
agtttttgat tacgatgtta taagaggaaa gaggacacat taacatcata catcaattaa 11940
ctacattctt ataacatcgt aatcaaaaga attgcaattt tgatgtataa caactgtcaa 12000
tgggttatgg aattgtatat tacatattat acggtatgtt ggtaacgaca aataccgatc 12060
ggtaattgtc tgccggtgta atagaattat atatatctat ctattacacc ggccttgtat 12120
acataataat aagttgtggt agtatgatct ccatatttat aatttaggac tttgtattca 12180
gtttttttgg aatcataaaa aataaaaaaa agttttacta atttaaaatt atttacattt 12240
ttttcactgt ttagtcgcgg atatggaatt cgatcctgcc aaaatcaata catcatctat 12300
agatcatgta acaatattac aatacataga tgaaccaaat gatataagac taacagtatg 12360
cattatcaca aaaataaatc cacatttggc taatcaattt cgggcttgga aaaaacgtat 12420
cgccggaagg gactatatga ctaacttatc tagagataca ggaatacaac aatcaaaact 12480
tactgaaact gtcaaaaaaa tagaaacata tatggtctat atatacacta caatttagtt 12540
attaattgga taaccgatgt gattatcaat caatattaag aaggttggta aattggtaca 12600
tagctaataa tacctataca cccaataata caacaaccat ttctgagttg gatatcatca 12660
aaatactgga taaatacgag gacgtgtata gagtaagtaa agaaaaagaa tgtgaaattt 12720
gctatgaagt tgtttactca aaacgataga tactttggtt tattggattc gtgtaatcat 12780
atattttgca taacatgcat caatatatgg catagaacac gaagagaaac cggtgcgtcg 12840
gataattgtc ctatatgtcg tacccgtttt agaaacataa caatgagcaa gttaactaat 12900
aaataaaaag tttaatttgt tgacgacgta tgtcgttatt ttttctcgta taaaagatta 12960
atttgattct aatataatct ttagtattgg ataaatatca attcaaatta attccattag 13020
attatatcat aaataaaaat agtagcacgc actacttcag ccaaatattc ttttttgaaa 13080
cgccatctat cgtagtgagg acacaagtga acctataatg agcaaattta ttagtatcgg 13140
ttacatgaag gactttacgt agagtggtga ttccactatc tgtggtacga acggtttcat 13200
cttctttgat gccatcaccc agatgttcta taaacttggt atcctttgcc aaccaataca 13260
tatagctaaa ctcaggcata tgttccacac atcctgaaca atgaaattct ccagaagatg 13320
ttacaatgtc tagatttgga catttggttt caaccgcgtt aacatatgag tgaacacacc 13380
catacatgaa agcgatgaga aataggattt tcatcttgcc aaaatatcac tagaaaaaat 13440
ttatttatca attttaaagg tataaaaaat acttattgtt gctcgaatat tttgtatttg 13500
atggtatacg gaagattaga aatgtaggta ttatcatcaa ctgattctat ggttttatgt 13560
attctatcat gtttcactat tgcgttggaa ataatatcat atgcttccac atatatttta 13620
ttttgtttta actcataata ctcacgtaat tctggattat tgacatatct atgaataatt 13680
ttagctccat gatcagtaaa tattaatgag aacatagtat taccacctac cattattttt 13740
ttcatctcat tcaattctta attgcaaaga tctatataat cattatagcg ttgacttatg 13800
gactctggaa tcttagacga tgtacagtca tctataatca tggcatattt aatacattgt 13860
tttatagcat agtcgttatc tacgatgtta gatatttctc tcaatgaatc aatcacacaa 13920
tctaatgtag gtttatgaca taatagcatt ttcagcagtt caatgttttt agattcgttg 13980
atggcaatgg ctatacatgt atatccgtta tttgatctaa tgttgacatc tgaaccggat 14040
tctagcagta aagatactag agattgttta ttatatctaa cagccttgtg aagaagtgtt 14100
tctcctcgtt tgtcaatcat gttaatgtct ttaagataag gtaggcaaat gtttatagta 14160
ctaagaattg ggcaagcata agacatgtca caaagaccct ttttgtatgt ataagtgtaa 14220
aaattataac attcatagtt ggatttacat aggtgtccaa tcgggatctc tccatcatcg 14280
agataattga tggcatctcc cttccttttt tagtagatat ttcatcgtgt aagaatcaat 14340
attaatattt ctaaagtatc cgtgtatagc ctctttattt accacagttc catattccac 14400
tagagggata tcgccgaatg tcatatactc aattagtata tgttggagga catccgagtt 14460
cattgttttc aatatcaaaa agatggtttc cttatcattt ctccatagtg gtacaatact 14520
acacattatt ccgtgcggct ttccattttc caaaaacaat ttgaccaaat ctacatcttt 14580
attgtatcta taatcactat ttagataatc agccataatt actcgagtgc aacatgttag 14640
atcgtctata tatgaataag ccgtgttatc tattcctttc attaacaatt taacgatgtc 14700
tatatctata tgagatgact taatataata ttgaagagct gtacaatagt ttttatctat 14760
aaaagacggc ttgattccgt gattaattag acatttaaca acttccggac gcacatatgc 14820
tctcgtatcc gactctgaat acagatgaga gatgatatac agatgcaata cggtaccgca 14880
atttcgtagt tgataatcat catacgcgta tcagtactcg tcctcataaa gaacactgca 14940
gccattttct atgaacaaat caataatttc aggaacagga tcatctgtca ttacataatt 15000
ttctataact gaacgatggt tttcacattt aacactcaag tcaaatccat gttctaccaa 15060
cacctttatc aagtcaacgt ctacattttt ggatttcata tagctgaata tattaaagtc 15120
atttatgttg ctaaatccag tggcttctag tagagccatc gctatatcct ttaactttaa 15180
catgtctact atttgtgtat tcttctaatg gggtagctgt ctccaatttt tgcgtaatgg 15240
attagtgcca ctgtctagta gtagtttgac gacctcgaca ttattacaat gctcattaaa 15300
aaggtatgcg tgtaaagcat tattcttgaa ttggttcctg gtatcattag gatctctgtc 15360
tctcaacatc tgtttaagtt catcgagagc cacctcctca ttttccaaat agtcaaacat 15420
tttgactgaa tgagctactg tgaactctat acacccacac aactaatgtc attaaatatc 15480
atgtcaaaaa cttgtacaat tattaataaa aataatttag tgtttaaatt ttaccagttc 15540
cagattttac acctccgtta accccacttt ttacaccact ggacgatcct cctccccaca 15600
ttccaccgcc accagatgta taagttttag atcctttatt actaccatca tgtccatgga 15660
taaagacact ccacatgccg ccactacccc ctttagaaga catattaata agacttaagg 15720
acaagtttaa caataaaatt aatcacgagt accctactac caacctacac tattatatga 15780
ttatagtttc tatttttaca gtaccttaac taaagtctct agtcacaaga gcaatactac 15840
caacctacac tattatatga ttatagtttc tatttttata ggaacgcgta cgagaaaatc 15900
aaatgtctaa tttctaacgg tagtgttgat aaacgattat cgtcaatgga tacctcctct 15960
atcatgtcgt ctattttctt actttgttct attaacttat tagcattata tattatttga 16020
ttataaaact tatattgctt attagcccaa tctgtaaata tcggattatt aacatatcgt 16080
ttctttgtag gtttatttaa catgtacatc actgtaagca tgtccgtacc atttatttta 16140
atttgacgca tatccgcaat ttctttttcg cagtcggtta taaattctat atatgatgga 16200
tacatgctac atgtgtactt ataatcgact aatatgaagt acttgataca tattttcagt 16260
aacgatttat tattaccacc tatgaataag tacctgtgat cgtctaggta atcaactgtt 16320
ttcttaatac attcgatggt tggtaattta ctcagaataa tttccaatat cttaatatat 16380
aattctgcta tttctgggat atatttatct gccagtataa cacaaatagt aatacatgta 16440
aacccatatt ttgttattat attaatgtct gcgccattat ctattaacca ttctactagg 16500
ctgacactat gcgacttaat acaatgataa agtatactac atccatgttt atatcatcaa 16560
tatacggctt acaaagtttt agtatcgata acacatccaa ctcacgcata gagaaggtag 16620
ggaataatgg cataatattt attaggttat catcattgtc attatctaca actaagtttc 16680
cattttttaa aatatactcg acaactttag gatctctatt gccaaatttt tgaaaatatt 16740
tatttatatg cttaaatcta tataatgtag ctccttcatc aatcatacat ttaataacat 16800
tgatgtatac tgtatgataa gatacatatt ctaacaatag atcttgtata gaatctgtat 16860
atcttttaag aattgtggat attattacgt aaactattac acaattctaa aatataaaac 16920
gtatcacggt cgaataatag ttgatcaact atataattat cgattttgtg atttttcttc 16980
ctaaactgtt tacgtaaata gttagataga atattcatta gttcatgacc actatagtta 17040
ctatcgaata acgcgtcaaa tatttcccgt ttaatatcgc atttgtcaag ataataatag 17100
agtgtggtat gttcacgata agtataataa cgcatctctt tttcgtgtga aattaaatag 17160
tttattacgt ccaaagatgt agcataacca tcttgtgacc tagtaataat ataataatag 17220
agaactgttt tacccattct atcatcataa tcagtggtgt agtcgtaatc gtaattgtct 17280
aattcatcat cccaattata atattcacca gcacgtctaa tctgttctat tttgatcttg 17340
tatccatact gtatgttgct acatgtaggt attcctttat ccaataatag tttaaacaca 17400
tctacattgg gatttgatgt tgtagcgtat ttttctacaa tattaatacc atttttgata 17460
ctatttattt ctataccttt cgaaattagt aatttcaata agtctatatc gatgttatca 17520
gaacatagat attcgagtat atcaaaatca ttgatatttt tatagtcgac tgacgacaat 17580
aacaaaatca caacatcgtt tttgatatta ttatttttct tggtaacgta tgcctttaat 17640
ggagtttcac catcatactc atataatgga tttgcaccac tttctatcaa tgattgtgca 17700
ctgctggcat cgatgttaaa tgttttacaa ctatcataga gtatcttatc gttaaccatg 17760
attggttgtt gatgctatcg cattttttgg tttctttcat ttcagttatg tatggattta 17820
gcacgtttgg gaagcatgag ctcatatgat ttcagtactg tagtgtcagt actattagtt 17880
tcaataagat caatctctag atctatagaa tcaaaacacg ataggtcaga agataatgaa 17940
tatctgtagg cttcttgttg tactgtaact tctcgttttg ttagatgttt gcatcgtgct 18000
ttaacatcaa tggtacaaat tttatcctcg ctttgtgtat catattcgtc cctactataa 18060
aattgtatat tcagattatc atgagatgtg tatacgctaa cggtatcaat aaacggagca 18120
caccatttag tcataaccgt aatccaaaaa tttttaaagt atatcttaac gaaagaagtt 18180
gtgtcattgt ctacggtgta tggtactaga tcctcataag tgtatatatc tagagtaatg 18240
tttaatttat caaatggttg ataatatgga tcctcatgac aatttccgaa gatggaaatg 18300
agatatagac atgcaataaa tctaattgcg gacatggtta ctccttaaaa aaatacgaat 18360
aatcaccttg gctatttagt aagtgtcatt taacactata ctcatattaa tccatggact 18420
cataatctct atacgggatt aacggatgtt ctatatacgg ggatgagtag ttttcttctt 18480
taactttata ctttttacta atcatattta gactgatgta tgggtaatag tgtttaaaga 18540
gttcgttctc atcatcagaa taaatcaata tctctgtttt tttgttatac agatgtatta 18600
cagcctcata tattacgtaa tagaacgtgt catctacctt attaactttc accgcatagt 18660
tgtttgcaaa tacggttaat cctttgacct cgtcgatttc cgaccaatct gggcgtataa 18720
tgaatctaaa ctttaatttc ttgtaatcat tcgaaataat ttttagtttg catccgtagt 18780
tatccccttt atgtaactgt aaatttctca acgcgatatc tccattaata atgatgtcga 18840
attcgtgctg tatacccata ctgaatggat gaacgaatac cgacggcgtt aatagtaatt 18900
tactttttca tctttacata ttgggtacta gttttactat cataagttta taaattccac 18960
aagctactat ggaataagcc aaccatctta gtataacaca catgtcttaa agtttattaa 19020
ttaattacat gttgttttat atatcgctac gaatttaaac agagaaatca gtttaggaaa 19080
aaaaaatatc tatctacatc atcacgtctc tgtattctac gatagagtgc tactttaaga 19140
tgagacatat ccgtgtcatc aaaaatatac tccattaaaa tgattattcc ggcagcgaac 19200
ttgatattgg atatatcaca acctttgtta atatctacga caatagacag cagtcccatg 19260
gttccataaa cagtgagttt atctttcttt gaagagatat tttgtagaga tcttataaaa 19320
ctgtcgaatg acatcgcatt tatatcttta gctaaatcgt atatgttacc atcgtaatat 19380
ctaaccgcgt ctatcttaaa cgtttccatc gctttaaaga cgtttccgat agatggtctc 19440
atttcatcag tcatactgag ccaacaaata taatcgtgta taacatcttt gatagaatca 19500
gactctaaag aaaacgaatc ggctttatta tacgcattca tgataaactt aatgaaaaat 19560
gtttttcgtt gtttaagttg gatgaatagt atgtcttaat aattgttatt atttcattaa 19620
ttaatattta gtaacgagta cactctataa aaacgagaat gacataacta gttatcaaag 19680
tgtctaggac gcgtaatttt catatggtat agatcctgta agcattgtct gtattctgga 19740
gctattttct ctatatctaa tttctgaacg ttcaccaatg tctctagcca ctttggcact 19800
aatagcgatc attcgcttag cgtcttctat attattaact ggttgattca atctatctag 19860
caatggaccg tcggacagcg tcattctcat gttcttaatc aatgtacata catcgccgtc 19920
atctaccaat tcatccaaca acataagctt tttaaaatca tcattataat aggtttgatc 19980
gttgtcattt ctccaaagaa tatatctaat aagtagagtc ctcatgatta gttaacaact 20040
attttttatg ttaaatcaat tagtacaccg ctatgtttaa tacttattca tattttagtt 20100
tttaggattg agaatcaata caaaaattaa tgcatcatta attttagaaa tacttagttt 20160
ccacgtagtc aatgaaacat ttgaactcat cgtacaggac gttctcgtac aggacgtaac 20220
tataaaccgg tttatatttg ttcaagatag atacaaatcc gataactttt tttacgaatt 20280
ctacgggatc cactttaaaa gtgtcatacc gggttctttt tattttttta aacagattaa 20340
tggtgtgatg ttgattaggt cttttacgaa tttgatatag aatagcgttt acatattctc 20400
cataatggtc aatcgccatt tgttcgtatg tcataaattc tttaattata tgacactgtg 20460
tattatttag ttcatccttg ttcatcatta ggaatctatc caatatggca attatactag 20520
aactataggt gcgttgtata cacatattga tgtgtctgtt tatacaatcc atgctactac 20580
cttcgggtaa aattgtagca tcatatacca tttctagtac tttaggttca ttgttatcca 20640
ttgcagagga cgtcatgatc gcatcctaaa aaaatatatt atttttatgt tattttgtta 20700
aaaataatca tcgaatacga atcatccagt ccactgaata gcaaaatctt tactattttg 20760
gtatcttcca atgtggctgc ctgatgtaat ggaaattcat tctctagaag atttttcaat 20820
gctccagcgt tcaacaacgt acatactaga cgcacgttat tatcagctat tgcataatac 20880
aaggcactat gtccatggac atccgcctta aatgcatctt tgctagagag aaagcttttc 20940
agctgcttag acttccaagt attaattcgt gacagatcca tgtctgaaac gagacgctaa 21000
ttagtgtata atttttgtca tattgcacca gaattaataa tatctctaat agatctgatt 21060
agtagataca tggctatcgc aaaacaacat atacacattt aataaaaata atatttatta 21120
agaaaattca gatttcacgt acccatcaat ataaataaaa taatgattcc ttacaccgta 21180
cccatattaa ggagattcta ccttacccat aaacaatata aatccagtaa tatcatgtct 21240
gatgatgaac acaaatggtg tattaaattc cagtttttca ggagatgatc tcgccgtagc 21300
taccataata gtagatgcct ctgctacagt tccttgttcg tcgacatcta tctttgcatt 21360
ctgaaacatt ttataaatat ataatgggtc cctagtcata tgtttaaacg acgcattatc 21420
tggattaaac atactaggag ccatcatttc ggctatcgac ttaatatccc tcttattttc 21480
gatagaaaat ttagggagtt taagattgta cactttattc cctaattgaa acgaccaata 21540
gtctaatttt gcagccgtaa tagaatctgt gaaatgggtc atattatcac ctattgccag 21600
gtacatacta atattagcat ccttatacgg aaggcgtacc atgtcatatt ctttgtcatc 21660
gattgtgatt gtatttcctt gcaatttagt aactacgttc atcatgggaa ccgttttcgt 21720
accgtactta ttagtaaaac tagcattgcg tgttttagtg atatcaaacg gatattgcca 21780
tataccttta aaatatatag tattaatgat tgcccataga gtattattgt cgagcatatt 21840
agaatctact acattagaca taccggatct acgttctact atagaattaa ttttattaac 21900
cgcatctcgt ctaaagttta atctatatag gccgaatcta tgatattgtt gataatacga 21960
cggtttaata cacacagtat tatctacgaa actttgataa gttagatcag tgtacgtata 22020
tttagatgtt ttcagcttag ctaatcctga tattaattct gtaaatgctg gacccagatc 22080
tctttttctc aaatccatag tcttcaataa ttctattcta gtattacctg atgcaggcaa 22140
tagcgacata aacatagaaa acgaataacc aaacggtgag aagacaatat tatcatcttg 22200
aatattttta tacgctacta taccggcatt ggtaaatcct tgtagacgat aggtagacgc 22260
tgaacacgtt aacgatagta tcaataacgc aatcatgatt ttatggtatt aataattaac 22320
cttattttta tgttcggtat aaaaattatt gatgtctaca catccttttg taattgacat 22380
ctatatatcc ttttgtataa tcaactctaa tcactttaac ttttacagtt ttccctacca 22440
gtttatccct atattcaaca tatctatcca tatgcatctt aacactctct gccaagatag 22500
cttcagagtg aggatagtca aaaagataaa tatatagagc ataatcattc tcgtatactc 22560
tgccctttat tacatcgccc gcattgggca acgaataaca aaatgcaagc atcttgttaa 22620
cgggctcgta aattgggata aaaattatgt ttttatatct attttattca agagaatatt 22680
caggaatttc tttttccggt tgtatctcat cgcagtatat atcatttgta cattgtttca 22740
tattttttaa tagtttacac cttttagtag gactagtatc gtacaattca tagctgtatt 22800
ttgaattcca atcacgcata aaaatatctt ctaattgttg acgaagacct aatccatcat 22860
ccggtgtaat attaatagat gctccacatg tatccgtaaa gtaatttcct gtccaatttg 22920
aggtacctat ataggccgtt ttatcggtta ccatatattt ggcatggttt accctagaat 22980
acggaatggg aggatcagca tctggtacaa taaatagctt tacttctata tttatgtttt 23040
tagattttag catagcgata gatcttaaaa agtttctcat gataaacgaa gatcgttgcc 23100
agcaactaat caatagctta acggatactt gtctgtctat agcggatctt cttaattcat 23160
cttctatata aggccaaaac aaaattttac ccgccttcga ataaataata gggataaagt 23220
tcataacaga tacataaacg aatttactcg catttctaat acatgacaat aaagcggtta 23280
aatcattggt tctttccata gtacatagtt gttgcggtgc agaagcaata aatacagagt 23340
gtggaacacc acttacgtta atactaagag gatgatctgt attataatac gacggataaa 23400
agtttttcca attatatggt agattgttaa ctccaagata ccagtatacc tcaaaaattt 23460
gagtgagatc cgctgccaag ttcctattat tgaagatcgc aatacccaat tctttgacct 23520
gagttagtga tctccaatcc atgttagcgc ttcctaaata aatatgtgta ttatcagata 23580
tccaaaattt tgtatgaaga actcctccta ggatatttgt aatatctatg tatcgtactt 23640
caactccggc catttgtagt ctttcaacat cctttaatgg tttgttagat ttattgacgg 23700
ctactctaac tcgtactcct cttttgggta attgtacaat ctcgtttaat attatcgtgc 23760
cgaaattcgt acccacttca tccgataaac tccaataaaa agatgatata tctagtgttt 23820
ttgtggtatt ggatagaatt tccctccaca tgttaaatgt agacaaatat actttatcaa 23880
attgcatacc tataggaata gtctctgtaa tcactgcgat tgtattatcc ggattcattt 23940
tatttgttaa aagaataatc ctatatcact tcactctatt aaaaatccaa gtttctattt 24000
ctttcatgac tgatttttta acttcatccg tttccttatg aagatgatgt ttggcacctt 24060
cataaatttt tatttctcta ttacaatttg catgttgcat gaaataatat gcacctaaaa 24120
catcgctaat ctcattgttt gttccctgga gtatgagagt cggggtgtta atcttggaaa 24180
ttatttttct aaccttgttg gtagccttca agacctgact agcaaatcca gccttaattt 24240
tttcatgatt gattaatggg tcgtattggt atttataaac tttatccata tctctagata 24300
ctgattctgg acatagcttt ccgactggcg catttggtgt gatggttccc ataagtttgg 24360
cagctagcag attcagtctt gaaacagcat ctgcattaac tagaggagac attagaatca 24420
ttgctgtaaa caagtttgga ttatcgtaag aggctagtat agaaattgtt gctcccatgg 24480
aatgacccaa taagtagatt taatagttac cacgtgctgt accaaagtca tcaatcatca 24540
ttttttcacc attacttctt ccatgtccaa tatgatcatg tgagaatact aaaattccta 24600
acgatgatat gttttcagct agttcgtcat aacgtccaga atgtttacca gctccatgac 24660
ttatgaatac taatgcctta ggatatgtaa tcattgtcca gattgaacat acagtttgca 24720
ctcatgattc acgttatata actatcaata ttaacagttc gtttgatgat catattattt 24780
ttatgtttta ttgataattg taaaaacata caattaaatc aatatagagg aaggagacgg 24840
ctactgtctt ttgtgagata gtcatggcga ctaaattaga ttatgaggat gctgtttttt 24900
actttgtgga tgatgataaa atatgtagtc gcgactccat catcgatcta atagatgaat 24960
atattacgtg gagaaatcat gttatagtgt ttaacaaaga tattaccagt tgtggaagac 25020
tgtacaagga attgatgaag ttcgatgatg tcgctatacg gtactatggt attgataaaa 25080
ttaatgagat tgtcgaagct atgagcgaag gagaccacta catcaatttt acaaaagtcc 25140
atgatcagga aagtttattc gctaccatag gaatatgtgc taaaatcact gaacattggg 25200
gatacaaaaa gatttcagaa tctagattcc aatcattggg aaacattaca gatctgatga 25260
ccgacgataa tataaacatc ttgatacttt ttctagaaaa aaaattgaat tgatgatata 25320
ggggtcttca taacgcataa ttattacgtt agcattctat atccgtgtta aaaaaaatta 25380
tcctatcatg tatttgagag ttttatatgt agcaaacatg atagctgtga tgccaataag 25440
ctttagatat tcacgcgtgc tagtgttagg gatggtatta tctggtggtg aaatgtccgt 25500
tatataatct acaaaacaat catcgcatat agtatgcgat agtagagtaa acatttttat 25560
agtttttact ggattcatac atcgtctacc caattcggtt atgaatgaaa ttgtcgccaa 25620
tcttacaccc aaccccttgt tatccattag tatagtatta acttcgttat ttatgtcata 25680
aactgtaaat gattttgtag atgccatatc atacatgata ttcatgtccc tattataatc 25740
attactaact ttatcacaat atatgttgat aatatctata tatgatctag tctttgtggg 25800
caactgtcta tacaagtcgt ctaaacgttg tttactcata tagtatcgaa cagccatcat 25860
tacatggtcc cgttccgttg atagataatc gagtatgtta gtggacttgt caaatctata 25920
taccatattt tctggaagtg gatatacata gtcgtgatca acattattgc tagcctcatc 25980
ttctatatcc tgtactatac catctacata atctacgata ttattacaca taaacatcga 26040
caacatacta ttgtttatta tctaagtcct gttgatccaa acccttgatc tcctctattt 26100
gtactatcta gagattgtac ttcttccagt tctggataat atatacgttg atagattagc 26160
tgagctattc tatctccagt atttacatta aacgtacatt ttccattatt aataagaatg 26220
actcctatgt ttcccctata atcttcgtct attacaccac ctcctatatc aatgcctttt 26280
agtgacagac cagacctagg agctattcta ccatagcaaa tcttaggcat ggacatacta 26340
atatctgtct taattaactg tctttctcct ggagggatag tataatcgta agcgctatac 26400
aaatcatatc cggcagcacc cggcgattgc ctagtaggag atttagctct gttagtttcc 26460
ttaacaaatc taactggtga gttaatattc atgttgaaca taaaactaat attttatttc 26520
aaaattattt accatcccat atattccatg aataagtgtg atgattgtac acttctatag 26580
tatctatata cgattcacga taaaatcctc ctatcaatag cagtttatta tccactatga 26640
tcaattctgg attatccctc ggataaatag gatcatctat cagagtccat gtattgctgg 26700
attcacaata aaattccgca tttctaccaa ccaagaataa ccttctaccg aacactaacg 26760
cgcatgattt ataatgagga taataagtgg atggtccaaa ctgccactga tcatgattgg 26820
gtagcaaata ttctgtagtt gtatcagttt cagaatgtcc tcccattacg tatataacat 26880
tgtttatgga tgccactgct ggattacatc taggtttcag aagactcggc atattaaccc 26940
aagcagcatc cccgtggaac caacgctcaa cagatgtggg atttggtaga cctcctacta 27000
cgtataattt attgttagcg ggtatcccgc tagcatacag tctggggcta ttcatcggag 27060
gaattggaat ccaattgttt gatatataat ttacagctat agcattgtta tgtatttcat 27120
tgttcatcca tccaccgatg agatatacta cttctccaac atgagtactt gtacacatat 27180
ggaatatatc tataatttga tccatgttca taggatactc tatgaatgga tacttgtatg 27240
atttgcgtgg ttgtttatca caatgaaata ttttggtaca gtctagtatc cattttacat 27300
tatttatacc tctgggagaa agataatttg acctgattac atttttgata aggagtagca 27360
gatttcctaa tttatttctt cgctttatat accacttaat gacaaaatcc tcatctggaa 27420
catttagttc atcgctttct agaataagtt tcatagatag ataatcaaaa ttgtctatga 27480
tgtcatcttc cagttccaaa aagtgtttgg caataaagtt tttagtatga cataagagat 27540
tggatagtcc gtattctata cccatcatgt aacactcgac acaatattcc tttctaaaat 27600
ctcgtaggat aaagtttata caagtgtaga tgataaattc tacagaggtt aatatagaag 27660
cacgtaataa attgacgacg ttatgactat ctatatatac ctttccagta tatgagtaaa 27720
taactataga agttagactg tgaatgtcaa ggtctagaca aaccctcgta actggatctt 27780
tatttttcgt gtatttttga cgtaaatgtg tgcgaaagta aggagataac tttttcaata 27840
tcgtagaatt gactattata ttgcctccta tggcatcaat aattgttttg aatttcttag 27900
tcatagacaa tgctaatata ttcttacagt acacagtatt gacaaatatc ggcatttatg 27960
tttctttaaa agtcaacatc taaagaaaaa tgattatctt cttgagacat aactcccatt 28020
ttttggtatt cacccacacg tttttcgaaa aaattagttt taccttctaa tgatatattt 28080
tccatgaaat caaacggatt ggtaacatta taaatttttt taaatcccaa ttcagaaatc 28140
aatctatccg cgacgaattc tatatatgtt ttcatcattt cacaattcat tcctataagt 28200
ttaactggaa gagccgcagt aagaaattct tgttcaatgg ataccgcatc tgttataata 28260
gatctaacgg tttcttcact cggtggatgc aataaatgtt taaacatcaa acatgcgaag 28320
tcgcagtgta gaccctcgtc tctactaatc aattcgttgg aaaacgtgag tccgggcatt 28380
aggccacgct ttttaagcca aaatatggaa gcgaatgatc cggaaaagaa gattccttct 28440
actgcagcaa aggcaataag tctctctcca taaccggcgc tgtcatgtat ccacttttga 28500
gcccaatcgg ccttcttttt tacacaaggc atcgtttcta tggcattaaa gagatagttt 28560
ttttcattac tatctttaac ataagtatcg atcaaaagac tatacatttc cgaatgaatg 28620
ttttcaatgg ccatctgaaa tccgtagaaa catctagcct cggtaatctg tacttctgta 28680
caaaatcgtt ccgccaaatt ttcattcact attccgtcac tggctgcaaa aaacgccaat 28740
acatgtttta taaaatattt ttcgtctggt gttagtttat tccaatcatt gatatcttta 28800
gatatatcta cttcttccac tgtccaaaat gatgcctctg cctttttata catgttccag 28860
atgtcatgat attggattgg gaaaataaca aatctatttg gatttggtgc aaggatgggt 28920
tccataacta aattaacaat aacaataaat tttttttcag ttatctatat gcctgtactt 28980
ggatcttttg tacatcgata tcgccgcaat cactacaata attacaagta ttattgatag 29040
cattgttatt agtactatca taattaaatt atcgttatta tcattttgta attgtgacat 29100
catactagat aaatcgtttg cgagattgtt gtgggaagcg ggcatggagg atgaattatc 29160
gttattatta tttaaagcct cccattcgga ttcacaaata tggcgcgcgt tcaacatttt 29220
atggaaacag ataacaagaa aactcgtcat cgttcaaatt tttaacgata gtaaaccgat 29280
taaacgtcga gctaatttct aacgctagcg actctgttgg atatgggttt ccagatatat 29340
atcttttcag ttcccctacg tatctataat catctgtagg aaatggaaga tatttccatt 29400
tatctactgt tcctaatatc atatgtggtg gtgtagtaga accattaagc gcgaaagatg 29460
ttatttcgca tcgtatttta acttcgcaat aatttctggt tagataacgc actctaccag 29520
tcaagtcaat gatattagcc tttacagata tattcatagt agtcgtaacg atgactccat 29580
cttttagatg cgatactcct ttgtatgtac cagaatcttc gtacctcaaa ctcgatatat 29640
ttaaacaagt taatgagata ttaacgcgtt ttatgaatga tgatatataa ccagaagttt 29700
tatcctcggt ggctagcgct ataaccttat cattataata ccaactagtg tgattaatat 29760
gtgacacgtt agtgtgggta caaatatgta cattatcgtc tacgtcgtat tcgatacatc 29820
cgcatacagc caacaaatat aaaatgacaa atactctaac gccgttcgta cccatcttga 29880
tgcggtttaa taaatgtttt gatttcaatt tattgtaaaa aaagattcgg ttttatactg 29940
ttcgatattc tcattgctta tattttcatc tatcatctcc acacagtcaa atccgtggtt 30000
agcatgcacc tcatcaaccg gtaaaagact atcggactct tctatcatta taactctaga 30060
atatttaatt tggtcattat taatcaagtc aattatctta tttttaacaa acgtgagtat 30120
tttactcatt ttttataaaa acttttagaa atatacagac tctatcgtgt gtctatatct 30180
tctttttata tccaatgtat ttatgtctga tttttcttca tttatcatat ataatggtcc 30240
aaattctaca cgtgcttcgg attcatccag atcattaagg ttcttataat tgtaacatcc 30300
ttctcttccc tcttctacat cttccttctt attcttattc ttagcgtcac agaatctacc 30360
acagcaggat cccatgacga gcgtcatatt aaactaatcc attttcaatt ataatatacg 30420
attagtaatg accattaaaa taaaaatatt cttcataacc ggcaagaaag tgaaaagttc 30480
acattgaaac tatgtcagta gtatacatca tgaaatgatg atatatatat actctatttt 30540
ggtggaggat tatatgatat aattcgtgga taatcattct taagacacat ttcttcattc 30600
gtaaatcttt tcacgttaaa tgagtgtcca tattttgcaa tttcttcata tgatggcggt 30660
gtacgtggac gaggctgctc ctgttcttgt tgtagtcgcc gactgtcgtg tctgcgttta 30720
gatccctcca ttatcgcgat tgcgtagatg gagtactatt ttataccttg taattaaatt 30780
tttttattaa ttaaacgtat aaaaacgttc cgtatctgta tttaagagcc agatttcgtc 30840
taatagaaca aatagctaca gtaaaaataa ctagaataat tgctacaccc actagaaacc 30900
acggatcgta atacggcaat cggttttcga taataggtgg aacgtatatt ttatttaagg 30960
acttaacaat tgtctgtaaa ccacaatttg cttccgcgga tcctgtatta actatctgta 31020
aaagcatatg ttgaccgggc ggagccgaac attctccgat atccaatttc tgtatatcta 31080
taatattatt aacctccgca tacgcattac agttcttttc tagcttggat accgcactag 31140
gtacatcgtc tagatctatt cctatttcct cagcgatagc tcttctatcc ttttccggaa 31200
gcaatgaaat cacttcaata aatgattcaa ccatgagtgt gaaactaagt cgagaattac 31260
tcatgcattt gttagttatt cggagcgcgc aatttttaaa ctgtcctata acctctccta 31320
tatgaatagc acaagtgaca ttagtaggga tagaatgttg agctaatttt tgtaaataac 31380
tatctataaa aagattatac aaagttttaa actctttagt ttccgccatt tatccagtct 31440
gagaaaatgt ctctcataat aaatttttcc aagaaactaa ttgggtgaag aatggaaacc 31500
tttaatctat atttatcaca gtctgttttg gtacacatga tgaattcttc caatgccgta 31560
ctaaattcga tatctttttc gatttctgga tatgttttta ataaagtatg aacaaagaaa 31620
tggaaatcgt aataccagtt atgtttaact ttgaaattgt tttttatttt cttgttaatg 31680
attccagcca cttgggaaaa gtcaaagtcg tttaatgccg atttaatacg ttcattaaaa 31740
acaaactttt tatcctttag atgaattatt attggttcat tggaatcaaa aagtaagata 31800
ttatcgggtt taagatctgc gtgtaaaaag ttgtcgcagc atggtagttc gtaaatttta 31860
atgtataaca gagccatctg taaaaagata aactttatgt attgtaccaa agatttaaat 31920
cctaatttga tagctagctc ggtatctact ttatctgccg aatacagtgc taggggaaaa 31980
attataatat ttcctctttc gtattcgtag ttagttctct tttcatgttc gaaaaagtga 32040
aacatgcggt taaaatagtt tataacatta atattactgt taataactgc cggataaaag 32100
tgggatagta atttcacgaa tttgatactg tcctttctct cgttaaacgc ctttaaaaaa 32160
actttagaag aatatctcaa tgatagttcc tgaccatcca tagtttgtat caataatagc 32220
aacatatgaa gaacacgttt atacagagta tgtaaaaatg ttaatttata gtttaatccc 32280
atggcccacg cacacacgat taattttttt tcatctccct ttagattgtt gtatagaaat 32340
ttgggtactg tgaactccgc cgtagtttcc atgggactat ataattttgt ggcctcgaat 32400
acaaatttta ctacatagtt atctatctta aagactatac catatcctcc tgtagatatg 32460
tgataaaaat cgtcgtttat aggataaaat cgtttatcct tttgttggaa aaaggatgaa 32520
ttaatgtaat cattctcttc tatctttagt agtgtttcct tattaaaatt cttaaaataa 32580
tttaacaatc taactgatgg agcccaattt tggtgtaaat ctaattggga cattatattg 32640
ttaaaataca aacagtctcc taatataaca gtatctgata atctatgggg agacatccat 32700
tgatattcag gggatgaatc attggcaaca cccatttatt gtacaaaaag ccccaattta 32760
caaacgaaag tccaggtttg atagagacaa actattaact attttgtctc tgtttttaat 32820
ttctttggta atgaaattat tcacaatatc agtatcttct ttatctacca gagattttac 32880
taacttgata accttggctg tctcattcaa tagggtagta atatttgtat gtgtgatatt 32940
gatatctttt agaagtgatt ctttgatggt gccagcatac gaattacaat aatgcagaaa 33000
ctcggttaac atgcaggaat tatagtaagc caattccaat tgttgcctgt gttgtattag 33060
agtgtcaata tgagcaatgg tgtccttgcg tttctctgat agaatgcgag cagcgatttt 33120
ggcgttatca tttgacgata tttctggaat gacgaatcct gtttctacta actttttggt 33180
aggacaaagt gaaacaatca agaagatagc ttctcctcct atttgtggaa gaaattgaac 33240
tcctctagat gatctccttg acagatattg gaccgaatta cagaagtacc tggaatgtaa 33300
agccctgaaa ccccctcatt ttttaagcag attgttgccg taaatcctgc actatgccca 33360
agatagagag ctcctttggt gaatccatct ctatgtttca gtttaaccaa gaaacagtca 33420
gctggtctaa aatttccatc tctatctaat acagcatcta acttgatgtc aggaactatg 33480
accggttatg ttatatgtaa cattgagtaa atccttaagt tcataatcat cactgtcatc 33540
agttatgtac gatccaaaca atgtttctac tggcatagtg gatacgaaga tgctatccat 33600
cagaatgttt ccctgattag tattttctat atagctattc ttctttaaac gattttccaa 33660
atcagtaact atgttcattt ttttaggagt aggacgccta gccagtatgg aagaggattt 33720
tctagatcct ctcttcaaca tctttgatct caatggaatg caaaacccca tagtgtaaca 33780
accaacgata aaaataatat tgtttttcac tttttataat tttaccatct gactcatgga 33840
ttcattaata tctttataag agctactaac gtataattct ttataactga actgagatat 33900
atacaccgga tctatggttt ccataattga gtaaatgaat gctcggcaat aactaatggc 33960
aaatgtataa aacaacgaaa ttatactaga gttgttaaag ttaatatttt ctatgagctg 34020
ttccaataaa ttatttgttg taactgcgtt caagtcataa atcatcttga tactatccag 34080
taaaccgttt ttaagttctg gaatattatt atcccattgt aaagccccta attcgactat 34140
cgaatatcct gctctgatag cagtttcaat atcgacggac gtcaatactg taataaaggt 34200
ggtagtattg tcatcatcgt gataaactac tggaatatgg tcgttagtag gtacggtaac 34260
tttacacaac gcgatatata actttccttt tgtaccattt ttaacgtagt tgggacgtcc 34320
tgcagggtat tgttttgaag aaatgatatc gagaacagat ttgatacgat atttgttgga 34380
ttcctgatta tttactataa tataatctag acagatagat gattcgataa atagagaagg 34440
tatatcgttg gtaggataat acatccccat tccagtattc tcggatactc tattaatgac 34500
actagttaag aacatgtctt ctattctaga aaacgaaaac atcctacatg gactcattaa 34560
aacttctaac gctcctgatt gtgtctcgaa tgcctcgtac aaggatttca aggatgccat 34620
agattctttg accaacgatt tagaattgcg tttagcatct gattttttta ttaaatcgaa 34680
tggtcggctc tctggtttgc taccccaatg ataacaatag tcttgtaaag ataaaccgca 34740
agaaaattta tacgcatcca tccaaataac cctagcacca tcggatgata ttaatgtatt 34800
attatagatt ttccatccac agttattggg ccagtatact gttagcaacg gtatatcgaa 34860
tagattactc atgtaaccta ctagaatgat agttcgtgta ctagtcataa tatctttaat 34920
ccaatctaag aaatttaaaa ttagattttt tacactgtta aagttaacaa aggtattacc 34980
cggatacgtg gatatcatat atggtattgg tccattatca gtaatagctc cataaactga 35040
tacggcgatg gtttttatat gtgtttgatc taacgaggaa gaaattcgcg cccacaattc 35100
atctctagat atgtatttaa tatcaaacgg taacacatca atttcgggac gcgtatatgt 35160
ttctaaattt ttaatccaaa tataatgatg acctatatgc cctattatca tactgtcaac 35220
tatagtacac ctagagaact tacgatacat ctgtttccta taatcgttaa attttacaaa 35280
tctataacat gctaaacctt ttgacgacaa ccattcatta atttctgata tggaatctgt 35340
attctcaata ccgtatcgtt ctaaagccag tgctatatct ccctgttcgt gagaacgctt 35400
tcgtataata tcgatcaacg gataatctga agtttttgga gaataatatg actcatgatc 35460
tatttcgtcc ataaacaatc tagacatagg aattggaggc gatgatctta attttgtgca 35520
atgagtcgtc aatcctataa cttctaatat tgtaatattc atcatcgaca taacactatc 35580
tatgttatca tcgtatatta gtataccatg accttcttca tttcgtgcca aaatgatata 35640
cagtcttaaa tagttacgca atatctcaat agtttcataa ttgttagctg ttttcatcaa 35700
ggtttgtatc ctgtttaaca tgatggcgtt ctatacgttt ctatttttta aatttttaac 35760
gatttactgt ggctagatac ccaatctctc tcaaatattt ttttagcctc gcttacaagc 35820
tgtttatcta tactattaaa actgacgaat ccgtgatttt ggtaatgggt tccgtcgaaa 35880
tttgccgaag tgatatgaac atattcgtcg tcgactatca acaattttgt attattctga 35940
atagtgaaaa ccttcacaga tagatcattt tgaacacaca acgcgtctag acttctggcg 36000
gttgccatag aatatacgtc gttcttatcc caattaccaa ctagaagtct gatcttaact 36060
cctctattaa tggctgcttc tataatggag ttgtaaatgt cgggccaata gtagctatta 36120
ccgtcgacac gtgtagtggg aactatggcc aaatgttcaa tatctatact agtcttagcc 36180
gacttgagtt tatcaataac tacatcagtg tctagatctc tagaatatcc caataggtgt 36240
tccggagaat cagtaaagaa cactccacct ataggattct taatatgata cgcagtgcta 36300
actggcagac aacaagccgc agagcataaa ttcaaccatg aattttttgc gctattaaag 36360
gctttaaaag tatcaaatct tctacgaaga tctgtggcca gcgggggata atcagaatat 36420
acacctaacg ttttaatcgt atgtatagat cctccagtaa atgacgcgtt tcctacataa 36480
catctttcat tatctgacac ccaaaaacaa ccgagtagta gtcccacatt atttttttta 36540
tctatattaa cggttataaa atttatatcc gggcagtgac tttgtagctc tcccagattt 36600
cttttccctc gttcatctag caaaactatt attttaatcc ctttttcaga tgcctctttt 36660
agtttatcaa aaataagcgc tcccctagtc gtactcagag gattacaaca aaaagatgct 36720
atgtatatat atttcttagc tagagtgata atttcgttaa aacattcaaa tgttgttaaa 36780
tgatcggatc taaaatccat attttctggt agtgtttcta ccagcctaca ttttgctccc 36840
gcaggtaccg gtgcaaatgg ccacatttag ttaacataaa aacttataca tcctgttcta 36900
tcaacgattc tagaatatca tcggctatat cgctaaaatt ttcatcaaag tcgacatcac 36960
aacctaactc agtcaatata ttaagaagtt ccatgatgtc atcttcgtct atttctatat 37020
ccgtatccat tgtagattgt tgaccgatta tcgagtttaa atcattacta atactcaatc 37080
cttcagaata caatctgtgt ttcattgtaa atttataggc ggtgtattta agttggtaga 37140
ttttcaatta tgtatcaata tagcaacagt agttcttgct cctccttgat tctagcatcc 37200
tcttcattat tttcttctac gtacataaac atgtccaata cgttagacaa cacaccgacg 37260
atggcggccg ccacagacac gaatatgact aaaccgatga ccatttaaaa acccctctct 37320
agctttcact taaactgtat cgattattct tttagaacat gtataatata aaaacattat 37380
tctatttcga atttaggctt ccaaaaattt ttcatccgta aaccgataat aatatatata 37440
gacttgttaa tagtcggaat aaatagatta atgcttaaac tatcatcatc tccacgatta 37500
gagatacaat atttacattt tttttgctgt ttcgaaactt tatcaataca cgttaataca 37560
aacccaggaa ggagatattg aaactgaggc tgttgaaaat gaaacggtga atacaataat 37620
tcagataatg taaaatcatg attccgtatt ctgatgatat tagaactgct aatggatgtc 37680
gatggtatgt atctaggagt atctatttta acaaagcatc gatttgctaa tatacaatta 37740
tcattttgat taattgttat tttattcata ttcttaaaag gtttcatatt tatcaattct 37800
tctacattaa aaatttccat ttttaattta tgtagccccg caatactcct cattacgttt 37860
cattttttgt ctataatatc cattttgttc atctcggtac atagattatc caattgagaa 37920
gcgcatttag tagttttgta cattttaagt ttattgacga atcgtcgaaa actagttata 37980
gttaacattt tattatttga taccctgata ttaatacccc tgccgttact attatttata 38040
actgatgtaa tccacgtaac attggaatta actatcgata gtaatgcatc gacgcttcca 38100
aaattgtcta ttataaactc accgataatt tttttattac atgttttcat attcattagg 38160
attattaaat ctttaatctt actacgattg tatgcgttga tattgcaaga cgtcattcta 38220
aaagacggag gatctccatc aaatgccaga caatcacgta caaagtacat ggaaataggt 38280
tttgttctat tgcgcatcat agatttatat agaacacccg tagaaatact aatttgtttt 38340
actctataaa atactaatgc atctatttca tcgttttgta taacgtcttt ccaagtgtca 38400
aattccaaat ttttttcatt gatagtacca aattcttcta tctctttaac tacttgcata 38460
gataggtaat tacagtgatg cctacatgcc gttttttgaa actgaataga tgcgtctaga 38520
agcgatgcta cgctagtcac aatcaccact ttcatattta gaatatatat atgtaaaaat 38580
atagtagaat ttcattttgt tttttttcta tgctataaat gaattctcat tttgcatctg 38640
ctcatactcc gttttatatc aataccaaag aaggaagata tctggttcta aaagccgtta 38700
aagtatgcga tgttagaact gtagaatgcg aaggaagtaa agcttcctgc gtactcaaag 38760
tagataaacc ctcatcaccc gcgtgtgaga gaagaccttc gtccccttcc agatgcgaga 38820
gaatgaataa cccaggaaaa caagttccgt ttatgaggac ggacatgcta caaaatatgt 38880
tcgcggctaa tcgcgataat gtagcttcta gacttttgtc ctaaaataca attatatcct 38940
tttcgatatt aataaatccg tgtcgtccag gttttttatc tctttcagta tgtgaataga 39000
taggtatttt atctctattc atcatcgaat ttaagagatc cgataaacat tgtttgtatt 39060
ctccagatgt cagcatctga tacaacaata tatgtgcaca taaacctctg gcacttattt 39120
catgtacctt ccccttatca ctaaggagaa tagtatttga gaaatatgta tacatgatat 39180
tatcatgaat tagatataca gaatttgtaa cactctcgaa atcacacgat gtgtcggcgt 39240
taagatctaa tatatcactc gataacacat tttcatctag atacactaga cattttttaa 39300
agctaaaata gtctttagta gtaacagtaa ctatgcgatt attttcatcg atgatacatt 39360
tcatcggcat attattacgc ttaccatcaa agactatacc atgtgtatat ctaacgtatt 39420
ctagcatggt tgccatacgc gcattaaact tttcaggatc tttggataga tcttccaatc 39480
tatctatttg agaaaacatt tttatcatgt tcaatagttg aaacgtcgga tccactatat 39540
agatattatc tataaagatt ttaggaacta cgttcatggt atcctggcga atattaaaac 39600
tatcaatgat atgattatcg ttttcatctt ttatcaccat atagtttcta agatatggga 39660
ttttacttaa tataatatta tttcccgtaa taaattttat tagaaatgcc aaatctataa 39720
gaaaagtcct cgaattagtt tgaagaatat ctatatcgcc gtaccgtata tttggattaa 39780
ttagatatag agaatatgat ccgtaacata tacaactttt attatggcgt ctaagatatt 39840
cttccatcaa cttattaaca tttttgacta gggaagatac attatgacgt cccattactt 39900
ttgccttgtc tattactgcg acgttcatag aatttagcat atctcttgcc aattcttcca 39960
ttgatgttac attataagaa attttagatg aaattacatt tggagcttta atagtaagaa 40020
ctcctaatat gtccgtgtat gtggtcacta atacagattg tagttctata atcgtaaata 40080
atttacctat attatatgtt tgagtctgtt tagaaaagta gctaagtata cgatctttta 40140
tttctgatgc agatgtatca acatcggaaa aaaatctttt tttattcttt tttactaaag 40200
atacaaatat gtctttgtta aaaacagtta ttttctgaat atttctagct tgtaatttta 40260
acatatgata ttcgttcaca ctaggtactc tgcctaaata ggtttctata atctttaatg 40320
taatattagg aaaagtattc tgatcaggat tcctattcat tttgaggatt taaaactctg 40380
attattgtct aatatggtct caacacaaac tttttcacag agcgatagag tttttgataa 40440
ctcgtttttc ttaagaaata taaaactact gtctccagag ctcgctctat cttttatttt 40500
atttaattcg atacaaactc ctgatactgg ttcagaaagt aattcattaa ttttcagtcc 40560
tttatagaag atatttaata tagataatac aaaatcttca gtttttgata tcgatctgat 40620
tgatcctaga actagatata ttaataacgt gctcattagg cagtttatgg cagcttgata 40680
attagatata gtatattcca gttcatattt attagatacc gcattgccca gattttgata 40740
ttctatgaat tcctctgaaa ataaatccaa aataactaga cattctattt tttgtggatt 40800
agtgtactct cttccctcta tcatgttcac tactggtgtc cacgatgata aatatctaga 40860
gggaatataa tatagtccat aggatgccaa tctagcaatg tcgaataact gtaattttat 40920
tcttcgctct tcattatgaa ttgattcttg aggtataaac ctaacacaaa ttatattatt 40980
agacttttcg tatgtaatgt ctttcatgtt ataagttttt aatcctggaa tagaatctat 41040
tttaatgagg cttttaaacg cagagttctc caacgagtca aagcataata ctctgttggt 41100
tttcttatat acgatgttac gattttcttc tttgaatgga ataggttttt gaattagttt 41160
ataattacaa cataatagat aaggaagtgt gcaaatagta cgcggaaaaa acataatagc 41220
tcccctgttt tcatccatgg ttttaagtaa atgatcactg gcttctttag tcaatggata 41280
ttcgaacatt aaccgtttca tcatcattgg acagaatcca tatttcttaa tgtaaagagt 41340
gatcaaatca ttgtgtttat tgtaccatct tgttgtaaat gtgtattcgg ttatcggatc 41400
tgctcctttt tctattaaag tatcgatgtc gatctcgtct aagaattcaa ctatatcgac 41460
atatttcatt tgtatacaca taaccattac taacgtagaa tgtataggaa gagatgtaac 41520
gggaacaggg tttgttgatt cgcaaactat tctaatacat aattcttctg ttaatacgtc 41580
ttgcacgtaa tctattatag atgccaagat atctatataa ttattttgta agatgatgtt 41640
aactatgtga tctatataag tagtgtaata attcatgtat ttcgatatat gttccaactc 41700
tgtctttgtg atgtctagtt tcgtaatatc tatagcatcc tcaaaaaata tattcgcata 41760
tattcccaag tcttcagttc tatcttctaa aaaatcttca acgtatggaa tataataatc 41820
tattttacct cttctgatat cattaatgat atagtttttg acactatctt ctgtcaattg 41880
attcttattc actatatcta agaaacggat agcgtcccta ggacgaacta ctgccattaa 41940
tatctctatt atagcttctg gacataattc atctattata ccagaattaa tgggaactat 42000
tccgtatcta tctaacatag ttttaagaaa gtcagaatct aagacctgat gttcatatat 42060
tggttcatac atgaaatgat ctctattgat gatagtgact atttcattct ctgaaaattg 42120
gtaactcatt ctatatatgc tttccttgtt gatgaaggat agaatatact caatagaatt 42180
tgtaccaaca aactgttctc ttatgaatcg tatatcatca tctgaaataa tcatgtaagg 42240
catacattta acaattagag acttgtctcc tgttatcaat atactattct tgtgataatt 42300
tatgtgtgag gcaaatttgt ccacgttctt taattttgtt atagtagata tcaaatccaa 42360
tggagctaca gttcttggct taaacagata tagtttttct ggaacgaatt ctacaacatt 42420
attataaagg actttgggta gataagtggg atgaaatcct attttaatta atgcgatagc 42480
cttgtcctcg tgcagatatc caaacgcttt tgtgatagta tggcattcat tgtctagaaa 42540
cgctctacga atatctgtga cagatatcat ctttagagaa tatactagtc gcgttaatag 42600
tactacaatt tgtatttttt aatctatctc aataaaaaaa ttaatatgta tgattcaatg 42660
tataactaaa ctactaactg ttattgataa ctagaatcag aatctaatga tgacgtaacc 42720
aagaagttta tctactgcca atttagctgc attattttta gcatctcgtt tagattttcc 42780
atctgcctta tcgaatactc ttccgtcgat atctacacag gcataaaatg taggagagtt 42840
actaggcccc actgattcaa tacgaaaaga ccaatctctc ttagttattt ggcagtactc 42900
attaataatg gtgacagggt tagcatcttt ccaatcaata atttttttag ccggaataac 42960
atcatcaaaa gacttatgat cctctctcat tgatttttcg cgggatacat catctattat 43020
ggcgtcagcc ataacatcag catccggctt atccgcctcc gttgtcataa accaacgagg 43080
aggaatatcg tcggagctgt acaccatagc actacgttga agatcgtaca gagctttatt 43140
aacttctcgc ttctccatat taagttgtct agttagttgt gcagcagtag ctccttcgat 43200
tccaatgttt ttaatagccg cacacacaat ctctgcgtca gaacgctcgt caatatagat 43260
cttagacatt tttagagaga actaacacaa ccagcaataa aactaattta ttttatcatt 43320
tttttattca tcatcctctg gtggttcgtc gtttctatcg aatgtggatc tgattaaccc 43380
gtcatctata ggtgatgctg gttctggaga ttctggagga gatggattat tatctggaag 43440
aatctctgtt atttccttgt tttcatgtat cgattgcgtt gtaacattaa gattgcgaaa 43500
tgctctaaat ttgggaggct taaagtgttg tttgcaatct ctacacgcat gtctaactag 43560
tggaggttcg tcagcggctc tagtttgaat catcatcggc gtagtattcc tacttttaca 43620
gttaggacac ggtgtattgt atttctcgtc gagaacgtta aaataatcgt tgtaactcac 43680
atcctttatt ttatctatat tgtattctac tcctttctta atgcatttta taccgaataa 43740
gagatagcga aggaattctt tttcggtgcc gctagtaccc ttaatcatat cacatagtgt 43800
tttatattcc aaatttgtgg caatagacgg tttatttcta tacgatagtt tgtttctgga 43860
atcctttgag tattctatac caatattatt ctttgattcg aatttagttt cttcgatatt 43920
agattttgta ttacctatat tcttgatgta gtactttgat gatttttcca tggcccattc 43980
tattaagtct tccaagttgg catcatccac atattgtgat agtaattctc ggatatcagt 44040
agcggctacc gccattgatg tttgttcatt ggatgagtaa ctactaatgt atacattttc 44100
catttataac acttatgtat taactttgtt catttatatt ttttcattat tatgttgata 44160
ttaacaaaag tgaatatata tgttaataat tgtattgtgg ttatacggct acaatttcat 44220
aatgagtgga agtcagtgtc cgatgatcaa tgacgatagc tttactctga aaagaaagta 44280
tcaaatcgat agtgcggagt caacaataaa aatggataag aagaggataa agtttcagaa 44340
tagagccaaa atggtaaaag aaataaatca gacaataaga gcagcacaaa ctcattacga 44400
gacattgaaa ctaggataca taaaatttaa gagaatgatt aggactacta ctctagaaga 44460
tatagcacca tctattccaa ataatcagaa aacttataaa ctattctcgg acatttcagc 44520
catcggcaaa gcatcacaga atccgagtaa gatggtatat gctctgctgc tttacatgtt 44580
tcccaatttg tttggagatg atcatagatt cattcgttat agaatgcatc caatgagtaa 44640
aatcaaacac aagatcttct ctcctttcaa acttaatctt attagaatat tagtggaaga 44700
aagattctat aataatgaat gcagatctaa taaatggaga ataattggaa cacaagttga 44760
taaaatgttg atagctgaat ctgataaata tacaatagat gcaaggtata acctaaaacc 44820
catgtataga atcaagggaa aatctgaaga agataccctc tttatcaaac agatggtaga 44880
acaatgtgtg acatcccagg aattggtgga aaaagtgttg aagatactgt ttagagattt 44940
gttcaagagt ggagaataca aagcgtacag atacgatgat gatgtagaaa atggatttat 45000
tggattggat acactaaaat taaacattgt tcatgatata gttgaaccat gtatgcctgt 45060
tcgtaggcca gtggctaaga tactgtgtaa agaaatggta aataaatact ttgagaatcc 45120
gctacatatt attggtaaaa atcttcaaga gtgcattgac tttgttagtg aataggcatt 45180
tcatctttct ccaatactaa ttcaaattgt taaattaata atggatagta taaatagtta 45240
ttagtgataa aatagtaaaa ataattatta gaataagagt gtagtatcat agataactct 45300
cttctataaa aatggatttt attcgtagaa agtatcttat atacacagta gaaaataata 45360
tagatttttt aaaggatgat acattaagta aagtaaacaa ttttaccctc aatcatgtac 45420
tagctctcaa gtatctagtt agcaattttc ctcaacacgt tattactaag gatgtattag 45480
ctaataccaa tttttttgtt ttcatacata tggtacgatg ttgtaaagtg tacgaagcgg 45540
ttttacgaca cgcatttgat gcacccacgt tgtacgttaa agcattgact aagaattatt 45600
tatcgtttag taacgcaata caatcgtaca aggaaaccgt gcataaacta acacaagatg 45660
aaaaattttt agaggttgcc gaatacatgg acgaattagg agaacttata ggcgtaaatt 45720
atgacttagt tcttaatcca ttatttcacg gaggggaacc catcaaagat atggaaatca 45780
tttttttaaa actgtttaag aaaacagact tcaaagttgt taaaaaatta agtgttataa 45840
gattacttat ttgggcttac ctaagcaaga aagatacagg catagagttt gcggataatg 45900
atagacaaga tatatacact ctatttcaac aaactggtag aatagtccat agcaatctaa 45960
cagaaacgtt tagagattat atctttcccg gagataagac tagctattgg gtgtggttaa 46020
acgaaagtat agctaatgat gcggatattg ttcttaatag acacgccatt accatgtatg 46080
ataaaattct tagttatata tactctgaga taaaacaagg acgcgttaat aaaaacatgc 46140
ttaagttagt ttatatcttt gagcctgaaa aagatatcag agaacttctg ctagaaatca 46200
tatatgatat tcctggagat atcctatcta ttattgatgc aaaaaacgac gattggaaaa 46260
aatattttat tagtttttat aaagctaatt ttattaacgg taatacattt attagtgata 46320
gaacgtttaa cgaggactta ttcagagttg ttgttcaaat agatcccgaa tatttcgata 46380
atgaacgaat tatgtcttta ttctctacga gtgctgcgga cattaaacga tttgatgagt 46440
tagatattaa taacagttat atatctaata taatttatga ggtgaacgat atcacattag 46500
atacaatgga tgatatgaag aagtgtcaaa tctttaacga ggatacgtcg tattatgtta 46560
aggaatacaa tacatacctg tttttgcacg agtcggatcc catggtcata gagaacggaa 46620
tactaaagaa actgtcatct ataaaatcca agagtagacg gctgaacttg tttagcaaaa 46680
acattttaaa atattattta gacggacaat tggctcgtct aggtcttgtg ttagatgatt 46740
ataaaggaga cttgttagtt aaaatgataa accatcttaa gtctgtggag gatgtatccg 46800
cattcgttcg attttctaca gataaaaacc ctagtattct tccatcgcta atcaaaacta 46860
ttttagctag ttataatatt tccatcatcg tcttatttca aaggtttttg agagataatc 46920
tatatcatgt agaagaattc ttggataaaa gcatccatct aaccaagacg gataagaaat 46980
atatacttca attgataaga cacggtagat catagaacag accaaatata ttattaataa 47040
tttgtatata catagatata attatcacac atttttgata aatgggaact gctgcaacaa 47100
ttcagactcc caccaaatta atgaataaag aaaatgcaga aatgattttg gaaaaaattg 47160
ttgatcatat agttatgtat attagtgacg aatcaagtga ttcagaaaat aatcctgaat 47220
atattgattt tcgtaacaga tacgaagact atagatctct cattataaaa agtgatcacg 47280
agtttgtaaa gctatgtaaa aatcatgcag agaaaagttc tccagaaacg caacaaatga 47340
ttatcaaaca catatacgaa caatatctta ttccagtatc tgaagtacta ttaaaaccta 47400
taatgtccat gggtgacata attacatata acggatgtaa agacaatgaa tggatgctag 47460
aacaactctc taccctaaac tttaacaatc tccgcacatg gaactcatgt agcataggca 47520
atgtaacgcg tctgttttat acatttttta gttatctgat gaaagataaa ctaaatatat 47580
aagtataatc ccattctaat actttaacct gatgtattac ctgcatctta ttagaatatt 47640
aacctaacta aaagacataa catagttgat aaaaagcggt aggatataaa tattatggct 47700
gccaccgttc cgcgttttga cgacgtgtac aaaaatgcac aaagaagaat tctagatcaa 47760
gaaacatttt ttagtagagg tctaagtaga ccgttaatga aaaacacata tctatttgat 47820
aattacgcgt atggatggat accagaaact gcaatttgga gtagtagata cgcaaactta 47880
gatgcaagtg actattatcc catttcgttg ggattactta aaaagttcga gtttctcatg 47940
tctctatata aaggtcctat tcccgtatat gaagaaaaag taaatactga attcattgct 48000
aatggatcgt tctctggtag atacgtatca tatcttcgaa agttttctgc ccttccaaca 48060
aacgagttta ttagtttttt gttactgact tccattccaa tctataatat cttgttctgg 48120
tttaaaaata ctcagtttga tattactaaa cacacattat tcagatacgt ctatacagat 48180
aatgccaaac acctggcgtt ggctaggtat atgcatcaaa caggagacta taagcctttg 48240
tttagtcgtc tcaaagagaa ttatatattt accggtcccg ttccaataag tatcaaagat 48300
atagatcacc ctaatcttag tagagcaaga agtccatccg attatgagac attagctaat 48360
attagtacta tattgtactt taccaagtat gatccggtat taatgttttt attgttttac 48420
gtacctgggt attcaattac tacaaaaatt actccagccg tagaatatct aatggataaa 48480
ctgaatctaa caaagagcga cgtacaactg ttgtaaatta ttttatgctt cgtaaaatgt 48540
aggttttgaa ccaaacattc tttcaaagaa tgagatgcat aaaactttat tatccaatag 48600
attgactatt tcggacgtca atcgtttaaa gtaaacttcg taaaatattc tttgatcact 48660
gccgagttta aaacttctat cgataattgt ttcatatgtt ttaatattta caagtttttt 48720
ggtccatggt acattagccg gacaaatata tgcaaaataa tatcgttctc caagttctat 48780
agtttctgga ttatttttat tatattcagt aaccaaatac atattagggt tatctgcgga 48840
tttataattt gagtgatgca ttcgactcaa cataaataat tctagaggag acgatctact 48900
atcaaattcg gatcgtaaat ctgtttctaa agaacggaga atatctatac atacctgatt 48960
agaattcatc cgtccttcag acaacatctc agacagtctg gtcttgtatg tcttaatcat 49020
attcttatga aacttggaaa catctcttct agtttcacta gtacctttat taattctctc 49080
aggtacagat tttgaattcg acgatgctga gtatttcatc gttgtatatt tcttcttcga 49140
ttgcataatc agattcttat ataccgcctc aaactctatt ttaaaattat taaacaatac 49200
tctattatta atcagtcgtt ctaactcttt cgctatttct atagacttat cgacatcttg 49260
actgtctatc tctgtaaaca cggagtcggt atctccatac acgctacgaa aacgaaatct 49320
gtaatctata ggcaacgatg ttttcacaat cggattaata tctctatcgt ccatataaaa 49380
tggattactt aatggattgg caaaccgtaa cataccgtta gataactctg ctccatttag 49440
taccgattct agatacaaga tcattctacg tcctatggat gtgcaactct tagccgaagc 49500
gtatgagtat agagcactat ttctaaatcc catcagacca tatactgagt tggctactat 49560
cttgtacgta tattgcatgg aatcatagat ggccttttca gttgaactgg tagcctgttt 49620
tagcatcttt ttatatctgg ctctctctgc caaaaatgtt cttaatagtc taggaatggt 49680
tccttctatc gatctatcga aaattgctat ttcagagatg aggttcggta gtctaggttc 49740
acaatgaacc gtaatatatc taggaggtgg atatttctga agcaagagct gattatttat 49800
ttcttcttcc aatctattgg tactaacaac gacaccgact aatgtttccg gagatagatt 49860
tccaaagata cacacattag gatacagact gttataatca aagattaata cattattact 49920
aaacattttt tgttttggag caaatacctt accgccttca taaggaaact tttgttttgt 49980
ttctgatcta actaagatag ttttagtttc caacaatagc tttaacagtg gacccttgat 50040
gactgtactc gctctatatt cgaataccat ggattgagga agcacatatg ttgacgcacc 50100
cgcgtctgtt tttgtttcta ctccataata ctcccacaaa tactgacaca aacaagcatc 50160
atgaatacag tatctagcca tatctaaagc tatgtttaga ttataatcct tatacatctg 50220
agctaaatca acgtcatcct ttccgaaaga taatttatat gtatcattag gtaaagtagg 50280
acatgatagt acgactttaa atccattttc ccaaatatct ttacgaatta ctttacatat 50340
aatatcctca tcaacagtca cataattacc tgtggttaaa acctttgcaa atgcagcggc 50400
tttgcctttc gcgtccgtag tatcgtcacc gatgaacgtc atttctctaa ctcctctatt 50460
taatacttta cccatgcaac tgaacgcgtt cttggatata gaatccaatt tgtacgaatc 50520
caatttttca gatttttgaa tgaatgaata tagatcgaaa aatatagttc cattattgtt 50580
attaacgtga aacgtagtat tggccatgcc gcctactccc ttatgactag actgatttct 50640
ctcataaata cagagatgta cagcttcctt tttgtccgga gatctaaaga taatcttctc 50700
tcctgttaat aactctagac gattagtaat atatctcaga tcaaagttat gtccgttaaa 50760
ggtaacgacg tagtcgaacg ttagttccaa caattgttta gctattcgta acaaaactat 50820
ttcagaacat agaactagtt ctcgttcgta atccatttcc attagtgact gtatcctcaa 50880
acatcctcta tcgacggctt cttgtatttc ctgttccgtt aacatctctt cattaatgag 50940
cgtaaacaat aatcgtttac cacttaaatc gatataacag taacttgtat gcgagattgg 51000
gttaataaat acagaaggaa acttcttatc gaagtgacac tctatatcta gaaataagta 51060
cgatcttggg atatcgaatc taggtatttt tttagcgaaa cagttacgtg gatcgtcaca 51120
atgataacat ccattgttaa tctttgtcaa atattgctcg tccaacgagt aacatccgtc 51180
tggagatatc ccgttagaaa tataaaacca actaatattg agaaattcat ccatggtggc 51240
attttgtatg ctgcgtttct ttggctcttc tatcaaccac atatctgcga cggagcattt 51300
tctatcttta atatctagat tataacttat tgtctcgtca atgtctatag ttctcatctt 51360
tcccaacggc ctcgcattaa atggaggagg agacaatgac tgatatattt cgtccgtaac 51420
tacgtaataa aagtaatgag gaaatcgtat aaatacggtc tcgccatttc gacatctgga 51480
tttcagatat aaaaatctgt tttcaccgtg actttcaaac caattaatgc accgaacatc 51540
catttataga atttagaaat atattttcat ttaaatgaat cccaaacatt ggggaagagc 51600
cgtatggacc attattttta tagtactttc gcaagcgggt ttagacggca acatagaagc 51660
gtgtaaacga aaactatata ctatagtcag cactcttcca tgtcctgcat gtagacggca 51720
cgcgactatc gctatagagg acaataatgt catgtctagc gatgatctga attatattta 51780
ttattttttc atcagattat ttaacaattt ggcatctgat cccaaatacg cgatcgatgt 51840
gacaaaggtt aaccctttat aaacttaacc cattataaaa cttatgatta gtcacgactg 51900
aaataaccgc gtgattattt tttggtataa ttctacacgg catggtttct gtaactatga 51960
attcaacccc cgttacatta gtgaaatctt taacaaacag caagggttcg tcaaagacat 52020
aaaactcatt gtttacaatc gaaatagacc ccctatcaca cttaaaataa aaaatatcct 52080
tatcctttac caccaaataa aattctgatt ggtcaatgtg aatgtattca cttaacagtt 52140
ccacaaattt atttattaac tccgaggcac atacatcgtc ggtatttttt atggcaaact 52200
ttactcttcc agcatccgtt tctaaaaaaa tattaacgag ttccatttat atcatccaat 52260
attattgaaa tgacgttgat ggacagatga tacaaataag aaggtacggt acctttgtcc 52320
accatctcct ccaattcatg ctctattttg tcattaactt taatgtatga aaacagtacg 52380
ccacatgctt ccatgacagt gtgtaacact ttggatacaa aatgtttgac attagtataa 52440
ttgtccaaga ctgtcaatct ataatagata gtagctataa tatattctat gatggtattg 52500
aagaagatga caatcttggc atattgatca tttaacacag acatggtatc aacagatagc 52560
ttgaatgaaa gagaatcagt aattggaata agcgtcttct cgatagagtg tccgtatacc 52620
aacatgtctg atattttgat gtattccatt aaattattta gttttttctt tttattctcg 52680
ttaaacagca tttctgtcaa cggaccccaa catcgttgac cgattaagtt ttgattgatt 52740
tttccgtgta aggcgtatct agtcagatcg tatagcctat ccaataatcc atcatctgtg 52800
cgtagatcac atcgtacact ttttaattct ctatagaaga gcgacagaca gcaatttctt 52860
tattctctac agatgtaaga tacttgaaga cattcctatg atgatgcaga attttggata 52920
acacggtatt gatggtatct gttaccataa ttcctttgat ggctgatagt gtcagagcac 52980
aagatttcca atctttgttt tgatatctat atcagacagc atggtgcgtc tgacaacaca 53040
aggattaaga cggaaagatg aaatgattct ctcaacatct tcaatggata ccttgctatt 53100
ttttctggca ttatctatat gtgcgagaat atcctctaga gaatcagtat cctttttgat 53160
gatagtggat ctcaatgaca tgggacgtct aaaccttctt attctatcac cagattgcat 53220
ggtgatttgt cttctttctt ttatcataat gtaatctcta aattcatcgg caaattgtct 53280
atatctaaaa tcataatatg agatgtttac ctctacaaat atctgttcgt ccaatgttag 53340
agtatctaca tcagttttgt attccaaatt aaacatggca acggatttaa ttttatattc 53400
ctctattaag tcctcgtcga taataacaga atgtagataa tcatttaatc catcgtacat 53460
ggttggaaga tgcttgttga caaaatcttt aattgtcttg atgaaggtgg gactatatct 53520
aacatcttga ttaataaaat ttataacatt gtccatagga tactttgtaa ctagttttat 53580
acacatctct tcatcggtaa gtttagacag aatatcgtga acaggtggta tattatattc 53640
atcagatata cgaagaacaa tgtccaaatc tatattgttt aatatattat atagatgtag 53700
cgtagctcct acaggaatat ctttaactaa gtcaatgatt tcatcaaccg ttagatctat 53760
tttaaagtta atcatatagg cattgatttt taaaaggtat gtagccttga ctacattctc 53820
attaattaac cattccaagt cactgtgtgt aagaagatta tattctatca taagcttgac 53880
tacatttggt cccgatacca ttaaagaatt cttatgatat aaggaaacag attttaggta 53940
ctcatctact ctacaagaat tttggagagc cttaacgata tcagtgacgt ttattatttc 54000
aggaggaaag aatctaacat tgagaatatc ggaattaata gcttccagat acagtgattt 54060
tggcaatagt ccgtgtaatc cataatccag taacacgagc tggtgcttgc tagacacctt 54120
ttcaatgttt aatttttttg aaataagctt tgataaagcc ttcctcgcaa attccggata 54180
catgaacatg tcggcgacat gattaagtat tgttttttca ttattttctc aacaagttct 54240
caatacccca atagatgata gaatatcacc caatgcgtcc atgttgtcta tttccaacag 54300
gtcgctatat ccaccaatag aagtttttcc aaaaaagatt ctaggaacag ttctaccacc 54360
agtaatttgt tcaaaatagt cacgcaattc attttcgggt ttaaattctt taatatcgac 54420
aatttcatac gctcctcttt tgaaactaaa cttatttaga atatccagtg catttctaca 54480
aaaaggacat gtatacttga caaaaattgt cactttgtta ttggccaacc tttgttgtac 54540
aaattcctcg gccattttaa tatttaagtg atataaaact atctcgactt atttaactct 54600
ttagtcgaga tatatggacg cagatagcta tatgatagcc aactacagaa ggcaaacgct 54660
ataaaaaaca taattacgac gagcatattt ataaatattt ttattcagca ttacttgata 54720
tagtaatatt aggcacagtc aaacattcaa ccactctcga tacattaact ctctcatttt 54780
ctttaacaaa ttctacaata tcttcgtaaa aagattcttg aaacttttta gaatatctat 54840
cgactctaga tgaaatagcg ttcgtcaaca tactatgttt tgtatacata aaggcgccca 54900
ttttaacagt ttctagtgac aaaatgctag cgatcctagg atcctttaga atcacataga 54960
ttgacgattc gtctctctta gtaactctag taaaataatc atacaatcta gtacgcgaaa 55020
taatattatc cttgacttga ggagatctaa acaatctagt tttgagaaca tcgataagtt 55080
catcgggaat gacatacata ctatctttaa tagaactctt ttcatccagt tgaatggatt 55140
cgtccttaac caactgatta atgagatctt ctattttatc attttccaga tgatatgtat 55200
gtccattaaa gttaaattgt gtagcgcttc tttttagtct agcagccaat actttaacat 55260
cactaatatc gatatacaaa ggagatgatt tatctatggt attaagaatt cgtttttcga 55320
catctgtcaa aaccaattcc tttttgcctg tatcatccag ttttccatcc tttgtaaaga 55380
aattattttc tactagacta ttaataagac tgataaggat tcctccataa ttgcacaatc 55440
caaacttttt aacaaaacta gactttacaa gatctacagg aatgcgtaat tcaggtttct 55500
tagcttgtga ttttttcttt tgtggacatt ttcttgtgac caactcatct accatttcat 55560
tgattttagc agtgaaataa gctttcaatg cacgggcact gatactattg aaaacgagtt 55620
gatcttcaaa ttccgccatt taagttcacc aaacaacttt taaatacaaa tatatcaata 55680
gtagtagaat aagaactata aaaaaaataa taattaacca ataccaaccc caacaaccgg 55740
tattattagt tgatgtgact gttttctcat cacttagaac agatttaaca atttctataa 55800
agtctgtcaa atcatcttcc ggagacccca taaatacacc aaatatagcg gcgtacaact 55860
tatccattta tacattgaat attggctttt ctttatcgct atcttcatca tattcatcat 55920
caatatcaac aagtcccaga ttacgagcca gatcttcttc tacattttca gtcattgata 55980
cacgttcact atctccagag agtccgataa cgttagccac cacttctcta tcaatgatta 56040
gtttcttgag tgcgaatgta atttttgttt ccgttccgga tctatagaag acgataggtg 56100
tgataattgc cttggccaat tgtctttctc ttttactgag tgattctagt tcaccttcta 56160
tagatctgag aatggatgat tctccagtcg aaacatattc taccatggat ccgtttaatt 56220
tgttgatgaa gatggattca tccttaaatg ttttctctgt aatagtttcc accgaaagac 56280
tatgcaaaga atttggaatg cgttccttgt gcttaatgtt tccatagacg gcttctagaa 56340
gttgatacaa cataggacta gccgcggtaa cttttatttt tagaaagtat ccatcgcttc 56400
tatcttgttt agatttattt ttataaagtt tagtctctcc ttccaacata ataaaagtgg 56460
aagtcatttg actagataaa ctatcagtaa gttttataga gatagacgaa caattagcgt 56520
attgagaagc atttagtgta acgtattcga tacattttgc attagattta ctaatcgatt 56580
ttgcatactc tataacaccc gcacaagtct gtagagaatc gctagatgca gtaggtcttg 56640
gtgaagtttc aactctcttc ttgattacct tactcatgat taaacctaaa taattgtact 56700
ttgtaatata atgatatata ttttcacttt atctcatttg agaataaaaa tgtttttgtt 56760
taaccactgc atgatgtaca gatttcggaa tcgcaaacca ccagtggttt tattttatcc 56820
ttgtccaatg tgaattgaat gggagcggat gcgggtttcg tacgtagata gtacattccc 56880
gtttttagac cgagactcca tccgtaaaaa tgcatactcg ttagtttgga ataactcgga 56940
tctgctatat ggatattcat agattgactt tgatcgatga aggctcccct gtctgcagcc 57000
atttttatga tcgtcttttg tggaatttcc caaatagttt tataaactcg cttaatatct 57060
tctggaaggt ttgtattctg aatggatcca ccatctgcca taatcctatt cttgatctca 57120
tcattccata attttctctc ggttaaaact ctaaggagat gcggattaac tacttgaaat 57180
tctccagaca atactctccg agtgtaaata ttactggtat acggttccac cgactcatta 57240
tttcccaaaa tttgagcagt tgatgcagtc ggcataggtg ccaccaataa actatttcta 57300
agaccgtatg ttctgatttt atcttttaga ggttcccaat tccaaagatc cgacggtaca 57360
acattccaaa gatcatattg tagaataccg ttactggcgt acgatcctac atatgtatcg 57420
tatggtcctt ccttctcagc tagttcacaa ctcgcctcta atgcaccgta ataaatggtt 57480
tcgaagatct tcttatttag atcttgtgct tccaggctat caaatggata atttaagaga 57540
ataaacgcgt ccgctaatcc ttgaacacca ataccgatag gtctatgtct cttattagag 57600
atttcagctt ctggaatagg ataataatta atatctataa ttttattgag atttctgaca 57660
attactttga ccacatcctt cagtttgaga aaatcaaatc gcccatctat tacaaacatg 57720
ttcaaggcaa cagatgccag attacaaacg gctacctcat tagcatccgc atattgtatt 57780
atctcagtgc aaagattact acacttgata gttcctaaat tttgttgatt actctttttg 57840
ttacacgcat ccttataaag aatgaatgga gtaccagttt caatctgaga ttctataatc 57900
gctttccaga cgactcgagc ctttattata gatttgtatc tcctttctct ttcgtatagt 57960
gtatacaatc gttcgaactc gtctccccaa acattgtcca atccaggaca ttcatccgga 58020
cacatcaacg accactctcc gtcatccttc actcgtttca taaagagatc aggaatccaa 58080
agagctataa atagatctct ggttctatgt tcctcgtttc ctgtattctt tttaagatcg 58140
aggaacgcca taatatcaga atgccacggt tccaagtata tggccataac tccaggccgt 58200
ttgtttcctc cctgatctat gtatctagcg gtgttattat aaactctcaa cattggaata 58260
ataccgtttg atataccatt ggtaccggag atatagcttc cactggcacg aatattacta 58320
attgatagac ctattccccc tgccatttta gagattaatg cgcatcgttt taacgtgtca 58380
tagataccct ctatgctatc atcgatcatg ttaagtagaa aacagctaga catttggtga 58440
cgactagttc ccgcattaaa taaggtagga gaagcgtgcg taaaccattt ttcagaaagt 58500
agattgtacg tctcaatagc tgagtctata tcccattgat gaattcctac tgcgacacgc 58560
attaacatgt gctgaggtct ttcaacgatc ttgttgttta ttttcaacaa gtaggatttt 58620
tccaaagttt taaaaccaaa atagttgtat gaaaagtctc gttcgtaaat aataaccgag 58680
ttgagtttat ccttatattt gttaactata tccatggtga tacttgaaat aatcggagaa 58740
tgtttcccat ttttaggatt aacatagttg aataaatcct ccatcacttc actaaatagt 58800
ttttttgttt ccttgtgtag atttgatacg gctattctgg cggctagaat ggcataatcc 58860
ggatgttgtg tagtacaagt ggctgctatt tcggctgcca gagtgtccaa ttctaccgtt 58920
gttactccat tatatattcc ttgaataacc ttcatagcta ttttaatagg atctatatga 58980
tccgtgttta agccataaca taattttcta atacgagacg tgattttatc aaacatgaca 59040
ttttccttgt atccatttcg tttaatgaca aacatttttg ttggtgtaat aaaaaaaatt 59100
atttaacttt tcattaatag ggatttgacg tatgtagcgt acaaaattat cgttcctggt 59160
atatagataa agagtcctat atatttgaaa atcgttacgg ctcgattaaa ctttaatgat 59220
tgcatagtga atatatcatt aggatttaac tccttgacta tcatggcggc gccagaaatt 59280
accatcaaaa gcattaatac agttatgccg atcgcagtta gaacggttat agcatccacc 59340
atttatatct aaaaattaga tcaaagaata tgtgacaaag tcctagttgt atactgagaa 59400
ttgacgaaac aatgtttctt acatattttt tttttattag taaccgactt aatagtagga 59460
actggaaaac tagacttgat tattctataa gtatagatac ccttccaaat aatattctct 59520
ttgataaaag ttccagaaaa tgtagaattt tttaaaaagt tatcttttgc tattaccaag 59580
attgtgttta gacgcttatt attaatatga gtgatgaaat ccacaccgcc tctagatatc 59640
gcttttattt ccacattaga tggtaaatcc aatagtgaaa ctatcttttt aggaatgtat 59700
ggactcgcgt ttagaggagt gaacgtctta ggcgtcggaa aggatgattc atcaaacgaa 59760
taaacaattt cacaaatgga tgttaatgta ttagtaggaa attttttgac gctagtggaa 59820
ttgaagattc taatggatga tgttctacct atttcatccg ataacatgtt aatttccgac 59880
accaacggtt ttaatatttc gatgatatac ggtagtctct ctttcggact tatatagctt 59940
attccacaat acgagtcatt atatactcca aaaaacaaaa taactagtat aaaatctgta 60000
tcgaatggga aaaacgaaat tatcgacata ggtatagaat ctggaacatt gaacgtatta 60060
atacttaatt ctttttctgt ggtaagtacc gataggttat tgacattgta tggttttaaa 60120
tattctataa cttgagactt gatagatatt agtgatgaat tgaaaattat ttttatcacc 60180
acgtgtgttt caggatcatc gtcgacgccc gtcaaccaac cgaatggagt aaaataaata 60240
tcattaatat atgctctaga tattagtatt tttatcaatc ctttgattat catcttctcg 60300
taggcgaatg attccatgat caagagtgat ttaagaacat cctccggagt attaatgggc 60360
ttagtaaaca gtccatcgtt gcaataataa aagttatcca agttaaagga tattatgcat 60420
tcgtttaaag atatcacctc atctgacgga gacaattttt tggtaggttt tagagacttt 60480
gaagctactt gtttaacaaa gttattcatc gtcgtttact attctattta attttgtagt 60540
taatttatca catatcacat taattgactt tttggtccat ttttccatac gtttatattc 60600
ttttaatcct gcgttatccg tttccgttat atccagggat agatcttgca agttaaatag 60660
aatgctctta aataatgtca ttttcttatc cgctaaaaat ttaaagaatg tataaacctt 60720
tttcagagat ttgaaactct taggtggtgt cctagtacac aatatcataa acaaactaat 60780
aaacattcca cattcagatt ccaacagctg attaacttct acattaatac agcctatttt 60840
cgctccaaat gtacattcga aaaatctgaa taaaacatcg atgtcacaat ttgtattatc 60900
caatacagaa tgtttgtgat tcgtgttaaa accatcggag aaggaataaa aataaaaatt 60960
attatagtgg tggaattcag ttggaatatt gcctccggag tcataaaagg atactaaaca 61020
ttgtttttta tcataaatta cacatttcca atgagacaaa taacaaaatc caaacattac 61080
aaatctagag gtagaacttt taattttgtc tttaagtata tacgataaga tatgtttatt 61140
cataaacgcg tcaaattttt catgaatcgc taaggagttt aagaatctca tgtcaaattg 61200
tcctatataa tccacttcgg atccataagc aaactgagag actaagttct taatacttcg 61260
attgctcatc caggctcctc tctcaggctc tattttcatc ttgacgacct ttggattttc 61320
accagtatgt attcctttac gtgataaatc atcgattttc aaatccattt gtgagaagtc 61380
tatcgcctta gatacttttt cccgtagtcg aggtttaaag aaatacgcta acggtatact 61440
agtaggtaac tcaaagacat catatataga atggtaacgc gtctttaact cgtcggttaa 61500
ctctttcttt tgatcgagtt cgtcgctact attgggtctg ctcaggtgcc ccgactctac 61560
tagttccaac atcataccga taggaataca agacactttg ccggcggttg tagatttatc 61620
atatttctcc actacatatc cgttacaatt tgttaaaaat ttagatacat ctatattgct 61680
acataatcca gctagtgaat atatatgaca taataaattg gtaaatccta gttctggtat 61740
tttactaatt actaaatctg tatatctttc catttatcat ggaaaagaat ttaccagata 61800
tcttcttttt tccaaactgc gttaatgtat tctcttacaa atattcacaa gatgaattca 61860
gtaatatgag taaaacggaa cgtgatagtt tctcattggc ggtgtttcca gttataaaac 61920
atagatggca taacgcacac gttgtaaaac ataaaggaat atacaaagtt agtacagaag 61980
cacgtggaaa aaaagtatct cctccatcac taggaaaacc cgcacacata aacctaaccg 62040
cgaagcaata tatatacagt gaacacacaa taagctttga atgttatagt tttctaaaat 62100
gtataacaaa tacagaaatc aattcgttcg atgagtatat attaagagga ctattagaag 62160
ctggtaatag tttacagata ttttccaatt ccgtaggtaa acgaacagat actataggtg 62220
tactagggaa taagtatcca tttagcaaaa ttccattggc ctcattaact cctaaagcac 62280
aacgagagat attttcagcg tggatttctc atagacctgt agttttaact ggaggaactg 62340
gagtgggtaa gacgtcacag gtacccaagt tattgctttg gtttaattat ttatttggtg 62400
gattctctac tctagataaa atcactgact ttcacgaaag accagtcatt ctatctcttc 62460
ctaggatagc tttagttaga ttgcatagca ataccatttt aaaatcattg ggatttaagg 62520
tactagatgg atctcctatt tctttacggt acggatctat accggaagaa ttaataaaca 62580
aacaaccaaa aaaatatgga attgtatttt ctacccataa gttatctcta acaaaactat 62640
ttagttatgg cactcttatt atagacgaag ttcatgagca tgatcaaata ggagatatta 62700
ttatagcagt agcgagaaag catcatacga aaatagattc tatgttttta atgactgcca 62760
cgttagagga tgacagggaa cggctaaaag tatttttacc taatcccgca tttatacata 62820
ttcctggaga tacactgttt aaaattagcg aggtatttat tcataataag ataaatccat 62880
cttccagaat ggcatacata gaagaagaaa agagaaattt agttactgct atacagatgt 62940
atactcctcc tgatggatca tccggtatag tctttgtggc atccgttgca cagtgtcacg 63000
aatataaatc atatttagaa aaaagattac cgtatgatat gtatattatt catggtaagg 63060
tcttagatat agacgaaata ttagaaaaag tgtattcatc acctaatgta tcgataatta 63120
tttctactcc ttatttggaa tccagcgtta ctatacgcaa tgttacacac atttatgata 63180
tgggtagagt ttttgtcccc gctccttttg gaggatcgca agaatttatt tctaaatcta 63240
tgagagatca acgaaaagga agagtaggaa gagttaatcc tgggacatac gtatatttct 63300
atgatctgtc ttatatgaag tctatacagc gaatagattc agaatttcta cataattata 63360
tattgtacgc taataagttt aatctaacac tccccgaaga tttgtttata atccctacaa 63420
atttggatat tctatggcgt acaaaggaat atatagactc gttcgatatt agtacagaaa 63480
catggaataa attattatcc aattattata tgaagatgat agagtatgct aaactttatg 63540
tactaagtcc tattctcgct gaggagttgg ataattttga gaggacggga gaattaacta 63600
gtattgtaca agaagccatt ttatctctaa atttacgaat taagatttta aattttaaac 63660
ataaagatga tgatacgtat atacactttt gtaaaatatt attcggtgtc tataacggaa 63720
caaacgctac tatatattat catagacctc taacgggata tatgaatatg atttcagata 63780
ctatatttgt tcctgtagat aataactaaa aatcaaactc taatgaccac atcttttttt 63840
agagatgaaa aattttccac atctcctttt gtagacacga ctaaacattt tgcagaaaaa 63900
agtttattag tgtttagata atcgtatact tcatcagtgt agatagtaaa tgtgaacaga 63960
taaaaggtat tcttgctcaa tagattggta aattccatag aatatattaa tcctttcttc 64020
ttgagatccc acatcatttc aaccagagac gttttatcca atgatttacc tcgtactata 64080
ccacatacaa aactagattt tgcagtgacg tcgtatctgg tattcctacc aaacaaaatt 64140
ttacttttag ttcttttaga aaattctaag gtagaatctc tatttgccaa tatgtcatct 64200
atggaattac cactagcaaa aaatgataga aatatatatt gatacatcgc agctggtttt 64260
gatctactat actttaaaaa cgaatcagat tccataattg cctgtatatc atcagctgaa 64320
aaactatgtt ttacacgtat tccttcggca tttcttttta atgatatatc ttgtttagac 64380
aatgataaag ttatcatgtc catgagagac gcgtctccgt atcgtataaa tatttcatta 64440
gatgttagac gcttcattag gggtatactt ctataaggtt tcttaatcag tccatcattg 64500
gttgcgtcaa gaactactat cggatgttgt tgggtatctc tagtgttaca catggcctta 64560
ctaaagtttg ggtaaataac tatgatatct ctattaatta tagatgcata tatttcattt 64620
gtcaaggata ttagtatcga cttgctatcg tcattaatac gtgtaatgta atcatataaa 64680
tcatgcgata gccaaggaaa atttaaatag atgttcatca tataatcgtc gctataattc 64740
atattaatac gttgacattg actaatttgt aatatagcct cgccacgaag aaagctctcg 64800
tattcagttt catcgataaa ggataccgtt aaatataact ggttgccgat agtctcatag 64860
tctattaagt ggtaagtttc gtacaaatac agaatcccta aaatattatc taatgttgga 64920
ttaatcttta ccataactgt ataaaatgga gacggagtca taactatttt accgtttgta 64980
cttactggaa tagacgaagg aataatctcc ggacatgctg gtaaagaccc aaatgtctgt 65040
ttgaagaaat ccaatgttcc aggtcctaat ctcttaacaa aaattacgat attcgatccc 65100
gatatccttt gcattctatt taccagcata tcacgaacta tattaagatt atctatcatg 65160
tctattctcc caccgttata taaatcgcct ccgctaagaa acgttagtat atccatacaa 65220
tggaatactt catttctaaa atagtattcg ttttctaatt ctttaatgtg aaatcgtata 65280
ctagaaaggg aaaaattatc tttgagtttt ccgttagaaa agaaccacga aactaatgtt 65340
ctgattgcgt ccgattccgt tgctgaatta atggatttac accaaaaact catataactt 65400
ctagatgtag aagcattcgc taaaaaatta gtagaatcaa aggatataag tagatgttcc 65460
aacaagtgag caattcccaa gatttcatct atatcattct cgaatccgaa attagaaatt 65520
cccaagtaga tatccttttt catccgatcg ttgatgaaaa tacgaacttt attcggtaag 65580
acaatcattt actaaggagt aaaataggaa gtaatgttcg tatgtcgtta tcatcgtata 65640
aattaaaggt gtgtttttta ccattaagtg acattataat tttaccaata ttggaattat 65700
aatataggtg tatttgcgca ctcgcgacgg ttgatgcatc ggtaaatata gctgtatcta 65760
atgttctagt cggtatttca tcatttcgct gtctaataat agcgttttct ctatctgttt 65820
ccattacagc tgcctgaagt ttattggtcg gataatatgt aaaataataa gaaatacata 65880
cgaataacaa aaataaaata agatataata aagatgccat ttagagatct aattttgttt 65940
aacttgtcca aattcctact tacagaagat gaggaatcgt tggagatagt gtcttcctta 66000
tgtagaggat ttgaaatatc ttatgatgac ttgataactt actttccaga taggaaatac 66060
cataaatata tttctaaagt atttgaacat gtagatttat cggaggaatt aagtatggaa 66120
ttccatgata caactctgag agatttagtc tatcttagat tgtacaagta ttccaagtgt 66180
atacggccgt gttataaatt aggagataat ctaaaaggca tagttgttat aaaggacagg 66240
aatatttata ttagagaagc aaatgatgac ttgatagaat atctcctcaa ggaatacact 66300
cctcagattt atacatattc taatgagcgc gtccccataa ctggttcaaa attaattctt 66360
tgtggatttt ctcaagttac atttatggcg tatacaacgt cgcatataac aacaaataaa 66420
aaggtagatg ttctcgtttc caaaaaatgt atagatgaac tagtcgatcc aataaattat 66480
caaatacttc aaaatttatt tgataaagga agcggaacaa taaacaaaat actcaggaag 66540
atattttatt cggtaaccgg tggccaaact ccataatttg ctttttctat ttcggatttt 66600
agaatttcca aattcaccag cgatttatcg gttttggtga aatccaagga tttattaatg 66660
tccacaaatg ccatttgttt tgtctgtgga ttgtatttga aaatggaaac gatgtagtta 66720
gatagatgcg ctgcaaagtt tcctattagg gttccgcgct ttacgtcacc cagcatactt 66780
gaatcaccat cctttaaaaa aaatgataag atatcaacat ggagtatatc atactcggat 66840
tttaattctt ctactgcatc actgacattt tcacaaatac tacaatacgg tttaccgaaa 66900
ataatcagta cgttcttcat ttatgggtat caaaaactta aaatcgttac tgctggaaaa 66960
taaatcactg acgatattag atgataattt atacaaagta tacaatggaa tatttgtgga 67020
tacaatgagt atttatatag ccgtcgccaa ttgtgtcaga aacttagaag agttaactac 67080
ggtattcata aaatacgtaa acggatgggt aaaaaaggga gggcatgtaa ccctttttat 67140
cgatagagga agtataaaaa ttaaacaaga cgttagagac aagagacgta aatattctaa 67200
attaaccaag gacagaaaaa tgctagaatt agaaaagtgt acatccgaaa tacaaaatgt 67260
taccggattt atggaagaag aaataaaggc agaaatgcaa ttaaaaatcg ataaactcac 67320
atttcaaata tatttatctg attctgataa cataaaaata tcattgaatg agatactaac 67380
acatttcaac aataatgaga atgttacatt attttattgt gatgaacgag acgcagaatt 67440
cgttatgtgt ctcgaggcta aaacacattt ctctaccaca ggagaatggc cgttgataat 67500
aagtaccgat caggatacta tgctatttgc atctactgat aatcatccta agatgataaa 67560
aaacttaact caactgttta aatttgttcc ctcggcagag gataactatt tagcaaaatt 67620
aacggcgtta gtgaatggat gtgatttctt tcctggactc tatggggcat ctataacacc 67680
caccaactta aacaaaatac aattgtttag tgattttaca atcgataata tagtcactag 67740
tttggcaatt aaaaattatt atagaaagac taactctacc gtagacgtgc gtaatattgt 67800
tacgtttata aacgattacg ctaatttaga cgatgtctac tcgtatgttc ctccttgtca 67860
atgcactgtt caagaattta tattttccgc attagatgaa aaatggaaca attttaaatc 67920
atcttattta gagaccgttc cgttaccctg ccaattaatg tatgcattag aaccacgcaa 67980
ggagattgat gtttcagaag ttaaaacttt atcatcttat atagatttcg aaaatactaa 68040
atcagatatc gatgttataa aatctatatc ttcgatcttc ggatattcta acgaaaactg 68100
taacactata gtgttcggca tctataagga taatttacta ctgagtataa atagttcatt 68160
ttactttaac gatagtctgt taataaccaa tactaaaagt gataatataa taaatatagg 68220
ttactagatt aaaaatggtg ttccaactcg tgtgctctac gtgcggcaaa gatatttctc 68280
acgaacgata taaattgatt atacgaaaaa aatcattaaa ggatgtactc gtcagtgtaa 68340
agaacgaatg ttgtaggtta aaattatcta cacaaataga acctcaacgt aacttaacag 68400
tgcaacctct attggatata aactaatatg gatccggtta attttatcaa gacatatgcg 68460
cctagaggtt ctattatttt tattaattat accatgtcat taacaagtca tttgaatcca 68520
tcgatagaaa aacatgtggg tatttattat ggtacgttat tatcggaaca cttggtagtt 68580
gaatctacct atagaaaagg agttcgaata gtcccattgg atagtttttt tgaaggatat 68640
cttagtgcaa aagtatacat gttagagaat attcaagtta tgaaaatagc agctgatacg 68700
tcattaactt tattgggtat tccgtatgga tttggtcata atagaatgta ttgttttaaa 68760
ttggtagctg aatgttataa aaatgccggt attgatacat cgtctaaacg aatattaggt 68820
aaagatattt ttctgagcca aaacttcaca gatgataata gatggataaa gatatatgat 68880
tctaataatt taacattttg gcaaattgat taccttaaag ggtgagttaa tatgcataac 68940
tactcctccg ttgttttttc cctcgttctt tttcttaacg ttgtttgcca tcactctcat 69000
aatgtaaaga tattctaaaa tggtaaactt ttgcatatcg gacgcagaaa ttggtataaa 69060
tgttgtaatt gtattatttc ccgtcaatgg actagtcaca gctccatcag ttttatatcc 69120
tttagagtat ttctcactcg tgtctaacat tctagagcat tccatgatct gtttatcgtt 69180
gatattggcc ggaaagatag attttttatt ttttattata ttactattgg caattgtaga 69240
tataacttct ggtaaatatt tttctacctt ttcaatctct tctattttca agccggctat 69300
atattctgct atattgttgc tagtatcaat accttttctg gctaagaagt catatgtggt 69360
attcactata tcagttttaa ctggtagttc cattagcctt tccacttctg cagaataatc 69420
agaaattggt tctttaccag aaaatccagc tactataata ggctcaccga tgatcattgg 69480
caaaatccta tattgtacca gattaatgag agcatatttc atttccaata attctgctag 69540
ttcttgagac attgatttat ttgatgaatc tagttggttc tctagatact ctaccatttc 69600
tgccgcatac aataacttgt tagataaaat cagggttatc aaagtgttta gcgtggctag 69660
aatagtgggc ttgcatgtat taaagaatgc ggtagtatga gtaaaccgtt ttaacgaatt 69720
atatagtctc cagaaatctg tggcgttaca tacatgagcc gaatgacatc gaagattgtc 69780
caatattttt aatagctgct ctttgtccat tatttctata tttgactcgc aacaattgta 69840
gataccatta atcactgatt cctttttcga tgccggacaa tagcacaatt gtttagcttt 69900
ggactctatg tattcagaat taatagatat atctctcaat acagattgca ctatacattt 69960
tgaaactatg tcaaaaattg tagaacgacg ctgttctgca gccatttaac tttaaataat 70020
ttacaaaaat ttaaaatgag catccgtata aaaatcgata aactgcgcca aattgtggca 70080
tatttttcag agttcagtga agaagtatct ataaatgtag actcgacgga tgagttaatg 70140
tatatttttg ccgccttggg cggatctgta aacatttggg ccattatacc tctcagtgca 70200
tcagtgttct accgcggagc cgaaaacatt gtgtttaatc ttcctgtgtc caaggtaaaa 70260
tcgtgtttgt gtagttttca caatgatgcc atcatagata tagaacctga tctggaaaat 70320
aatctagtaa aactttctag ttatcatgta gtaagtgtcg attgtaacaa ggaactgatg 70380
cctattagga cagatactac tatttgtcta agtatagatc aaaagaaatc ttacgtgttt 70440
aattttcaca agtatgaaga aaaatgttgt ggtagaaccg tcattcattt agaatggttg 70500
ttgggcttta tcaagtgtat tagtcagcat cagcatttgg ctattatgtt taaagatgac 70560
aatattatta tgaagactcc tggtaatact gatgcgtttt ccagggaata ttctatgact 70620
gaatgttctc aagaactaca aaagttttct ttcaaaatag ctatctcgtc tctcaacaaa 70680
ctacgaggat tcaaaaagag agtcaatgtt tttgaaacta gaatcgtaat ggataatgac 70740
gataacattc taggaatgtt gttttcggat agagttcaat cctttaagat caacatcttt 70800
atgacgtttt tagattaata ctttcaatga gataaatatg ggtggcagag taagtgttga 70860
gctccctaaa cgggatccgc ctccgggagt acccactgat gagatgttat taaacgtgga 70920
taaaatgcat gacgtgatag ctcccgctaa gcttttagaa tatgtgcata taggaccact 70980
agcaaaagat aaagaggata aagtaaagaa aagatatcca gagtttagat tagtcaacac 71040
aggacccggt ggtctttcgg cattgttaag acaatcgtat aatggaaccg cacccaattg 71100
ctgtcgcact tttaatcgta ctcattattg gaaaaaggat ggaaagatat cagataagta 71160
tgaagagggt gcagtattag aatcgtgttg gccagacgtt cacgacactg gaaaatgcga 71220
tgttgattta ttcgactggt gtcaggggga tacgttcgat agaaacatat gccatcagtg 71280
gatcggttca gcctttaata ggagtgatag aactgtagag ggtcaacaat cgttaataaa 71340
tctgtataat aagatgcaaa cattatgtag taaagatgct agtgtaccaa tatgtgaatc 71400
atttttgcat catttacgcg cacacaatac agaagatagc aaagagatga tcgattatat 71460
tctaagacaa cagtctgcgg actttaaaca gaaatatatg agatgtagtt atcccactag 71520
agataagtta gaagagtcat taaaatatgc ggaacctcga gaatgttggg atccagagtg 71580
ttcgaatgcc aatgttaatt tcttactaac acgtaattat aataatttag gactttgcaa 71640
tattgtacga tgtaatacta gcgtgaacaa cttacagatg gataaaactt cctcattaag 71700
attgtcatgt ggattaagca atagtgatag attttctact gttcccgtca atagagcaaa 71760
agtagttcaa cataatatta aacattcgtt cgacctaaaa ttgcatttga tcagtttatt 71820
atctctcttg gtaatatgga tactaattgt agctatttaa atgggtgccg cggcaagcat 71880
acagacgacg gtgaatacac tcagcgaacg tatctcgtct aaattagaac aagaagcgaa 71940
cgctagtgct caaacaaaat gtgatataga aatcggaaat ttttatatcc gacaaaacca 72000
tggatgtaac ctcactgtta aaaatatgtg ctctgcggac gcggatgctc agttggatgc 72060
tgtgttatca gccgctacag aaacatatag tggattaaca ccggaacaaa aagcatacgt 72120
accagctatg tttactgctg cgttaaacat tcagacgagt gtaaacactg ttgttagaga 72180
ttttgaaaat tatgtgaaac agacttgtaa ttctagcgcg gtcgtcgata acaaattaaa 72240
gatacaaaac gtaatcatag atgaatgtta cggagcccca ggatctccaa caaatttgga 72300
atttattaat acaggatcta gcaaaggaaa ttgtgccatt aaagcgttga tgcaattgac 72360
gactaaggcc actactcaaa tagcacctag acaagttgct ggtacaggag ttcagtttta 72420
tatgattgtt atcggtgtta taatattggc agcgttgttt atgtactatg ccaagcgtat 72480
gttgttcaca tccaccaatg ataaaatcaa acttatttta gccaataagg aaaacgtcca 72540
ttggactact tacatggaca cattctttag aacttctccg atggttattg ctaccacgga 72600
tatgcaaaac tgaaaatata ttgataatat tttaatagat taacatggaa gttatcgctg 72660
atcgtctaga cgatatagtg aaacaaaata tagcggatga aaaatttgta gattttgtta 72720
tacacggtct agagcatcaa tgtcctgcta tacttcgacc attaattagg ttgtttattg 72780
atatactatt atttgttata gtaatttata tttttacggt acgtctagta agtagaaatt 72840
atcaaatgtt gttggcgttg gtggcgctag tcatcacatt aactattttt tattacttta 72900
tactataata gtactagact gacttctaac aaacatctca cctgccataa ataaatgctt 72960
gatattaaag tcttctattt ctaacactat tccatctgtg gaaaataata ctctgacatt 73020
atcgctaatt gacacatcgg tgagtgatat gcctataaag taataatctt ctttgggcac 73080
atataccagt gtaccaggtt ctaacaacct atttactggt gctcctgtag catacttttt 73140
ctttaccttg agaatatcca tcgtttgctt ggtcaatagc gatatgtgat tttttatcaa 73200
ccactcaaaa aagtaattgg agtgttcata tcctctacgg gctattgtct catggccgtg 73260
tatgaaattt aagtaacacg actgtggtag atttgttcta tagagccggt tgccgcaaat 73320
agatagaact accaatatgt ctgtacaaat gttaaacatt aattgattaa cagaaaaaac 73380
aatgttcgtt ctgggaatag aaaccagatc aaaacaaaat tcgttagaat atatgccacg 73440
tttatacatg gaatataaaa taactacagt ttgaaaaata acagtatcat ttaaacattt 73500
aacttgcggg gttaatttca caactttact gtttttaaac tgttcaaaat atagcatcga 73560
tccatgagaa atacgtttag ccgcctttaa tagaggaaat cccaccgcct ttctggatct 73620
caccaacgac gatagttctg accagcaact tatttcttca tcatccacct gttttaacat 73680
ataataggca ggagatagat atccgtcatt gcaatattcc ttttcgtagg cacacaatct 73740
aatattgata aaatctccat tctcttctct gcatttatta tcttgtttcg gtggctgatt 73800
aggctgtagt cttggtttag gctttggtat atcgttgttg aatctatttt ggtcattaaa 73860
tctttcattt cttcctggta tatttctatc acctcgtttg gttggatttt tgtctatatt 73920
atcgtttgta acatcggtac gggtattcat ttatcacaaa aaaaacttct ctaaatgagt 73980
ctactgctag aaaacctcat cgaagaagat accatatttt ttgcaggaag tatatctgag 74040
tatgatgatt tacaaatggt tattgccggc gcaaaatcca aatttccaag atctatgctt 74100
tctattttta atatagtacc tagaacgatg tcaaaatatg agttggagtt gattcataac 74160
gagaatatca caggggcaat gtttaccaca atgtataata taagaaacaa tttgggtcta 74220
ggagatgata aactaactat tgaagccatt gaaaactatt tcttggatcc taacaatgag 74280
gttatgcctc ttatcattaa taatacggat atgactgccg tcattcctaa aaaaagtggt 74340
aggagaaaga ataagaacat ggttattttc cgtcaaggat catcacctat cttgtgtatt 74400
ttcgaaactc gtaaaaagat taatatttat aaagaaaata tggaatccgc gtcgactgag 74460
tatacaccta tcggagacaa caaggctttg atatctaaat atgcgggaat taatgtcctg 74520
aatgtgtatt ctccttccac atccatgaga ttgaatgcca tttacggatt caccaataaa 74580
aataaactag agaaacttag tactaataag gaactagaat cgtatagttc tagccctctt 74640
caagaaccca ttaggttaaa tgattttctg ggactattgg aatgtgttaa aaagaatatt 74700
cctctaacag atattccgac aaaggattga ttactataaa tggagaatgt tcctaatgta 74760
tactttaatc ctgtgtttat agagcccacg tttaaacatt ctttattaag tgtttataaa 74820
cacagattaa tagttttatt tgaagtattc attgtattca ttctaatata tgtatttttt 74880
agatctgaat taaatatgtt cttcatgcct aaacgaaaaa tacccgatcc tattgataga 74940
ttacgacgtg ctaatctagc gtgtgaagac gataaattaa tgatctatgg attaccatgg 75000
atgacaactc aaacatctgc gttatcaata aatagtaaac cgatagtgta taaagattgt 75060
gcaaagcttt tgcgatcaat aaatggatca caaccagtat ctcttaacga tgttcttcgc 75120
agatgatgat tcatttttta agtatttggc tagtcaagat gatgaatctt cattatctga 75180
tatattgcaa atcactcaat atctagactt tctgttatta ttattgatcc aatcaaaaaa 75240
taaattagaa gccgtgggtc attgttatga atctctttca gaggaataca gacaattgac 75300
aaaattcaca gactttcaag attttaaaaa actgtttaac aaggtcccta ttgttacaga 75360
tggaagggtc aaacttaata aaggatattt gttcgacttt gtgattagtt tgatgcgatt 75420
caaaaaagaa tcctctctag ctaccaccgc aatagatcct attagataca tagatcctcg 75480
tcgcgatatc gcattttcta acgtgatgga tatattaaag tcgaataaag tgaacaataa 75540
ttaattcttt attgtcatca tgaacggcgg acatattcag ttgataatcg gccccatgtt 75600
ttcaggtaaa agtacagaat taattagacg agttagacgt tatcaaatag ctcaatataa 75660
atgcgtgact ataaaatatt ctaacgataa tagatacgga acgggactat ggacgcatga 75720
taagaataat tttgaagcat tggaagcaac taaactatgt gatgtcttgg aatcaattac 75780
agatttctcc gtgataggta tcgatgaagg acagttcttt ccagacattg ttgaattctg 75840
tgagcgtatg gcaaacgaag gaaaaatagt tatagtagcc gcactcgatg ggacatttca 75900
acgtaaaccg tttaataata ttttgaatct tattccatta tctgaaatgg tggtaaaact 75960
aactgctgtg tgtatgaaat gctttaagga ggcttccttt tctaaacgat tgggtgagga 76020
aaccgagata gagataatag gaggtaatga tatgtatcaa tcggtgtgta gaaagtgtta 76080
cgtcggctca taatattata ttttttatct aaaaaactaa aaataaacat tgattaaatt 76140
ttaatataat acttaaaaat ggatgttgtg tcgttagata aaccgtttat gtattttgag 76200
gaaattgata atgagttaga ttacgaacca gaaagtgcaa atgaggtcgc aaaaaaactg 76260
ccgtatcaag gacagttaaa actattacta ggagaattat tttttcttag taagttacag 76320
cgacacggta tattagatgg tgccaccgta gtgtatatag gatctgctcc cggtacacat 76380
atacgttatt tgagagatca tttctataat ttaggagtga tcatcaaatg gatgctaatt 76440
gacggccgcc atcatgatcc tattttaaat ggattgcgtg atgtgactct agtgactcgg 76500
ttcgttgatg aggaatatct acgatccatc aaaaaacaac tgcatccttc taagattatt 76560
ttaatttctg atgtgagatc caaacgagga ggaaatgaac ctagtacggc ggatttacta 76620
agtaattacg ctctacaaaa tgtcatgatt agtattttaa accccgtggc gtctagtctt 76680
aaatggagat gcccgtttcc agatcaatgg atcaaggact tttatatccc acacggtaat 76740
aaaatgttac aaccttttgc tccttcatat tcagctgaaa tgagattatt aagtatttat 76800
accggtgaga acatgagact gactcgagtt accaaatcag acgctgtaaa ttatgaaaaa 76860
aagatgtact accttaataa gatcgtccgt aacaaagtag ttgttaactt tgattatcct 76920
aatcaggaat atgactattt tcacatgtac tttatgctga ggaccgtgta ctgcaataaa 76980
acatttccta ctactaaagc aaaggtacta tttctacaac aatctatatt tcgtttctta 77040
aatattccaa caacatcaac tgaaaaagtt agtcatgaac caatacaacg taaaatatct 77100
agcaaaaatt ctatgtctaa aaacagaaat agcaagagat ccgtacgcag taataaatag 77160
aaacgtacta ctgagatata ctaccgatat agagtataat gatttagtta ctttaataac 77220
cgttagacat aaaattgatt ctatgaaaac tgtgtttcag gtatttaacg aatcatccat 77280
aaattatact ccggttgatg atgattatgg agaaccaatc attataacat cgtatcttca 77340
aaaaggtcat aacaagtttc ctgtaaattt tctatacata gatgtggtaa tatctgactt 77400
atttcctagc tttgttagac tagatactac agaaactaat atagttaata gtgtactaca 77460
aacaggcgat ggtaaaaaga ctcttcgtct tcccaaaatg ttagagacgg aaatagttgt 77520
caagattctc taccgtccta atataccatt aaaaattgtt agatttttcc gcaataacat 77580
ggtaactgga gtagagatag ccgatagatc tgttatttca gtcgctgatt aatcaattag 77640
tagagatgag ataagaacat tataataatc aataatatat tttatatctt atatcttgtt 77700
tagaaaaatg ctaatattaa aatagctaac gctagtaatc caatcggaag ccatttgata 77760
tctataatag ggtatctaat ttcctgattc agatagcgga cagctatatt ctcggtagct 77820
actcgtttgg aatcacaaac attatttaca tctaatttac tatctgtaat ggaaacgttt 77880
cccaatgaaa tggtacaatc cgatacattg cattttgtta tatttttttt taaagaggct 77940
ggtaacaacg catcgcttcg tttacatggc tcgtaccaac aataataggg taatcttgta 78000
tctattccta tccgtactat gcttttatca ggataaatac atttacatcg tatatcgtct 78060
ttgttagcat cacagaatgc ataaatttgt tcgtccgtca tgataaaaat ttaaagtgta 78120
aatataacta ttattttata gttgtaataa aaagggaaat ttgattgtat actttcggtt 78180
ctttaaaaga aactgacttg ataaaaatgg ctgtaatctc taaggttacg tatagtctat 78240
atgatcaaaa agagattaat gctacagata ttatcattag tcatgttaaa aatgacgacg 78300
atatcggtac cgttaaagat ggtagactag gtgctatgga tggggcatta tgtaaaactt 78360
gtgggaaaac ggaattggaa tgtttcggtc actggggtaa agtaagtatt tataaaactc 78420
atatagttaa gcctgaattt atttcagaaa ttattcgttt actgaattat atatgtattc 78480
actgcggatt attgcgttca cgagaaccgt attccgacga tattaaccta aaagagttat 78540
cgggacacgc tcttaggaga ttaaaggata aaatattatc caagaaaaag tcatgttgga 78600
acagtgaatg tatgcaaccg tatcaaaaaa ttactttttc aaagaaaaag gtttgtttcg 78660
tcaacaagtt ggatgatatt aacgttccta attctctcat ctatcaaaag ttaatttcta 78720
ttcatgaaaa gttttggcca ttattagaaa ttcatcaata tccagctaac ttattttata 78780
cagactactt tcccatccct ccgttgatta ttagaccggc tattagtttt tggatagata 78840
gtatacccaa agaaaccaat gaattaactt acttattagg tatgatcgtt aagaattgta 78900
acttgaatgc tgatgaacag gttatccaga aggcggtaat agaatacgat gatattaaaa 78960
ttatttctaa taacacttcc agtatcaatt tatcatatat cacatccggc aaaaataata 79020
tgattagaag ttatatcgtc gcccggcgaa aagatcagac cgctagatct gtaattggtc 79080
ccagtacatc tatcaccgtt aatgaggtag gaatgcccgc atatattaga aatacactta 79140
cagaaaagat atttgttaat gcctttacag tggataaagt taaacaacta ttagcgtcaa 79200
accaagttaa attttacttt aataaacgat taaaccaatt aacaagaata cgccaaggaa 79260
agtttatcaa aaataaaata catttattgc ctggtgattg ggtagaagta gctgttcaag 79320
aatatacaag tattattttt ggaagacagc cgtctctaca tagatacaac gtcatcgctt 79380
catctatcag agctaccgaa ggagatacta tcaaaatatc tcccggaatt gtcaactctc 79440
aaaatgctga tttcgacgga gatgaagaat ggatgatatt ggagcaaaat cctaaagccg 79500
taattgaaca aagtattctt atgtatccga cgacgttact caaacacgat attcatggag 79560
cccccgttta tggatctatt caagatgaaa tcgtagcagc gtattcattg tttaggatac 79620
aagatctttg tttagatgaa gtattgaaca tcttggggaa atatggaaga gagttcgatc 79680
ctaaaggtaa atgtaaattc agcggtaaag atatctatac ttacttgata ggtgaaaaga 79740
ttaattatcc gggtctctta aaggatggtg aaattattgc aaacgacgta gatagtaatt 79800
ttgttgtggc tatgaggcat ctgtcattgg ctggactctt atccgatcat aagtcgaacg 79860
tggaaggtat caactttatt atcaagtcat cttatgtttt taagagatat ctatctattt 79920
acggttttgg ggtgacattc aaagatctga gaccaaattc gacgttcact aataaattgg 79980
aggccatcaa cgtagaaaaa atagaactta tcaaagaagc atacgccaaa tatctcaacg 80040
atgtaagaga cgggaaaata gttccattat ctaaagcttt agaggcggac tatgtggaat 80100
ccatgttatc caacttgaca aatcttaata tccgagagat agaagaacat atgagacaaa 80160
cgctgataga tgatccagat aataacctcc tgaaaatggc caaagcgggt tataaagtaa 80220
atcccacaga actaatgtat attctaggta cttatggaca acagaggatt gatggtgaac 80280
cagcagagac tcgagtattg ggtagagtct taccttacta tcttccagac tctaaggatc 80340
cagaaggaag aggttacatt cttaattctt taacaaaagg attaacgggt tctcaatatt 80400
acttttcgat gctggttgca agatctcaat ctactgatat cgtctgtgaa acatcacgta 80460
ccggaacact ggctagaaaa atcattaaaa agatggagga tatggtggtc gacggatacg 80520
gacaagtagt tataggtaat acgctcatca agtacgccgc caattatacc aaaattctag 80580
gctcagtatg taaacctgta gatcttatct atccagatga gtccatgact tggtatttgg 80640
aaattagtgc tctgtggaat aaaataaaac agggattcgt ttactctcag aaacagaaac 80700
ttgcaaaaaa gacattggcg ccgtttaatt tcctagtatt cgtcaaaccc accactgagg 80760
ataatgctat taaggttaag gatctgtacg atatgattca taacgtcatt gatgatgtga 80820
gagagaaata cttctttacg gtatctaata tagattttat ggagtatata ttcttgacgc 80880
atcttaatcc ttctagaatt agaattacaa aagaaacggc tatcactatc tttgaaaagt 80940
tctatgaaaa actcaattat actctaggtg gtggaactcc tattggaatt atttctgcac 81000
aggtattgtc tgagaagttt acacaacaag ccctgtccag ttttcacact actgaaaaaa 81060
gtggtgccgt caaacaaaaa cttggtttca acgagtttaa taacttgact aatttgagta 81120
agaataagac cgaaattatc actctggtat ccgatgatat ctctaaactt caatctgtta 81180
agattaattt cgaatttgta tgtttgggag aattaaatcc aaacatcact cttcgaaaag 81240
aaacagatag gtatgtagta gatataatag tcaatagatt atacatcaag agagcagaaa 81300
ttaccgaatt agtcgtcgaa tatatgattg aacgattcat ctcctttagc gtcattgtaa 81360
aggaatgggg tatggaaaca ttcattgagg atgaggataa tattagattt actgtctacc 81420
taaatttcgt tgaaccggaa gaattgaatc ttagtaagtt tatgatggtt cttccgggtg 81480
ccgccaacaa gggcaagatt agtaaattca agattcctat ctctgattat acgggatatg 81540
acgacttcaa tcaaacaaaa aagctcaata agatgactgt agaactcatg aatctaaaag 81600
aattgggttc tttcgatttg gaaaacgtca acgtgtatcc tggagtatgg aatacatacg 81660
atatcttcgg tatcgaggcc gctcgtgaat acttgtgcga agccatgtta aacacctatg 81720
gagaagggtt cgattatctg tatcagcctt gtgatcttct cgctagttta ctatgtgcta 81780
gttacgaacc agaatcagtg aataaattca agttcggcgc agctagtact cttaagagag 81840
ctacgttcgg agacaataaa gcattgttaa acgcggctct tcataaaaag tcagaaccta 81900
ttaacgataa tagtagctgc cactttttta gcaaggtccc taatatagga actggatatt 81960
acaaatactt tatcgacttg ggtcttctca tgagaatgga aaggaaacta tctgataaga 82020
tatcttctca aaagatcaag gaaatggaag aaacagaaga cttttaattc ttatcaataa 82080
catatttttc tatgatctgt cttttaaacg atggattttc cacaaatgcg cctctcaagt 82140
ccctcataga atgatacacg tataaaaaat atagcatagg caatgactcc ttatttttag 82200
acattagata tgccaaaatc atagccccgc ttctatttac tcccgcagca caatgaacca 82260
acacgggctc gtttcgttga tcacatttag ataaaaaggc ggttacgtcg tcaaaatatt 82320
tactaatatc ggtagttgta tcatctacca acggtatatg aataatatta atattagagt 82380
taggtaatgt atatttatcc atcgtcaaat ttaaaacata tttgaactta acttcagatg 82440
atggtgcatc catagcattt ttataatttc ccaaatacac attattggtt actcttgtca 82500
ttatagtggg agatttggct ttgtgcatat ctccagttga acgtagtagt aagtatttat 82560
acaaactttt cttatccatt tataacgtac aaatggataa aactacttta tcggtaaacg 82620
cgtgtaattt agaatacgtt agagaaaagg ctatagtagg cgtacaagca gccaaaacat 82680
caacacttat attctttgtt attatattgg caattagtgc gctattactc tggtttcaga 82740
cgtctgataa tccagtcttt aatgaattaa cgagatatat gcgaattaaa aatacggtta 82800
acgattggaa atcattaacg gatagcaaaa caaaattaga aagtgataga ggtagacttc 82860
tagccgctgg taaggatgat atattcgaat tcaaatgtgt ggatttcggc gcctatttta 82920
tagctatgcg attggataag aaaacatatc tgccgcaagc tattaggcga ggtactggag 82980
acgcgtggat ggttaaaaag gcggcaaagg tcgatccatc tgctcaacaa ttttgtcagt 83040
atttgataaa acacaagtct aataatgtta ttacttgtgg taatgagatg ttaaatgaat 83100
taggttatag cggttatttt atgtcaccgc attggtgttc cgattttagt aatatggaat 83160
agtgttagat aaatgcggta acgaatgttc ctgtaaggaa ccataacagc ttagatttaa 83220
cgttaaagat gagcataaac ataataaaca aaattacaat caaacctata acattaatat 83280
caaacaatcc aaaaaatgaa atcagtggag tagtaaacgc gtacataact cctggataac 83340
gtttagcagc tgccgttcct attctagacc aaaaattcgg tttcatgttt tcgaaacggt 83400
attctgcaac aagtcgagga tcgtgttcta catatttggc ggcgttatcc agtatctgcc 83460
tattgatctt catttcgttt tcgattctgg ctatttcaaa ataaaatccc gatgatagac 83520
ctccagactt tataatttca tctacgatgt tcagcgccgt agtaactcta ataatatagg 83580
ctgataagct aacatcatac cctcctgtat atgtgaatat ggcatgattt ttgtccatta 83640
caagctcggt tttaacttta ttgcctgtaa taatttctct catctgtagg atatctattt 83700
ttttgtcatg cattgccttc aagacgggac gaagaaacgt aatatcctca ataacgttat 83760
cgttttctac aataactaca tattctacct ttttattttc taactcggta aaaaaattag 83820
aatcccatag ggctaaatgt ctagcgatat ttcttttcgt ttcctctgta cacatagtgt 83880
tacaaaaccc tgaaaagaag tgagtatact tgtcatcatt tctaatgttt cctccagtcc 83940
actgtataaa cgcataatcc ttgtaatgat ctggatcatc cttgactacc acaacatttc 84000
ttttttctgg cataacttca ttgtccttta catcatcgaa cttctgatca ttaatatgct 84060
catgaacatt aggaaatgtt tctgatggag gtctatcaat aactggcaca acaataacag 84120
gagttttcac cgccgccatt tagttattga aattaatcat atacaactct ttaatacgag 84180
ttatattttc gtctatccat tgtttcacat ttacatattt cgacaaaaag atataaaatg 84240
cgtattccaa tgcttctctg tttaatgaat tactaaaata tacaaacacg tcactgtctg 84300
gcaataaatg atatcttaga atattgtaac aatttatttt gtattgcaca tgttcgtgat 84360
ctatgagttc ttcttcgaat ggcataggat ctccgaatct gaaaacgtat aaataggagt 84420
tagaataata atatttgaga gtattggtaa tatataaact ctttagcggt ataattagtt 84480
tttttctctc gatttctatt tttagatgtg atggaaaaat gactaatttt gtagcattag 84540
tatcatgaac tctaatcgag atcttaatat cttcgtcaca cgttagttct ttgaagtttt 84600
taagagatgc atcagttggt tcgaccgatg gagtaggtgc aacaattttt tgttcgatgt 84660
atgtatgtac tggagccatt gtcttaacta taatggtgct tgtatcgaaa aactttaatg 84720
cagataatgg aagctcttcg ccgcgacttt ctacatcgta attgggttct aacgccgatc 84780
tctgaatgga tactagtttt ctaagttcta atgtgattct ctgaaaatgt aaatccaatt 84840
cctccggcat tatagatgtg tatacatcgg taaataaaac tatagtatcc aacgatccct 84900
tctcgcaaat tctagtctta accaaaaaat cgtatataac cacggagatg gcgtatttaa 84960
gagtggattc ttctaccgtt ttgttcttgg atttcatata agaaactata aagtccgcac 85020
tactgttaag aatgattact aacgcaacta tatagtttaa attaagcatc ttggaaacat 85080
aaaataactc tgtagacgat acttgacttt cgaataagtt tgcagacaaa cgaagaaaga 85140
acagacctct cttaatttca gaagaaaact ttttttcgta ttcctgacgt ctagagttta 85200
tatcaataag aaagttaaga attagtcggt taatgttgta tttcattacc caagtttgag 85260
atttcataat attatcaaaa gacatgataa tattaaagat aaagcgctga ctatgaacga 85320
aatagctata tggttcgctc aagaatatag tcttgttaaa cgtggaaacg ataactgtat 85380
ttttaatcac gtcagcggca tctaaattaa atataggtat atttattcca cacactctac 85440
aatatgccac accatcttca taataaataa attcgttagc aaaattatta attttagtga 85500
aatagttagc gtcaactttc atagcttcct tcaatctaat ttgatgctca cacggtgcga 85560
attccactct aacatccctt ttccatgcct caggttcatc gatctctata atatctagtt 85620
ttttgcgttt cacaaacaca ggctcgtctc tcgcgatgag atctgtatag taactatgta 85680
aatgataact agatagaaag atgtagctat atagatgacg atcctttaag agaggtatga 85740
tgactttacc ccaatcagat agactgttgt tatggtcttc ggaaaaagaa tttttataaa 85800
tttttccagt attttccaaa tatacgtact taacatctaa aaaatcctta atgataatag 85860
gaatggataa tccgtctatt ttataaagaa atacatatcg cacattatac ttttttttgg 85920
aaatgggaat accgatgtgt ctacataaat atgcaaagtc taaatatttt ttagagaatc 85980
ttagttggtc caaattcttt tccaagtacg gtaatagatt tttcatattg aacggtatct 86040
tcttaatctc tggttctagt tccgcattaa atgatgaaac taagtcacta tttttataac 86100
taacgattac atcacctcta acatcatcat ttaccagaat actgatcttc ttttgtcgta 86160
aatacatgtc taatgtgtta aaaaaaagat catacaagtt atacgtcatt tcatctgtgg 86220
tattcttgtc attgaaggat aaactcgtac taatctcttc tttaacagcc tgttcaaatt 86280
tatatcctat atacgaaaaa atagcaacca gtgtttgatc atccgcgtca atattctgtt 86340
ctatcgtagt gtataacaat cgtatatctt cttctgtgat agtcgatacg ttataaaggt 86400
tgataacgaa aatattttta tttcgtgaga taaagtcatc gtaggatttt ggacttatat 86460
tcgcgtctag tagatatgct tttatttttg gaatgatctc aattagaata gtctctttag 86520
agtccattta aagttacaaa caactaggaa attggtttat gatgtataat ttttttagtt 86580
tttatagatt ctttattcta tacttaaaaa atgaaaataa atacaaaggt tcttgagggt 86640
tgtgttaaat tgaaagcgag aaataatcat aaattatttc attatcgcga tatccgttaa 86700
gtttgtatcg taatggcgtg gtcaattaca aataaagcgg atactagtag cttcacaaag 86760
atggctgaaa tcagagctca tctaaaaaat agcgctgaaa ataaagataa aaacgaggat 86820
attttcccgg aagatgtaat aattccatct actaagccca aaaccaaacg agccactact 86880
cctcgtaaac cagcggctac taaaagatca accaaaaagg aggaagtgga agaagaagta 86940
gttatagagg aatatcatca aacaactgaa aaaaattctc catctcctgg agtcagcgac 87000
attgtagaaa gcgtggctgc tgtagagctc gatgatagcg acggggatga tgaacctatg 87060
gtacaagttg aagctggtaa agtaaatcat agtgctagaa gcgatctttc tgacctaaag 87120
gtggctaccg acaatatcgt taaagatctt aagaaaatta ttactagaat ctctgcagta 87180
tcgacggttc tagaggatgt tcaagcagct ggtatctcta gacaatttac ttctatgact 87240
aaagctatta caacactatc tgatctagtc accgagggaa aatctaaagt tgttcgtaaa 87300
aaagttaaaa cttgtaagaa gtaaatgcgt gcactttttt ataaagatgg taaactcttt 87360
accgataata attttttaaa tcctgtatca gacgataatc cagcgtatga ggttttgcaa 87420
catgttaaaa ttcctactca tttaacagat gtagtagtat atgaacaaac gtgggaggag 87480
gcgttaacta gattaatttt tgtgggaagt gattcaaaag gacgtagaca atacttttac 87540
ggaaaaatgc atgtacagaa tcgcaacgct aaaagagatc gtatttttgt tagagtatat 87600
aacgttatga aacgaattaa ttgttttata aacaaaaata taaagaaatc gtccacagat 87660
tccaattatc agttggcggt ttttatgtta atggaaacta tgttttttat tagatttggt 87720
aaaatgaaat atcttaagga gaatgaaaca gtagggttat taacactaaa aaataaacac 87780
atagaaataa gtcccgatga aatagttatc aagtttgtag gaaaggacaa agtttcacat 87840
gaatttgttg ttcataagtc taatagacta tataaaccgc tattgaaact gacggatgat 87900
tctagtcccg aagaatttct gttcaacaaa ctaagtgaac gaaaggtata cgaatgtatc 87960
aaacagtttg gtattagaat caaggatctc cgaacgtatg gagtcaatta tacgttttta 88020
tataattttt ggacaaatgt aaagtccata tctcctcttc cgtcaccaaa aaagttaata 88080
gcgttaacta tcaaacaaac tgctgaagtg gtaggtcata ctccatcaat ttcaaaaaga 88140
gcttatatgg caacgactat tttagaaatg gtaaaggata aaaatttttt agatgtagta 88200
tctaaaacta cgttcgatga attcctatct atagtcgtag atcacgttaa atcatctacg 88260
gatggatgat atagatcttt acacaaataa ttacaagacc gataaatgga aatggataag 88320
cgtatgaaat ctctcgcaat gacagctttc ttcggagagc taaacacatt agatattatg 88380
gcattgataa tgtctatatt taaacgccat ccaaacaata ccattttttc agtggataag 88440
gatggtcagt ttatgattga tttcgaatac gataattata aggcttctca atatttggat 88500
ctgaccctca ctccgatatc tggagatgaa tgcaagactc acgcatcgag tatagccgaa 88560
caattggcgt gtgtggatat tattaaagag gatattagcg aatatatcaa aactactccc 88620
cgtcttaaac gatttataaa aaaataccgc aatagatcag atactcgtat cagtcgagat 88680
acagaaaagc ttaaaatagc tctagctaaa ggcatagatt acgaatatat aaaagacgct 88740
tgttaataag taaatgaaaa aaaactagtc gtttataata aaacacaata tggatgccaa 88800
catagtatca tcttctacta ttgcaacgta tatagacgct ttagcgaaga atgcttcaga 88860
attagaacag aggtctaccg catacgaaat aaataatgaa ttggaactag tatttattaa 88920
gccgccatta attactttga caaatgtagt gaatatctct acgattcagg aatcgtttat 88980
tcgatttacc gttactaata aggaaggtgt taaaattaga actaagattc cattatctaa 89040
ggtacatggt ctagatgtaa aaaatgtaca gttagtagat gctatagata acatagtttg 89100
ggaaaagaaa tcattagtga cggaaaatcg tcttcacaaa gaatgcttgt tgagactatc 89160
gacagaggaa cgtcatatat ttttggatta caagaaatat ggatcctcta tccgactaga 89220
attagtcaat cttattcaag caaaaacaaa aaactttacg atagacttta agctaaaata 89280
ttttctagga tccggtgccc agtctaaaag ttctttatta cacgctatta atcatccaaa 89340
gtcaaggcct aatacatctc tggaaataga attcacacct agagacaatg aaaaagttcc 89400
atatgatgaa ctaataaagg aattgacgac tctatcacgt catatattta tggcttctcc 89460
agagaatgta attctttctc cgcctattaa cgcgcctata aaaaccttta tgttgcctaa 89520
acaagatata gtaggtttgg atctggaaaa tctatatgcc gtaactaaga ctgacggaat 89580
tcctataact atcagagtta catcaaaagg gttgtattgt tattttacac atcttggtta 89640
tattattaga tatcctgtta agagaataat agattccgaa gtagtagtct ttggtgaggc 89700
agttaaggat aagaactgga ccgtatatct cattaagcta atagagcctg tgaatgcaat 89760
caatgataga ctagaagaaa gtaagtatgt tgaatctaaa ctagtggata tttgtgatcg 89820
gatagtattc aagtcaaaga aatacgaagg tccgtttact acaactagtg aagtcgtcga 89880
tatgttatct acatatttac caaagcaacc agaaggtgtt attctgttct attcaaaggg 89940
acctaaatct aacattgatt ttaaaattaa aaaggaaaat actatagacc aaactgcaaa 90000
tgtagtattt aggtacatgt ccagtgaacc aattatcttt ggagaatcgt ctatctttgt 90060
agagtataag aaatttagca acgataaagg ctttcctaaa gaatatggtt ctggtaagat 90120
tgtgttatat aacggcgtta attatctaaa taatatctat tgtttggaat atattaatac 90180
acataatgaa gtgggtatta agtccgtggt tgtacctatt aagtttatag cagaattctt 90240
agttaatgga gaaatactta aacctagaat tgataaaacc atgaaatata ttaactcaga 90300
agattattat ggaaatcaac ataatatcat agtcgaacat ttaagagatc aaagcatcaa 90360
aataggagat atctttaacg aggataaact atcggatgtg ggacatcaat acgccaataa 90420
tgataaattt agattaaatc cagaagttag ttattttacg aataaacgaa ctagaggacc 90480
gttgggaatt ttatcaaact acgtcaagac tcttcttatt tctatgtatt gttccaaaac 90540
atttttagac gattccaaca aacgaaaggt attggcgatt gattttggaa acggtgcgga 90600
cctggaaaaa tacttttatg gagagattgc gttattggta gcgacggatc cggatgctga 90660
tgctatagct agaggaaatg aaagatacaa caaattaaac tctggaatta aaaccaagta 90720
ctacaaattt gactacattc aggaaactat tcgatccgat acatttgtct ctagtgtcag 90780
agaagtattc tattttggaa agtttaatat catcgactgg cagtttgcta tccattattc 90840
ttttcatccg agacattatg ctaccgtcat gaataactta tccgaactaa ctgcttctgg 90900
aggcaaggta ttaatcacta ccatggacgg agacaaatta tcaaaattaa cagataaaaa 90960
gacttttata attcataaga atttacctag tagcgaaaac tatatgtctg tagaaaaaat 91020
agctgatgat agaatagtgg tatataatcc atcaacaatg tctactccaa tgactgaata 91080
cattatcaaa aagaacgata tagtcagagt gtttaacgaa tacggatttg ttcttgtaga 91140
taacgttgat ttcgctacaa ttatagaacg aagtaaaaag tttattaatg gcgcatctac 91200
aatggaagat agaccgtcta caaaaaactt tttcgaacta aatagaggag ccattaaatg 91260
tgaaggttta gatgtcgaag acttacttag ttactatgtt gtttatgtct tttctaagcg 91320
gtaaataata atatggtatg ggttctgata tccccgttct aaatgcatta aataattcca 91380
atagagcgat ttttgttcct ataggacctt ccaactgtgg atactctgta ttgttaatag 91440
atatattaat acttttgtcg ggtaacagag gttctacgtc ttctaaaaat aaaagtttga 91500
taacatctgg cctgttcata aataaaaact tggcgattct atatatactc ttattatcaa 91560
atctagccat tgtcttatag atgtgagcta ctgtaggtgt accatttgat tttctttcta 91620
atactatata tttctctcga agaagttctt gcacatcatc tgggaataaa atactactgt 91680
tgagtaaatc agttattttt tttatatcga tattgatgga catttttata gttaaggata 91740
ataagtatcc caaagtcgat aacgacgata acgaagtatt tatactttta ggaaatcaca 91800
atgactttat cagatcaaaa ttaacaaaat taaaggagca tgtatttttt tctgaatata 91860
ttgtgactcc agatacatat ggatctttat gcgtcgaatt aaatgggtct agttttcagc 91920
acggtggtag atatatagag gtggaggaat ttatagatgc tggaagacaa gttagatggt 91980
gttctacatc caatcatata tctgaagata tgcacactga taaatttgtc atttatgata 92040
tttatacgtt tgattcgttc aagaataaac gattggtatt tgtacaggtg cctccatcat 92100
taggagatga tagctatttg actaatccgt tattgtctcc gtattatcgt aattcagtag 92160
ccagacaaat ggtcaatgat atgattttta atcaagattc atttttaaaa tatttattag 92220
aacatctgat tagaagccac tatagagttt ctaaacatat aacaatagtt agatacaagg 92280
ataccgaaga attaaatcta acgagaatat gttataatag agataagttt aaggcgtttg 92340
tattcgcttg gtttaacggc gtttcggaaa atgaaaaggt actagatacg tataaaaagg 92400
tatctaattt gatataatga attcagtgac tgtatcacac gcgccatata ctattactta 92460
tcacgatgat tgggaaccag taatgagtca attggtagag ttttataacg aagtagccag 92520
ttggctgcta cgagacgaga cgtcgcctat tcctgataag ttctttatac agttgaaaca 92580
accgcttaga aataaacgag tatgtgtgtg tggtatagat ccgtatccga aagatggaac 92640
tggtgtaccg ttcgaatcac caaattttac aaaaaaatca attaaggaga tagcttcatc 92700
tatatctaga ttaaccggag taattgatta taaaggttat aaccttaata taatagacgg 92760
ggttataccc tggaattatt acttaagttg taaattagga gaaacaaaaa gtcacgcgat 92820
ctactgggat aagatttcca agttactgct gcagcatata actaaacacg ttagtgttct 92880
ttattgtttg ggtaaaacag atttctcgaa tatacgggca aagttagaat ccccggtaac 92940
taccatagtc ggatatcatc cagcggctag agaccgccaa ttcgagaaag atagatcatt 93000
tgaaattatc aacgttttac tggaattaga caacaaggca cctataaatt gggctcaagg 93060
gtttatttat taatgcttta gtgaaatttt aacttgtgtt ctaaatggat gcaactatta 93120
gaggtaatga tgttatcttt gttcttaaga ctataggtgt cccgtcagcg tgcagacaaa 93180
atgaagatcc aagatttgta gaagcattta aatgcgacga gttagaaaga tatattgaga 93240
ataatccaga atgtacacta ttcgaaagtc ttagggatga ggaagcatac tctatagtca 93300
gaattttcat ggatgtagat ttagacgcgt gtctagacga aatagattat ttaacggcta 93360
ttcaagattt tattatcgag gtgtcaaact gtgtagctag attcgcgttt acagaatgcg 93420
gtgccattca tgaaaatgta ataaaatcca tgagatctaa tttttcattg actaagtcta 93480
caaatagaga taaaacaagt tttcatatta tctttttaga cacgtatacc actatggata 93540
cattgatagc tatgaaacga acactattag aattaagtag atcatctgaa aatccactaa 93600
ccagatcgat agacactgcc gtatatagga gaaaaacaac tcttcgggtt gtaggtacta 93660
ggaaaaatcc aaattgcgac actattcatg taatgcaacc accgcatgat aatatagaag 93720
attacctatt cacttacgtg gatatgaaca acaatagtta ttacttttct ctacaacgac 93780
gattggagga tttagttcct gataagttat gggaaccagg gtttatttca ttcgaagacg 93840
ctataaaaag agtttcaaaa atattcatta attctataat aaactttaat gatctcgatg 93900
aaaataattt tacaacggta ccactggtca tagattacgt aacaccttgt gcattatgta 93960
aaaaacgatc gcataaacat ccgcatcaac tatcgttgga aaatggtgct attagaattt 94020
acaaaactgg taatccacat agttgtaaag ttaaaattgt tccgttggat ggtaataaac 94080
tgtttaatat tgcacaaaga attttagaca ctaactctgt tttattaacc gaacgaggag 94140
accatatagt ttggattaat aattcatgga aatttaacag cgaagaaccc ttgataacaa 94200
aactaattct gtcaataaga catcaactac ctaaggaata ttcaagcgaa ttactctgtc 94260
cgaggaaacg aaagactgta gaagctaaca tacgagacat gttaatagat tcagtggaga 94320
ccgataccta tccggataaa cttccgttta aaaatggtgt attggacctg gtagacggaa 94380
tgttttactc tggagatgat gctaaaaaat atacgtgtac tgtatcaacc ggatttaaat 94440
ttgacgatac aaagttcgtc gaagacagtc cagaaatgga agagttaatg aatatcatta 94500
acgatatcca accattaacg gatgaaaata agaaaaatag agagttgtac gaaaaaactt 94560
tatctagttg tttatgcggt gctaccaaag gatgtttaac attctttttt ggagaaactg 94620
caactggaaa gtcgacaacc aaacgtttgt taaagtctgc tatcggtgac ctgtttgttg 94680
agacgggtca aacaatttta acagatgtat tggataaagg acctaatcca tttatcgcta 94740
acatgcattt gaaaagatct gtattctgta gcgaactacc tgattttgcc tgtagtggat 94800
caaagaaaat tagatctgac aatattaaaa agttgacaga accttgtgtc attggaagac 94860
cgtgtttctc caataaaatt aataatagaa accatgcgac aatcattatc gatactaatt 94920
acaaacctgt ctttgatagg atagataacg cattaatgag aagaattgcc gtcgtgcgat 94980
tcagaacaca cttttctcaa ccttctggta gagaggctgc tgaaaataat gacgcgtacg 95040
ataaagtcaa actattagac gaggggttag atggtaaaat acaaaataat agatatagat 95100
tcgcatttct atacttgttg gtgaaatggt acaaaaaata tcatgttcct attatgaaac 95160
tatatcctac accggaagag attccggact ttgcattcta tctcaaaata ggtactctgt 95220
tagtatctag ctctgtaaag catattccat taatgacgga cctctccaaa aagggatata 95280
tattgtacga taatgtggtt actcttccgt tgactacttt ccaacagaaa atatccaagt 95340
attttaattc tagactattt ggacacgata tagagagctt catcaataga cataagaaat 95400
ttgccaatgt tagtgatgaa tatctgcaat atatattcat agaggatatt tcatctccgt 95460
aaatatatgc tcatatattt atagaagata tcacatatct aaatgaatac cggaatcata 95520
gatttatttg ataatcatgt tgatagtata ccaactatat tacctcatca gttagctact 95580
ctagattatc tagttagaac tatcatagat gagaacagaa gcgtgttatt gttccatatt 95640
atgggatcag gtaaaacaat aatcgctttg ttgttcgcct tggtagcttc cagatttaaa 95700
aaggtttaca ttctagtgcc taatattaac attttgaaaa tttttaatta taatatgggt 95760
gtagctatga acttgtttaa tgacgaattc atagctgaga atatctttat tcattccaca 95820
acaagttttt attctcttaa ttataacgat aacgtcatta attataacgg attatctcgc 95880
tacaataact ctatttttat cgttgatgag gcacataata tctttgggaa taatactgga 95940
gaacttatga ccgtgataaa aaataaaaac aagattcctt ttttactatt gtctggatct 96000
cccattacta acacacctaa tactctgggt catattatag atttaatgtc cgaagagacg 96060
atagattttg gtgaaattat tagtcgtggt aagaaagtaa ttcagacact tcttaacgaa 96120
cgaggtgtga atgtacttaa ggatttgctt aaaggaagaa tatcatatta cgaaatgcct 96180
gataaagatc taccaacgat aagatatcac ggacgtaagt ttctagatac tagagtagta 96240
tattgtcaca tgtctaaact tcaagagaga gattatatga ttactagacg acagctatgt 96300
tatcatgaaa tgtttgataa aaatatgtat aacgtgtcaa tggcagtatt gggacaactt 96360
aatctgatga ataatttaga tactttattt caggaacagg ataaggaatt gtacccaaat 96420
ctgaaaataa ataatggcgt gttatacgga gaagaattgg taacgttaaa cattagttcc 96480
aaatttaaat actttattaa tcggatacag acactcaacg gaaaacattt tatatacttt 96540
tctaattcta catatggcgg attggtaatt aaatatatca tgctcagtaa tggatattct 96600
gaatataatg gttctcaggg aactaatcca catatgataa acggcaaacc aaaaacattt 96660
gctatcgtta ctagtaaaat gaaatcgtct ttagaggatc tattagatgt gtataattct 96720
cctgaaaacg atgatggcag tcaattgatg tttttgtttt cgtcaaacat tatgtccgaa 96780
tcctatactc tgaaagaggt aaggcatatt tggtttatga ctatcccaga tactttttct 96840
caatacaacc aaattcttgg acgatctatt agaaaattct cttacgccga tatttctgaa 96900
ccagttaatg tatatctttt agccgccgta tattccgatt tcaatgacga agtgacgtca 96960
ttaaacgatt acacacagga tgaattaatt aatgttttac catttgacat caaaaagctg 97020
ttgtatctaa aatttaagac taaagaaacg aatagaatat actctattct tcaagagatg 97080
tctgaaacgt attctcttcc accacatcca tcaattgtaa aagttttatt gggagaattg 97140
gtcagacaat ttttttataa taattctcgt attaagtata acgataccaa gttacttaaa 97200
atggttacat cagttataaa aaataaagaa gacgctagga attacataga tgatattgta 97260
aacggtcact tctttgtatc gaataaagta tttgataaat ctcttttata caaatacgaa 97320
aacgatatta ttacagtacc gtttagactt tcctacgaac catttgtttg gggagttaac 97380
tttcgtaaag aatataacgt ggtatcttct ccataaaact gatgagatat ataaagaaat 97440
aaatgtcgag ctttgttacc aatggatacc ttccagttac attggagcca cacgagctga 97500
cgttagacat aaaaactaat attaggaatg ccgtatataa gacgtatctc catagagaaa 97560
ttagtggtaa aatggccaag aaaatagaaa ttcgtgaaga cgtggaatta cctctcggcg 97620
aaatagttaa taattctgta gttataaacg ttccgtgtgt aataacctac gcgtattatc 97680
acgttgggga tatagtcaga ggaacattaa acatcgaaga tgaatcaaat gtaactattc 97740
aatgtggaga tttaatctgt aaactaagta gagattcggg tactgtatca tttagcgatt 97800
caaagtactg cttttttcga aatggtaatg cgtatgacaa tggcagcgaa gtcactgccg 97860
ttctaatgga ggctcaacaa ggtatcgaat ctagttttgt ttttctcgcg aatatcgttg 97920
actcataaaa aagagaatag cggtaagtat aaacacgaat actatggcaa taattgcgaa 97980
tgttttattc ccttcgatat atttttgata atatgaaaaa catgtctctc tcaaatcgga 98040
caaccatctc ataaaatagt tctcgcgcgc tggagaggta gttgctgctc gtataatctc 98100
cccagaataa tatacttgcg tgtcgtcgtt caatttatac ggatttctat agttctctgt 98160
tatataatgc ggttttccat catgattaga cgacgacaat agtgttctaa atttagatag 98220
ttgatcagaa tgaatgttta ttggcgttgg aaaaattatc catacagcgt ctgcagagtg 98280
gttgatagtt gttcctagat atgtaaaata atccaactta ctaggcagca aattgtctag 98340
ataaaatact gaatcaaacg gtgcagacgt attggtggat ctaatggaat ccaattgatt 98400
aactatcttt tgaaaatata catttttatg atccgatact tgtaagaata tagaaataat 98460
gataagtcca tcatcgtgtt tttttgcctc ttcataagaa ctatattttt tcttattcca 98520
atgaacaaga ttaatctctc cagagtattt gtacacatct atcaagtgat tggatccata 98580
atcgtcttcc tttccccaat atatacgtag tgatgataac acatattcat tggggagaaa 98640
ccctccactt atatatcctc ctttaaaatt aatccttact agttttccag tgttctggat 98700
agtggttggt ttcgactcat tataatgtat gtctaacggc ttcaatcgcg cgttagaaat 98760
tgctttttta gtttctatat taataggaga tagttgttgc ggcatagtaa aaatgaaatg 98820
ataactgttt aaaaatagct cttagtatgg gaattacaat ggatgaggaa gtgatatttg 98880
aaactcctag agaattaata tctattaaac gaataaaaga tattccaaga tcaaaagaca 98940
cgcatgtgtt tgctgcgtgt ataacaagtg acggatatcc gttaatagga gctagaagaa 99000
cttcattcgc attccaagcg atattatctc aacaaaattc agattctatc tttagagtat 99060
ccactaaact attacggttt atgtactaca atgaactaag agaaatcttt agacggttga 99120
gaaaaggttc tatcaacgat atcgatcctc actttgaaga gttaatatta ttgggtggta 99180
aactagataa aaaggaatct attaaagatt gtttaagaag agaattaaaa gaggaaagtg 99240
atgaacgtat aacagtaaaa gaatttggaa atgtaattct aaaacttaca acacgggata 99300
aattatttaa taaagtatat ataagttatt gcatggcgtg ttttattaat caatcgttgg 99360
aggatttatc gcatactagt atttacaatg tagaaattag aaagattaaa tcattaaatg 99420
attgtattaa cgacgataaa tacgaatatc tgtcttatat ttataatatg ctagttaata 99480
gtaaatgaac ttttacagat ctagtataat tagtcagatt attaagtata atagacgact 99540
agctaagtct attatttgcg aggatgactc tcaaattatt acactcacgg cattcgttaa 99600
ccaatgccta tggtgtcata aacgagtatc cgtgtccgct attttattaa ctactgataa 99660
caaaatatta gtatgtaaca gacgagatag ttttctctat tctgaaataa ttagaactag 99720
aaacatgtct agaaagaaac gattatttct gaattattcc aattatttgt ccaaacagga 99780
aagaagtata ctatcgtcat ttttttctct agatccagct actactgata atgatagaat 99840
agatgctatt tatccgggtg gcatacccaa aaggggtgag aatgttccag agtgtttatc 99900
cagggaaatt aaagaagaag ttaatataga caattctttt gtattcatag acactcggtt 99960
ttttattcat ggcatcatag aagataccat tattaataaa ttttttgagg taatcttctt 100020
tgtcggaaga atatctttaa cgagtgatca aatcattgat acatttaaaa gtaatcatga 100080
aatcaaggat ctaatatttt tagatccgaa ttcaggtaat ggactccaat acgaaattgc 100140
aaaatatgct ctagatactg caaaactcaa atgttatggc catagaggat gttattacga 100200
atcattaaaa aaattaactg aggatgattg attagaaaat ataaattaat ttaccatcgt 100260
gtatttttat aacgggattg tccggcatat catgtagata gttaccgtct acatcgtata 100320
ctcgaccatc tacgccttta aatcctctat ttattgacat taatctatta gaattggaat 100380
accaaatatt agtaccctca attagtttat tggtaatatt ttttttagac gatagatcga 100440
tggctcttga aaccaaggtt ttccaaccgg actcattgtc gatcggtgag aagtcttttt 100500
cattagcatg aatccattct aatgatgtat gtttaaacac tctaaacaat tggacaaatt 100560
cttttgattt gctttgaatg atttcaaata ggtcttcgtc tacagtaggc ataccattag 100620
ataatctagc cattataaag tgcacgttta catatctacg ttctggagga gtaagaacgt 100680
gactattgag acgaatggct cttcctacta tctgacgaag agacgcctcg ttccatgtca 100740
tatctaaaat gaagatatca ttaattgaga aaaaactaat accctcgcct ccactagaag 100800
agaatacgca tgttttaatg cattctccgt tagtgtttga ttcttggtta aactcagcca 100860
ccgccttgat tctagtatct tttgttctag atgagaactc tatattagag ataccaaaga 100920
ctttgaaata tagtaataag atttctattc ctgactgatt aacaaatggt tcaaagacta 100980
gacatttacc atgggatgct aatattccca aacatacatc tataaatttg acgcttttct 101040
cttttaattc agtaaataga gagatatcag ccgcactagc atcccctttc aatagttctc 101100
cctttttaaa ggtatctaat gcggatttag aaaactctct atctcttaat gaatttttaa 101160
aatcattata tagtgttgct atctcttgcg cgtattcgcc cggatcacga ttttgtcttt 101220
caggaaagct atcgaacgta aacgtagtag ccatacgtct cagaattcta aatgatgata 101280
tacctgtttt tatttcagcg agtttagcct tttgataaat ttcttcttgc tttttcgaca 101340
tattaacgta tcgcattaat actgttttct tagcgaatga tgcagaccct tctacgtcat 101400
caaaaataga aaactcgtta ttaactatgt acgaacatag gcctcctagt ttggagacta 101460
attctttctc atcaactaga cgtttattct caaatagcga ttggtgttgt aaggatcctg 101520
gtcgtagtaa gttaaccaac atggtgaatt cttgcacact attaacgata ggtgtagccg 101580
ataaacaaat catcttatgg ttttttaatg cgatggtctt agataaaaaa ttatatactg 101640
aacgagtagg acggatctta ccatcttctt tgattaatga tttagaaatg aagttatgac 101700
attcatcaat aatgacgcat attctactct tggaattaat agttttgata ttagtaaaaa 101760
atttatttct aaaattttga tcatcgtaat taataaaaat acaatccttc gttatctctg 101820
gagcgtatct gagtatagtg ttcatccaag gatcttctat caaagccttt ttcaccaata 101880
agataatagc ccaattcgta taaatatcct taagatgttt gagaatatat acagtagtca 101940
ttgttttacc aacacccgtt tcatggaaca ataaaagaga atgcatactg tctaatccta 102000
agaaaactct tgctacaaaa tgttgataat ccttgaggcg tactacgtct gttcccatca 102060
tttcaacagg catattagta gttctgcgca atgcataatc gatataggcc gcgtgtgatt 102120
tactcattta tgagtgataa gtaataacta tgttttaaaa atcacagcag tagtttaact 102180
agtcttctct gatgtttgtt ttcgatactt tttgaatcag aagtcatact agaataaagc 102240
aacgagtgaa cgtaatagag agcttcgtat actctattcg aaaactctaa gaacttatta 102300
atgaattccg tatccactgg attgtttaaa atactaaatt gaacactgtt cacatccttc 102360
caagaagaag acttagtgac ggacttaaca tgagacataa ataaatccaa atttttttta 102420
caaacatcac tagccaccat aatggcgcta tctttcaacc agctatcgct tacgcatttt 102480
agcagtctaa catttttaaa gagactacaa tatattctca tagtatcgat tacacctcta 102540
ccgaataaag ttggaagttt aataatacaa tatttttcgt ttacaaaatc aaataatggt 102600
cgaaacacgt cgaaggttaa catcttataa tcgctaatgt atagattgtt ttcagtgaga 102660
tgattattag atttaatagc atctcgttca cgtttgaaca gtttattgtg tgcgctgagg 102720
tcggcaacta cggcgtccgc tttagtactc ctcccataat actttacgct attaatcttt 102780
aaaatttcat agactttatc tagatcgctt tctggtaaca tgatatcatg tgtaaaaagt 102840
tttaacatgt cggtcggcat tctatttaga tcattaactc tagaaatctg aagaaagtaa 102900
ttagctccgt attccagact aggtaatggg cttttaccta aagacaagtt aagttctggc 102960
aatgtttcat aaaatggaag aaggacatgc gttccctccc ggatattttt tacaatttca 103020
tccatttaca actctatagt ttgttttcat tattattagt tattatctcc cataatcttg 103080
gtaatactta ccccttgatc gtaagatacc ttatacaggt cattacatac aactaccaat 103140
tgtttttgta cataatagat tggatggttg acatccatgg tggaataaac tactcgaaca 103200
gatagtttat ctttccccct agatacattg gccgtaatag ttgtcggcct aaagaatatc 103260
tttggtgtaa agttaaaagt tagggttctt gttccattat tgctttttgt cagtagttca 103320
ttataaattc tcgagatggg tccgttctct gaatatagaa catcatttcc aaatctaact 103380
tctagtctag aaataatatc ggtcttattc ttaaaatcta ttcccttgat gaagggatcg 103440
ttaatgaaca aatccttggc ctttgattcg gctgatctat tatctccgtt atagacgtta 103500
cgttgactag tccaaagact tacaggaata gatgtatcga tgatgttgat actatgtgat 103560
atgtgagcaa agattgttct cttagtggca tcactatatg ttccagtaat ggcggaaaac 103620
tttttagaaa tgttatatat aaaagaattt tttcgtgttc caaacattag cagattagta 103680
tgaagataaa cactcatatt atcaggaaca ttatcaattt ttacatacac atcagcatct 103740
tgaatagaaa cgataccatc ttctggaacc tcaacaatct cggcagactc cggataacca 103800
gtcggtgggc catcactaac aataactaga tcatccaaca atctactcac atatgcatct 103860
atataatctt tttcatcttg tgagtaccct ggatacgaaa taaatttatt atccgtattt 103920
ccataataag gtttagtata aacagagagc gatgttgccg catgaacttc agttacagtc 103980
gccgttggtt ggtttatttg acctattact ctcctaggtt tctctataaa cgatggttta 104040
atttgtacat tcttaaccat atatccaata aagctcaatt caggaacata aacaaattct 104100
ttgttgaacg tttcaaagtc gaacgaagag tcacgaataa cgatatcgga tactggattg 104160
aaggttaccg ttacggtaat ttttgaatcg gatagtttaa gactgctgaa tgtatcttcc 104220
acatcaaacg gagttttaat ataaacgtat actgtagatg gttctttaat agtgtcatta 104280
ggagttaggc caatagaaat atcattaagt tcactagaat atccagagtg tttcaaagca 104340
attgtattat tgatacaatt attatataat tcttcgccct caatttccca aataacaccg 104400
ttacacgaag agatagatac gtgattaata catttatatc caacatatgg tacgtaaccg 104460
aatcttccca tacctttaac ttctggaagt tccaaactca gaaccaaatg attaagcgca 104520
gtaatatact gatccctaat ttcgaagcta gcgatagcct gattgtctgg accatcgttt 104580
gtcataactc cggatagaga aatatattgc ggcatataca aagttggaat ttgactatcg 104640
actgcgaaga cattagaccg tttaatagag tcatccccac cgatcaaaga attaatgata 104700
gtattattca ttttctattt aaaatggaaa aagcttacaa taaactccgt agagaaatat 104760
ctataatttg tgagttttcc ttaaagtaac agcttccgta aacgccgtct ttatctctta 104820
gtaggtttat tgtatttatg accttttcct tatcttcata gaatactaaa ggcaacaaag 104880
aaatttttgg ttcttctcta agagctacgt gagacttaac catagaagcc aacgaatccc 104940
tacatatttt agaacagaaa tacccaactt caccaccctt gaatgtctca atactaatag 105000
gtctaaaaac caaatcttga ttacaaaacc aacacttatc aattacacta tttgtcttaa 105060
tagacacatc tgccatagat ttataatact ttggtagtat acaagcgagt gcttcttctt 105120
tagcgggctt aaagactgct ttaggtgctg aaataaccac atctggaagg cttactcgct 105180
tagccattta attacggaac tattttttta tacttctaat gagcaagtag aaaacctctc 105240
atctacaaaa acatactcgt gtccataatc ctctaccata gttacacgtt ttttagatct 105300
catatgtgct aaaaagtttt cccatactaa ttggttacta ttatttttcg tataattttt 105360
aacagtttga ggttttagat ttttagttac agaagtgata tcgaatattt tatccaaaaa 105420
gaatgaataa ttaattgtct tagaaggagt gttttcttgg caaaagaata ccaagtgctt 105480
aaatatttct actacttcat taatcttttc tgtactcaga ttcagtttct catcttttac 105540
ttgattgatt atttcaaaga ctaacttata atccttttta tttattctct cgttagcctt 105600
aagaaaacta gatacaaaat ttgcatctac atcatccgtg gatatttgat ttttttccat 105660
gatatccaag agttccgaga taatttctcc agaacattga tgagacaata atctccgcaa 105720
tacatttctc aaatgaataa gtttattaga cacatggaag tttgactttt tttgtacctt 105780
tgtacatttt tgaaatacag actcgcaaaa aatacaatat tcatatcctt gttcagatac 105840
tataccgttg tgtctacaac cgctacataa tcgtagattc atgttaacac tctacgtatc 105900
tcgtcgtcca atattttata taaaaacatt ttatttctag acgttgccag aaaatcctgt 105960
aatattttta gttttttggg ctgtgaataa agtatcgccc taatatggtt accgtcctcc 106020
gccaatatag tagttaaatt atccgcacat gcagaagaac accgcttagg cggattcagt 106080
acaatgttat atttttcgta ccaactcatt taaatatcat aatctaaaat agttctgtaa 106140
tatgtctagc gctaatatat tgatcataat cctgtgcata aattaagata caacaatgtc 106200
tcgaaatcat cgacatggct tcttccatag ttagaagatc gtcgtcaaag ttagcaacgt 106260
gattcatcaa catttgctgt tttgaggcag caaatactga accgtcgcca ttcaaccatt 106320
cataaaaacc atcgtctgaa tccattgata atttcttgta ctggtttttg agagctcgca 106380
tcaatctagc atttctagct cccggattga aaacagaaag aggatcgtac atccagggtc 106440
cattttctgt aaatagaatc gtataatgtc ccttcaagaa gatatcagac gatccacaat 106500
caaagaattg gtctccgagt ttgtaacaaa ctgcggactt taacctatac atgataccgt 106560
ttagcatgat ttctggtgat acgtcaatcg gagtatcatc tattagagat ctaaagccgg 106620
tgtaacattc tccaccaaac atattcttat tctgacgtcg ttctacataa aacatcattg 106680
ctccattaac gataacaggg gaatgaacag cactacccat cacattagtt cccaatggat 106740
caatgtgtgt aactccagaa catcttccat atcctatgtt aggaggagcg aacaccactc 106800
ttccactatt gccatcgaat gccatagaat aaatatcctt ggaattgata gaaatcggac 106860
tgtcggatgt tgtgatcatc ttcataggat taacaactat gtatggtgcc gcctgaagtt 106920
tcatatcgta actgatgccg tttataggtc tagccacaga aaccaacgta ggtctaaatc 106980
caactataga caaaatagaa gccaatatct gttcttcatc tgtcataact tgagagcatc 107040
cagtatgaat aatcttcatt agatggggat ctaccgcatc atcatcgtta caataaaaaa 107100
ttcccattct aatgttcata attgcttttc taatcatggt atgcatgttt gctctctgaa 107160
tctctgtgga aattagatct gatacacctg taatcactat cggattatcc tccgtaagac 107220
gattaaccaa caacatataa ttataagact ttacttttct aaattcataa agttgctgga 107280
ttaggctata ggtgtctcca tgtacatacg cgttctcgag cgcaggaagt ttaataccga 107340
atagtgccat cagaatagga tgaatatagt aattagtttc tggttttcta taaataaaag 107400
acaaatcttg tgaactagac atatcggtaa aatgcatgga ttggaatcgt gtagtcgaca 107460
gaagaatatg atgattagat ggagagtata ttttatctaa ctctttgagt tggtcaccga 107520
ttctaggact agctcgagaa tgaataagta ctaaaggatg agtacatttc acagaaacac 107580
tagcattgtt caatgtgctc tttacatggg taaggagttg aaatagctcg tttctatttg 107640
ttctgacaat atttagttta ttcataatgt taagcatatc ctgaatagta aagttagatg 107700
tgtcatactt gttagtagtt agatatttag caattgcatt cccatcattt ctcaatctcg 107760
tactccaatc atgcgtggat gctacttcgt cgatggaaac catacaatcc tttttgatag 107820
gctgttgaga ttgattattt cctgcacgtt taggtttggt acgttgattt ctagcccctg 107880
cggatataaa gtcatcgtct acaattttgg ataatgaatt gcatacacta caagacaaag 107940
atttatcaga agtgtgaata tgatcttcat ctaccaaaga aagagtttga ttagtataac 108000
tagattttag tcctgcgtta gatgttaaaa aaacatcgct attgaccacg gcttccatta 108060
tttatattcg tagtttttac tcgaaagcgt gattttaata ttcaatctta ttacttttgg 108120
aatcgttcaa aacctttgac taattgtaga atttgatcta ttgccctacg cgtatactcc 108180
cttgcatcat atacgttcgt caccagatcg tttgtttcgg cctgaagttg gtgcatatct 108240
ctttcaacat tcgacatgag atccttaagg gccatatcgt ctagattttg ttgagatgct 108300
gctcctggat ttggattttg ttgtgctgtt gtacatactg taccaccagt aggtgtagga 108360
gtacatacag tggccacaat aggaggttga ggaggtgtaa ccgttggagt agtacaagaa 108420
atacttccat ccgattgttg tgtacatgta gttgttggta acgtctgaga aggttgggta 108480
gatggcggcg tcgtcgtctt ttgatcttta ttaaatttag agataatatc ctgaacagca 108540
ttgctcggcg tcaacgctgg aaggagtgaa ctcgccggcg catcagtatc tgcagacagc 108600
caatcaaaaa gattagacat atcagatgat gtattagttt gttgtcgtgg ttttggtgta 108660
ggagccggtg tagctgttgg aaccggctgt ggagttatat gaatagttgg ttgtagcggt 108720
tggataggct gtctgctggc ggccatcata ttatctctag ctagttgttc tcgcaactgt 108780
ctttgataat acgactcttg agactttagt cctatttcaa tcgcttcatc ctttttcgta 108840
tccggatcct tttcttcaga ataatagatt gacgactttg gtgtagagga ttctgccagc 108900
ccctgtgaga acttgttaaa gaagtccatt taaggcttta aaattgaatt gcgattataa 108960
gattaaatgg cagacacaga cgatattatc gactatgaat ccgatgatct caccgaatac 109020
gaggatgatg aagaagagga agaagatgga gagtcactag aaactagtga tatagatccc 109080
aaatcttctt ataagattgt agaatcagca tccactcata tagaagatgc gcattccaat 109140
cttaaacata tagggaatca tatatctgct cttaaacgac gctatactag acgtataagt 109200
ctatttgaaa tagcgggtat aatagcagaa agctataact tgcttcaacg aggaagatta 109260
cctctagttt cagaattttc tgacgaaacg atgaagcaaa atatgctaca tgtaattata 109320
caagagatag aggagggttc ttgtcctata gtcatcgaaa agaacggaga attgttgtcg 109380
gtaaacgatt ttgacaaaga tggtctaaaa ttccatctag actatattat caaaatttgg 109440
aaacttcaaa aacgatatta gaatttatac gaatatcgtt ctctaaatgt cacaatcaag 109500
tctcgcatgt tcagcaattt attgtcgtac tttatatcgt gttcattaac gatatcttgc 109560
aaaatagtaa tgattctatc ttccttcgat agatattctt cagagattat tgtcttatat 109620
tctttcttgt tatcagatat gaatttgata agactttgaa cattattgat acccgtctgt 109680
ttaatttttt ctacagatat tttagttttg gcagattcta tcgtatctgt caatagacat 109740
ccaacatcga cattcgacgt caattgtcta taaatcaacg tataaatttt agaaataaca 109800
ttagcgaatt gttgtgcatt gatgtcgtta ttctgaaaca gtatgatttt aggtagcatt 109860
ttcttaacaa agagaacgta tttattgtta ctcagttgaa cagatgatat atccagatta 109920
ctaacgcatc tgattccata taccaaactt tcagaagaaa tggtgtacaa ttgtttgtat 109980
tcattcaatg tctctttttc agaaattagt ttagagtcga atactgcaat aattttcaag 110040
agatagtttt catcagataa gattttattt agtgtagata tgataaaact attgttttgt 110100
tggagaactt gatacgccgc gttctctgta gtcgacgctc tcaaatggga aacaatctcc 110160
attatttttt tggaatcgga tacaatatct tcggtatctt gacgcaatct agtatacata 110220
gagttaagag aaattagagt ttgtacatta agcaacatgt ctctaaatgt ggctgcaaac 110280
ttttcctttt ccacatcatc tagtttatta tataccgatt tcacaacggc accagattta 110340
aggaaccaga atgaaaaact ctgataacta caatatttca tcatagttac gattttatca 110400
tcttctatag ttggtgtaat agcgcatacc tttttctcca agactggaac caacgtcata 110460
aaaatgttta aatcaaaatc catatcaaca tctgatgcgc taagaccagt ctcgcgttca 110520
agattatctt tactaatggt gacgaactca tcgtatagaa ctctaagttt gtccattatt 110580
tatttacaga tttagttgtt taatttattt gtgctcttcc agagttggga tagtattttt 110640
ctaacgtcgg tattatatta ttaggatcta cgttcatatg tatcataata ttaatcatcc 110700
acgttttgat aaatctatct ttagcttctg aaataacgta tttaaacaaa ggagaaaaat 110760
atttagctac ggcatcagac gcaataacat tttttgtaaa tgtaacgtat ttagacgaca 110820
gatcttcgtt aaaaagtttt ccatctatgt agaatccatc ggttgttaac accattcccg 110880
cgtcagattg aataggagtt tgaatagttt gttttggaaa tagatccttc aataacttat 110940
agttgggtgg gaaaaaatcg attttatcac tagactcttt cttttttact atcattacct 111000
catgaactat ttcttgaatg agtatatgta ttttctttcc tatatcggac gcgttcattg 111060
gaaaatatac catgtcgtta actataagaa tatttttatc ctcgtttaca aactgaataa 111120
tatcagatgt agttcgtaaa cgaactatat catcaccagc acaacatcta actatatgat 111180
atccactagt ttcctttagt cgtttattat cttgttccat attagcagtc attccatcat 111240
ttaagaaggc gtcaaagata atagggagaa atgacatttt ggattctgtt acaactttac 111300
caaaattaag gatatacgga cttactatct ttttctcaac gtcgatttga tgaacacacg 111360
atgaaaatgt acttcgatga gattgatcat gtagaaaaca acaagggata caatatttcc 111420
acatatcatg aaatatatta agaaatccca ccttattata tttccccaaa ggatccatgc 111480
atgtaaacat tatgccgtta tcattaataa agacttcttt ctcatcggat ctgtaaaagt 111540
tgttactgat ttttttcatt ccaggatcta gataattaat aatgatgggt tttctattct 111600
tattctttgt attttggcat atcctagacc agtaaacagt ttccactttg gtaaaatcag 111660
cagacttttg aacgctatta aacatggcat taatggcaat aactaaaaat gtaaaatatt 111720
tttctatgtt aggaatatgg tttttcactt taatagatat atggtttttg gccaaaatga 111780
tagatatttt tttatccgag gatagtaaaa tattattagt cgccgtctct ataaaaatga 111840
agctagtctc gatatccaat tttattctag aattgatagg agtcgccaaa tgtaccttat 111900
acgttatatc tcccttgatg cgttccattt gtgtatctat atcggacaca agatctgtaa 111960
atagttttac gttattaatc atcacggtat cgccgtcgct agataacgct aatgtaccat 112020
ccaagtccca aatggagaga tttaactgtt catcgtttag aataaaatga ttaccggtca 112080
tattaataaa gtgttcatcg tatctagata acaacgactt ataattaatg tccaagtctt 112140
gaactcgctg aatgatcttt tttaacccag ttagttttag attggtacga aatatattgt 112200
taaactttga ttctacagta atgtccaaat ctagttgtgg aaatacttcc atcaacattg 112260
tttcaaactt gataatatta ttatctacat cttcatacga tccaaattcc ggaatagatg 112320
tatcgcacgc tctggccacc cagataacca aaaagtcaca cgctccagga tatacattgt 112380
ataaaaagct atcgtttttt agtagtgttt ttttctgagt atatacgaag ggattaaaaa 112440
tagtattatc aacgtaacta tattccaaat tattcttatg agaatagata ataatatcgt 112500
ccttaatatc taacaaattt cctaaatatc cctttaattg agtcattcga agcgtcaata 112560
gaatatgtct cttaactatt tccggctgtt gtatatttaa atgacttcgt aaaaaataat 112620
atatgggcga cttctcatct atgtaatcat atggagtgag atatagggct cgttctacct 112680
cctgcccctt acccacctgt aataccaatt gcggacttac tatatatcgc atatttatat 112740
cgtggggtaa agtgaaaatc tactaccgat gatgtaagtc ttacaatgtt cgaaccagta 112800
ccagatctta atttggaggc ctccgtagaa ctaggggagg taaatataga tcaaacaaca 112860
cctatgataa aggaaaatag cggttttata tcccgtagta gacgtctatt cgcccataga 112920
tctaaggatg atgagagaaa actagcacta cgattctttt tacaaagact ttatttttta 112980
gatcatagag agattcatta tttgttcaga tgcgttgacg ctgtaaaaga cgtcactatt 113040
accaaaaaaa ataacattat cgtggcgcct tatatagcac ttttaactat cgcatcaaaa 113100
ggatgcaaac ttacagaaac aatgattgaa gcattctttc cagaactata taatgaacat 113160
agtaagaaat ttaaattcaa ctctcaagta tccatcatcc aagaaaaact cggataccag 113220
tttggaaact atcacgttta tgattttgaa ccgtattact ctacagtagc tctggctatt 113280
cgagatgaac attcatctgg catttttaat atccgtcaag agagttatct ggtaagttca 113340
ttatctgaaa taacatatag attttatcta attaatctaa aatctgatct tgttcaatgg 113400
agtgctagta cgggcgctgt aattaatcaa atggtaaata ctgtattgat tacagtgtat 113460
gaaaagttac aactggtcat agaaaatgat tcacaattta catgttcatt ggctgtggaa 113520
tcaaaacttc caataaaatt acttaaagat agaaatgaat tatttacaaa attcatcaac 113580
gagttaaaaa agaccagttc attcaagata agcaaacgcg ataaggatac gctactaaaa 113640
tattttactt aggactggag ttagaattta tagacgactc atttcgttta tcattattag 113700
tattcttctt gttatcttgt tcagaaatat acagcaatgc tatgcctaat actaaataca 113760
ttatcatgct tgcaatggct ctaacaacga cgaaccaaaa tgaatttggt cgtagctttt 113820
gttcacaaaa atacataaag aaatgtctac ataaatctat ggcgccattg gctacttgaa 113880
atagcgccag tcctcctaca gattttaata tagctgtata acatgacatt tattcatcat 113940
caaaagagac agagtcacca tctgtcatat ttagattttt tttcatgtgt tcaaagtatc 114000
ctctactcat ttcattataa tagtttatca tacttagaat tttaggacgg atcaatgagt 114060
aagacttgac tagatcgtca gtagtaattt gtgcatcgtc tattctgcat ccgcttcgtc 114120
gaataatgta tagcatcgct ttgagattct ccatagctat caagtcttta tacaatgaca 114180
tggaaatatc tgtgaatact ttatacttct ccaacatcga tgccttaaca tcatcgccta 114240
ctttagcatt gaaaatacgt tctattgtgt agatggatgt agcaagattt ttaaacaaca 114300
atgccatttt acacgatgat tgcctcaagt ctccaatcgt ttgtttagaa cgattagcta 114360
cagagtccaa tgcttggctg actagcatat tattatcttt agaaattgta ttcttcaatg 114420
aggcgtttat catatctgtg atttcgttag tcatattaca gtctgactgg gttgtaatgt 114480
tatccaacat atcacctatg gatacggtac acgtaccagc atttgtaata atcctatcta 114540
agatgttgta tggcattgcg cagaaaatat cttctcctgt aatatttcca ctctcgataa 114600
atctactcag attattctta aatgccttat tctctggaga aaagatatca gtgtccatca 114660
tttcattaat agtatacgca gaaaagatac cacgagtatc aattctatcc aagatactta 114720
tcggttccga gtcacagata atggtttcct ctccttcggg agatcctgca tagaaatatc 114780
taggacaata gtttctatac tgtctgtaac tctgataatc tctaaagtca ctaactgata 114840
ccatgaaatt gagaagatca aacgctgaag taattaattt ttctgcctcg tttttactac 114900
aactagtttt catcaatgta gtgacgatgt attgtttagt tactcttggt ctaatactga 114960
tgatagagat attattactt cccataatgg atcttctagt agtcacctta aagcccattg 115020
atgcaaatag cagatagata aagtcttggt atgactcctt tctaatatag tacggactac 115080
ctttgtcacc caactttata cccacataag ccataacaac ctctttaata gccgtttcat 115140
gaggtttatc agccatgagc ctgagtagtt ggaagaatct catgaatcct gtctcagaaa 115200
gtcctatatg catgatagat ttatctttcc tgggaaactc tcgtatagtc atagatgaaa 115260
tactcttcaa agtttctgaa ataagattag taacagtctt acctccgact actctaggta 115320
acaaacaaac tctaataggt gttttctctg cggagataat atcagaaagg atagagcaat 115380
aagtagtatt attgtgatta taaagaccga atacataaca ggtagaattt ataaacatca 115440
tgtcctgaag gtttttagac ttgtattcct cgtaatccat accgtcccaa aacatggatt 115500
tggtaacttt gatagccgta gatctttgtt ccttcgccaa caggttaaag aaattaataa 115560
agaatttgtg gtttctacct atgtctacaa attgcacgtt tggaagcgcc acggttacat 115620
tcactgcagc attttgagga tcgcgagtat gaagtacgat gttattgttt actggtatat 115680
ctggaaagaa ttctaccagt ctaggaataa gagattgata tcgcatagaa atacaaaagt 115740
tcataatctc atcatctaag agcattttgt taccattgta ataaatatcc actctgtcat 115800
atgtataaat gaagtactgt tcaaacatga tgagatgttt atatgttggc atagtagtga 115860
gatctacgtt tggtaatggc aatgtattaa gattaactcc ataatgtcta gcagcatctg 115920
cgatgttata agcgttgtca aagcggggtc gatcttgtgc tgttatatat tgtctaacac 115980
ctataagatt atcaaaatct tgtctgctta atacaccgtt aacaattttt gccttgaatt 116040
cttttattgg tgcattaata acatccttat agaggatgtt aaacaaataa gtgttatcaa 116100
agttaagatc tggatatttc ttttctgcta gaacatccat tgagtcggag ccatctggtt 116160
taatataacc accgataaat ctagctctgt attctgtatc cgtcaatcta atattaagaa 116220
ggtgttgagt gaaaggtgga agatcgtaaa agctgtgagt attaatgata ggattagttt 116280
ccgaactaat gttaattggg gtattaataa tatctatatt tccagcgtta agtgtaacat 116340
taaacagttt taattcacgt gacgtggtat caattaaata attaatgccc aatttggata 116400
tagcagcctg aagctcatct tgtttagtta cggatcctaa tgagttatta agcaatatat 116460
cgaacggatg aacgaaggtt gttttaagtt ggtcacatac tttgtaatct agacatagat 116520
gcggaagaac ggtagaaact atacgaaata aatattcaga gtcctctaat tgatcaagag 116580
taactattga cttaataggc atcatttatt tagtattaaa tgacgaccgt accagtgacg 116640
gatatacaaa acgatttaat tacagagttt tcagaagata attatccatc taacaaaaat 116700
tatgaaataa ctcttcgtca aatgtctatt ctaactcacg ttaacaacgt ggtagataga 116760
gaacataatg ccgccgtagt gtcatctcca gaggaaatat cctcacaact taatgaagat 116820
ctatttccag atgatgattc tccggccact attatcgaac gagtacaacc tcatactact 116880
attattgacg atactccacc tcctacgttt cgtagagagt tattgatatc ggaacaacgt 116940
caacaacgag aaaaaagatt taatattaca gtatcgaaaa atgctgaagc aataatggaa 117000
tctagatcta tgatatcttc tatgccaaca caaacaccat ccttgggagt agtttatgat 117060
aaagataaaa gaattcagat gttggaggat gaagtggtta atcttagaaa tcaacgatct 117120
aatacaaaat catctgataa tttagataat tttaccagaa tactatttgg taagactccg 117180
tataaatcaa cagaagttaa taagcgtata gccatcgtta attatgcaaa tttgaacggg 117240
tctcccttat cagtcgagga cttggatgtt tgttcagagg atgaaataga tagaatctat 117300
aaaacgatta aacaatatca cgaaagtaga aaacgaaaaa ttatcgtcac taacgtgatt 117360
attattgtca taaatattat cgagcaagca ttgctaaaac tcggatttga agaaatcaaa 117420
ggactgagta ccgatatcac ttcagaaatt atcgatgtgg agatcggaga tgactgcgat 117480
gctgtagcat caaaactagg aatcggtaac agtccggttc ttaatattgt attgtttata 117540
ctcaagatat tcgttaaacg aattaaaatt atttaattta atacattccc atatccagac 117600
aacaatcgtc tggattaatc tgttcctgtc gtctcatacc ggacgacata ttaatctttt 117660
tattagtagg catcttttta gatggtttct ttttcccagc attaactgag tcgataccta 117720
gaagatcgtg attgatctct ccgaccattc cacgaacttc taattggccg tctctgacgg 117780
taccataaac tattttacca gcattagtaa cagcttggac aatctgacca tccatcgcat 117840
tgtacgatgt agtagtaact gttgttctac gtctaggagc accagaagta tttttggagc 117900
ccttggatgt tgatgtagaa gaagacgagg attttgattt tggtttacat gtaatacatt 117960
ttgtatcaca tgcgccggca gtcacatctg tttgagaatt aagattattg ttgcctcctt 118020
tgacggctgc atctccaccg atttgcgcta gtagattttt aagctgtggt gtaatcttat 118080
taactgtttc gatataatca tcgtaactgc ttctaacggc taaatttttt ttatccgcca 118140
tttagaagct aaaaatattt ttatttatgc agaagattta actagattat acaatgaact 118200
aatatgatcc ttttccagat tatttacaaa cttggtattt tttggttctg gaggaggcga 118260
atttaaattc ggacttggat ttggattttg tgggttcttg atcttattat acagcgcata 118320
taggatggcg acggtaactg ctacgcaaat accgatcaac aaaagaatac caatcattta 118380
ttgacaataa cttcactatt gatcaagtat gcaatatatc atcttttcac taaataagta 118440
gtaataatga ttcaacaatg tcgagatata tggacgataa taatttagtt catggaaata 118500
tcgctatgat tggtatgaat gactccgcta actctgtggg gcgcgcagtg ctttccccac 118560
atagaataaa ttagcattcc gactgtgata ataataccaa gtataaacgc cataatactc 118620
aatactttcc atgtacgagt gggactggta gacttactaa agtcaataaa ggcgaagata 118680
cacgaaagaa tcaaaagaat gattccagcg attagcacgc cggaaaaata atttccaatc 118740
ataagcatca tatccattta actaataaaa attttaaatc gccgaatgaa caaagtggaa 118800
tataaaccat ataaaaacaa tagtttgtac tgcaaaaata atatctattt ttgttttcga 118860
agatatggta aaattaaata gtagtacaca gcatgttata actaacagca gcaacggctc 118920
gtaattactt atcatttact agacgaaaag gtggtgggat attttcttgc tcaaataata 118980
cgaatatatc acccatccat tttatgcgat gtttatatac tctaatcttt aatagatcta 119040
tagacgacgg gtttaccaac aatatagatt ttatcgattc atctaattta aacccttcct 119100
taaacgtgaa tgatctatta tctggcataa cgatgactct acccgatgaa tcggacaatg 119160
tactgggcca tgtagaataa attatcaacg aattatcgtc tacgaacatt tatatcattt 119220
gttttaattt tagtacgcga ataaatagat ataaaataga aaataacaga tattacaacc 119280
aatgttatgg ccgcgcccaa ccaggtaggc agttttattt tatcttttac tacaggttct 119340
cctggatgta cgtcaccaac ggcggacgta gttctagtac aattagacgt aagttccgct 119400
tgggaatttt ttaacgctaa agagttaacg ttaatcgtgc acccaacgta tttacatcta 119460
gttctttgaa catcttgatt ataatataac cattttctat ctctagattc gtcggtgcac 119520
tcatgtaacc aacataccct aggtcctaaa tatttatctc cggaattaga ttttggataa 119580
ttcgcgcacc aacaatttct atttccttta tgatcgttac aaaagacgta taatgccgta 119640
tccccaaaag taaaataatc aggacgaata attctaataa actcagaaca atatctcgca 119700
tccatatgtt tggagcaaat atcggaataa gtagacatag ccggtttccg ttttgcacgt 119760
aaccattcta aacaattggg gtttccagga tcgtttctac aaaatccagt catgaaatca 119820
tcacaatgtt ctgtcttgta attattatta aatatttttg gacagtgttt ggtatttgtc 119880
ttagaacaac attttgccac gctatcacta tcgcccagga gataatcctt ttttataaaa 119940
tgacatcgtt gcccggatgc tatataatca gtagcgtgtt ttaaatcctt aatatattca 120000
ggagttacct cgttctgata atagattaat gatccaggac gaaatttgaa agaactacat 120060
ggttctccat gaattaatac atattgttta gcaaattcag gaactataaa actactacaa 120120
tgatctatcg acataccatc tatcaaacaa aacttgggtt taatttctcc cggagatgtt 120180
tcataatagt acgtataact ttcttctgca aacttaacag ctctattata ttcaggataa 120240
ttaaaaccta attccatata tttgtctcgt atatctgcta ttcctggtgc tattttgatt 120300
ctattaagag taacggctgc ccccattttt aataatcgtc agtatttaaa ctgttaaatg 120360
ttggtatatc aacatttacc ttatttcccg cagtataagg tttgttgcag gtatactgtt 120420
caggaatggt tacatttata ctttttctat agtcctgtct ttcgatgttc atcacatatg 120480
caaagaacag aataaacaaa ataatgtaag aaataatatt aaatatctgt gaattcgtaa 120540
atacattgat tgccataata attacagcag ctacaataca tacaatagac attcccacag 120600
tgttgccatt acctccacga tacatttgag ttactaagca ataggtaata actaagctag 120660
taagaggcaa tagaaaagat gagataaata tcatcaatat agagattaga ggagggctat 120720
atagagccaa gacgaacaaa atcaaaccga gtaacgttct aacatcatta tttttgaaga 120780
ttcccaaata atcattcatt cctccataat cgttttgcat catacctcca tctttaggca 120840
taaacgattg ctgctgttcc tctgtaaata aatctttatc aagcactcca gcacccgcag 120900
agaagtcgtc aagcatattg taatatctta aataactcat ttatatatta aaaaatgtca 120960
ctattaaaga tggagtataa tctttatgcc gaactaaaaa aaatgacttg tggtcaaccc 121020
ctaagtcttt ttaacgaaga cggggatttc gtagaagttg aaccgggatc atcctttaag 121080
tttctgatac ctaagggatt ttacgcctct ccttccgtaa agacgagtct agtatttgaa 121140
acattaacaa cgaccgataa taaaattact agtatcaatc caacaaatgc gccaaagtta 121200
tatcctcttc aacgcaaagt cgtatctgaa gtagtttcta atatgaggaa aatgatcgaa 121260
tcaaaacgtc ctctatacat cactcttcac ttggcgtgtg gatttggtaa gactattacc 121320
acgtgttatc ttatggctac acacggtaga aaaaccgtca tttgcgtacc caataaaatg 121380
ttaatacatc aatggaagac acaggtagag gcagtcggat tggaacataa gatatccata 121440
gatggagtaa gtagtctatt aaaggaacta aagactcaaa gtccggatgt attaatagta 121500
gtcagtagac atctgacaaa cgatgccttt tgtaaatata tcaataagca ttatgatttg 121560
ttcatcttgg atgaatcaca tacgtataat ctgatgaaca atacagcagt tacaagattt 121620
ttagcgtatt atcctccgat gatgtgttat tttttaactg ctacacctag accatctaac 121680
agaatttatt gtaacagtat tattaatatt gccaagttat ccgatctaaa aaaaactatc 121740
tatgcagtag atagtttttt tgagccatat tccacagata atattagaca tatgataaaa 121800
cgattagatg gaccatctaa taaatatcat atatataccg agaagttatt atctgtagac 121860
gagcctagaa atcaacttat tcttaatacc ctggtagaag aattcaagtc aggaactatt 121920
aatcgcattt tagttattac taaactacgt gaacatatgg tattcttcta caaacgatta 121980
ttagattttt tcggatcaga ggttgtattt ataggagacg cccaaaatag acgtactcca 122040
gatatggtca aatcaatcaa ggaactaaat agatttatat tcgtatccac cttattttat 122100
tccggtactg gtttagatat tcctagtttg gattctttgt tcatttgctc ggcagtaatc 122160
aacaatatgc aaatagagca attactaggg agggtatgtc gagaaacaga actattagat 122220
aggacggtat atgtatttcc tagcacatcc atcaaagaaa taaagtacat gataggaaat 122280
ttcgttcaac gaattattag tctgtctgta gataaactag gatttaaaca aaaaagttat 122340
cggaaacatc aagaatccga tcccacttct gtatgtacaa catcctccag agaagaacgt 122400
gtattaaata gaatatttaa ctcgcaaaat cgttaagaag tttaagcgac gatccgcatg 122460
ctgcgcaggc cagtgtatta cccctcatag tattaatata atccaatgat acttttgtga 122520
tgtcggaaat cttaaccaat ttagactgac aggcagaaca cgtcatgcaa tcatcatcgt 122580
catcgataac tgtagtcttg ggcttctttt tgcggctctt cattccggaa cgcacattgg 122640
tgctatccat ttaggtagta aaaaataagt cagaatatgc cctatagcac gatcgtgcaa 122700
aacctggtat atcgtctcta tctttatcac aatatagtgt atcgacatct ttattattat 122760
tgacctcgtt tatcttggaa catggaatgg gaacattttt gttatcaacg gccacctttg 122820
ccttaattcc agatgttgta aaattataac taaacagtct atcatcgaca caaatgaaat 122880
tcttgtttag acgtttgtag tttacgtatg cggctcgttc gcgtctcatt ttttcagata 122940
ttgcaggtac tataatatta aaaataagaa tgaaataaca taggattaaa aataaagtta 123000
tcatgacttc tagcgctgat ttaactaact taaaagaatt acttagtctg tacaaaagtt 123060
tgaaattttc agattctgcg gctatagaaa agtataattc tttggtagaa tggggaacat 123120
ctacttactg gaaaataggc gtgcaaaagg tagctaatgt cgagacgtca atatctgatt 123180
attatgatga ggtaaaaaat aaaccgttta atattgatcc gggctattac attttcttac 123240
cggtatattt tgggagcgtc tttatttatt cgaagggtaa aaatatggta gaacttggat 123300
ctggaaactc ttttcaaata ccagatgata tgcgaagtgc gtgtaacaaa gtattagaca 123360
gcgataacgg aatagacttt ctgagatttg ttttgttaaa caatagatgg ataatggaag 123420
atgctatatc aaaatatcag tctccagtta atatatttaa actagctagt gagtacggat 123480
taaacatacc caaatattta gaaattgaaa tagaggaaga cacattattt gacgacgagt 123540
tatactctat tatagaacgc tctttcgatg ataaatttcc aaaaatatcc atatcgtata 123600
ttaagttggg agaacttagg cggcaagttg tagacttttt caaattctca ttcatgtata 123660
ttgagtccat caaggtagat cgtataggag ataatatttt tattcctagc gttataacaa 123720
aatcaggaaa aaagatatta gtaaaagatg tagaccattt aatacgatcc aaggttagag 123780
aacatacatt tgtaaaagta aaaaagaaaa acacattttc cattttatac gactatgatg 123840
gaaacggaac agaaactaga ggagaagtaa taaaacgaat tatagacact ataggacgag 123900
actattatgt taacggaaag tatttctcta aggttggtag tgcaggctta aagcaattga 123960
ctaataaatt agatattaat gagtgcgcaa ctgtcgatga gttagttgat gagattaata 124020
aatccggaac tgtaaaacga aaaataaaaa accaatcagc atttgattta agcagagaat 124080
gtttgggata tccagaagcg gattttataa cgttagttaa taacatgcgg ttcaaaatag 124140
aaaattgtaa ggttgtaaat ttcaatattg aaaatactaa ttgtttaaat aacccgagta 124200
ttgagactat atatggaaac tttaaccagt tcgtctcaat ctttaatatc gtcaccgatg 124260
tcaaaaaaag attattcgag tgaaataata tgcgcctttg atataggtgc aaaaaatcct 124320
gccagaactg ttttagaagt caaggataac tccgttaggg tattggatat atcaaaatta 124380
gactggagtt ctgattggga aaggcacata gctaaagatt tgtcacaata tgaatacact 124440
acagttcttc tagaacgtca gcctagaagg tcgccgtacg tcaaatttat ctattttatt 124500
aaaggctttt tatatcatac atcggctgcc aaagttattt gcgtctcgcc tgtcatgtct 124560
ggtaattcat atagagatcg aaaaaagaga tcggtcgaag catttcttga ttggatggac 124620
acattcggat tgcgagactc cgttccggat agacgcaaat tagacgatgt agcggatagt 124680
ttcaatttgg ctatgagata cgtattagat aaatggaata ctaattatac accttataat 124740
aggtgtaaat ctagaaatta cataaaaaaa atgtaataac gttagtaacg ccattatgga 124800
taatctattt acctttctac atgaaataga agatagatat gccagaacta tttttaactt 124860
tcatctaata agttgcgatg aaataggaga tatatatggt cttatgaaag aacgcatttc 124920
ctcagaggat atgtttgata atatagtgta taataaagat atacatcatg ccattaagaa 124980
actagtgtat tgcgacatcc aacttactaa acacattatt aatcagaata cgtatccggt 125040
atttaacgat tcttcacaag tgaaatgttg tcattatttc gatataaact cagataatag 125100
caatattagc tctcgtacag tagagatatt tgagagggaa aagtcatctc ttgtatcata 125160
tattaaaact accaataaga agagaaaggt caattatggg gaaataaaga aaactgtaca 125220
tggaggcact aatgcaaatt acttttccgg taaaaagtct gatgagtatc tgagcactac 125280
agtcaggtcc aacattaatc aaccttggat caaaaccatt tctaagagaa tgagagtaga 125340
tatcattaat cactctatag taacgcgtgg aaaaagctct atattacaaa ctatagaaat 125400
tatttttact aatagaacat gtgtgaaaat attcaaggat tctactatgc acattattct 125460
atccaaggac aaggatgaaa aggggtgtat acacatgatt gacaaattat tctatgtcta 125520
ttataattta tttctgttgt tcgaggatat catccaaaac gagtacttta aagaagtagc 125580
taatgttgta aaccacgtac tcacggctac ggcattagat gagaaattat tcctaattaa 125640
gaaaatggct gaacacgatg tttatggagt tagcaatttc aaaataggga tgtttaacct 125700
gacatttatt aagtcgttgg atcataccgt tttcccctct ctgttagatg aggatagcaa 125760
aataaagttt tttaagggga aaaagctcaa tattgtagca ttacgatctc tggaggattg 125820
tataaattac gtgactaaat ccgagaatat gatagaaatg atgaaggaaa gatcgactat 125880
tttaaatagc atagatatag aaacggaatc ggtagatcgt ctaaaagaat tgcttctaaa 125940
atgaaaaaaa aacactaatt cagaaatgga tcaacgactc ggatataagt ttttggtgcc 126000
tgatcctaaa gccggagttt tttatagacc gttacatttc caatatgtat cgtattctaa 126060
ttttatattg catcgattgc atgaaatctt gaccgtcaag cggccactct tatcgtttaa 126120
gaataataca gaacgaatta tgatagaaat tagcaatgtt aaagtgactc ctccagatta 126180
ctcacctata atcgcgagta ttaaaggtaa gagttatgac gcattagcca cgttcactgt 126240
aaatatcttt aaagaggtaa tgaccaaaga gggtatatcc atcactaaaa taagtagtta 126300
tgagggaaaa gattctcatt tgataaaaat tccgctacta ataggatacg ggaataaaaa 126360
tccacttgat acagccaagt atcttgttcc taatgtcata ggtggagtct ttatcaataa 126420
acaatctgtc gaaaaagtag gaattaatct agtagaaaag attacaacat ggccaaaatt 126480
tagggttgtt aagccaaact cattcacttt ctcgttttcc tccgtatccc ctcctaatgt 126540
attaccgaca agatatcgcc attacaagat atctctggat atatcacaat tggaagcgtt 126600
gaatatatca tcgacaaaga catttataac ggtcaatatt gttttgctgt ctcaatattt 126660
atctagagtg agtctagaat tcattagacg tagtttatca tacgatatgc ctccagaagt 126720
tgtctatcta gtaaacgcga taatagatag tgctaaacga attactgaat ctattactga 126780
ctttaatatt gatacataca ttaatgacct ggtggaagct gaacacatta aacaaaaatc 126840
tcagttaacg atcaacgagt tcaaatatga aatgctgcat aactttttac ctcatatgaa 126900
ctatacaccc gatcaactaa agggatttta tatgatatct ttactaagaa agtttctcta 126960
ctgtatctac cacacttcta gatatccaga tagagattcg atggtttgtc atcgcatcct 127020
aacgtacggc aaatattttg agacgttggc acatgatgaa ttagagaatt acataggcaa 127080
catccgaaac gatatcatga acaatcacaa gaacagaggc acttacgcgg taaacattca 127140
tgtactaaca actcctggac ttaatcatgc attttctagt ctattgagtg gaaagttcaa 127200
aaagtcagac ggtagttatc gaacacatcc tcactattca tggatgcaga atatttctat 127260
tcctaggagt gttggatttt atccggatca agtaaagatt tcaaagatgt tttctgtcag 127320
aaaataccat ccaagtcaat atctttactt ttgttcatcg gacgttccgg aaagaggtcc 127380
tcaggtaggt ttagtatctc aattgtctgt cttgagttcc attacaaata tactaacgtc 127440
tgagtatttg gatttggaaa agaaaatttg tgagtatatc agatcatatt ataaagatga 127500
tataagttac tttgaaacag gatttccaat cactatagaa aatgctctag tcgcatctct 127560
taatccaaat atgatatgtg attttgtaac tgactttaga cgtagaaaac ggatgggatt 127620
cttcggtaac ttggaggtag gtattacttt agttagggat cacatgaatg aaattcgcat 127680
taatattgga gcgggaagat tagtcagacc attcttggtt gtggataacg gagagctcat 127740
gatggatgtg tgtccggagt tagaaagcag attagacgac atgacattct ctgacattca 127800
gaaagagttt ccgcatgtca tcgaaatggt agatatagaa caatttactt ttagtaacgt 127860
atgtgaatcg gttcaaaaat ttagaatgat gtcaaaggat gaaagaaagc aatacgattt 127920
atgtgacttt cctgccgaat ttagagatgg atatgtagca tcttcactag tgggaatcaa 127980
tcacaattct ggacccagag ctattcttgg atgtgctcaa gctaaacaag ctatctcttg 128040
tctgagctcg gatatacgaa ataaaataga caatggaatt catttgatgt atccagagag 128100
gccaatcgtg attagtaagg ctttagaaac ttcaaagatt gcggctaatt gcttcggcca 128160
acatgttact atagcattaa tgtcgtacaa aggtatcaat caagaggatg gaattatcat 128220
caaaaaacaa tttattcaga gaggcggtct cgatattgtt acagccaaga aacatcaagt 128280
agaaattccg ttggaaaact ttaataacaa agaaagagat aggtctaacg cctattcaaa 128340
attagaaagt aatggattag ttagactgaa tgctttcttg gaatccggag acgctatagc 128400
acgaaatatc tcatcaagaa ctcttgaaga tgattttgct agagataatc agattagctt 128460
tgatgtttcc gaaaaatata ccgatatgta caaatctcgc gttgaacgag tacaagtaga 128520
acttactgac aaagttaagg tacgagtatt aaccatgaaa gaaagaagac ccattctagg 128580
agacaaattt accactagaa cgagtcaaaa gggaacagtc gcgtatatcg cggatgaaac 128640
ggaacttcca tacgatgaaa atggtatcac accagatgtc attattaatt ctacatccat 128700
cttctctaga aaaactatat ctatgttgat agaggttatt ttaacagccg catattctgc 128760
taagccgtac aacaataagg gagaaaaccg acctgtctgt tttcctagta gtaacgaaac 128820
atccatcgat acatatatgc aattcgctaa acaatgttat gagcattcaa atccgaaatt 128880
gtctgatgaa gaattatcgg ataaaatctt ttgtgaaaag attctctatg atcctgaaac 128940
ggataagcct tatgcatcca aagtattttt tggaccaatt tattacttgc gtctgaggca 129000
tttaactcag gacaaggcaa ccgttagatg tagaggtaaa aagacgaagc tcattagaca 129060
ggcgaatgag ggacgaaaac gtggaggagg tatcaagttc ggagaaatgg agagagactg 129120
tttaatagcg catggtgcag ccaatactat tacagaagtt ttgaaagatt cggaagaaga 129180
ttatcaagat gtgtatgttt gtgaaaattg tggagacata gcagcacaaa tcaagggtat 129240
taatacatgt cttagatgtt caaaacttaa tctctctcct ctcttaacaa aaattgatac 129300
cacgcacgta tctaaagtat ttcttactca aatgaacgcc agaggcgtaa aagttaaatt 129360
agatttcgaa cgaaggcctc cttcgtttta taaaccatta gataaagttg atctcaaacc 129420
gtcttttctg gtgtaatatt ctagtttggt agtagataca tatcaatatc atcaaattcg 129480
agatccgaat tataaaatgg gcgtggattg ttaactatag aatcggacgt ctgatattcg 129540
aaaatctgtg gagttttagg ttttggtgga ggtgtaactg ctacttggga tactgaagtc 129600
tgatattcag aaagctgggg gatgttctgg ttcgacatcc accgatggtg tcacatcact 129660
aatcggttcg gtaacgtctg tggacgatgg aggcaccact tctacaggtt ctggttcttt 129720
atcctcagtc atcaacggag ctacttcaat gcgaggaaat gtataatttg gtaatggttt 129780
ctcatgtgga tctgaagaag aggtaagata tctactagaa agataccgat cacgttctag 129840
ttctcttttg tagaacttaa ctttttcttt ctccgcatct agttgatatt ccaacctctt 129900
cacgttcgca tgggttacct ccgcagtttt tacgagcgat ttcacgttca gccttcatgc 129960
gtcttatagc atgaattcgc ttatcgttat cgggtttagc ttctgtcacc ttagcaattc 130020
cttttttatt aaactctaca taatcatatc catttctatt gtttgttcta atataaacga 130080
gtatagcatc attgctaaat ttttcaatag tatcgaaaac agaatatcct aaaccatata 130140
atatatattc aggaacactc aaactaaatg tccaggattc tcctaaatac gtaaacttta 130200
atagtgcgaa atcattcaaa aatctaccac ttatagatag atagatagta cataaatgcg 130260
tatagtagtc tacctatctc tttattatga aaaccggcat tacgatcata tatgtcgtga 130320
tatacctgtg atccgtttac gttaaaccat aaatacatgg gtgatcctat aaacatgaat 130380
ttatttctaa ttctcagagc tatagttaat tgaccgtgta atatttgctt acatgcatac 130440
ttgatacgat cattaataag atttttatca ttgctcgtta tttcagaatc gtatatataa 130500
ggagtaccat cgtgattctt accagatatt atacaaaata ctatatataa aatatattga 130560
cccacgttag taatcatgta aatgtttaac gttttaaatt ttgtattcaa tgatccatta 130620
tcatacgcta gcatggtctt atgatattca ttctttaaaa tataatattg tgttagccat 130680
tgcattgggg ctcctaatgg agatttttta ttctcatcca ttttaggata ggctttcata 130740
aagtccctaa taacttcgtg aataatgttt ctatgttttc tactgatgca tgtatttgct 130800
tcgatttttt tatcccatgt ttcatctatc atagatttaa acgcagtaat gctcgcaaca 130860
ttaacatctt gaaccgttgg tacaattccg ttccataaat ttataatgtt cgccatttat 130920
ataactcatt ttttgaatat acttttaatt aacaaaagag ttaagttact catatggacg 130980
ccgtccagtc tgaacatcaa tctttttagc cagagatatc atagccgctc ttagagtttc 131040
agcgtgattt tccaacctaa atagaacttc atcgttgcgt ttacaacact tttctatttg 131100
ttcaaacttt gttgttacat tagtaatctt tttttccaaa ttagttagcc gttgtttgag 131160
agtttcctca ttgtcgtctt catcggcttt aacaattgct tcgcgtttag cctctggctt 131220
tttagcagcc gttgtagaaa aaaattcagt tgctggaatt gcaagatcgt catctccggg 131280
gaaaagagtt ccgtccattt aaagtacaga ttttagaaac tgacactctg cgttatttat 131340
atttggtaca acacatggat tataaatatt gatgttaata acatcagaaa atgtaaagtc 131400
tatacattgt tgcatcgtgt taaattttct aatggatcta gtattattgg gtccaacttc 131460
tgcctgaaat ccaaatatgg aagcggatac aaaaccgttt cctggataaa ccacacatct 131520
ccacttttgc tttacatcag aaattgtgtc gttgacatct tgaactctcc tatctaatgc 131580
cggtgttcca cctatagatt ttgaatattc gaatgctgca tgagtagcat taaattcctt 131640
aatattgcca taattttcat atattgagta accctggata aaaagtaaac acaccgcagc 131700
cgtagctacc acaataaaaa aaattgatag agagttcatt tataatctat tagaagctga 131760
caaaattttt ttacacgcat cagacaatgc tttaataaat agttcaacat ctacttttgt 131820
catatcgaac cgatggtatg attctaacct agaattacat ccgaaaaagt tgactatgtt 131880
catagtcatt aagtcattaa caaacaacat tccagactct ggattataag acgatactgt 131940
ttcgtcacaa ttacctacct taatcatgtg attatgaata ttggctatta gagcaccttc 132000
taagaaatct ataatatctt tgaaacacga tttaaaatca aaccacgaat atacttctac 132060
gaagaaagtt agtttaccca taggagaaat aactataaat ggagatctaa atacaaaatc 132120
cggatctatg atagttttaa cattattata ttctctatta aatacctcca catctaaaaa 132180
tgttaatttt gaaactatgt cttcgtttat taccgtacct gaactaaacg ctataagctc 132240
tattgtttga gaactcttta aacgatattc ttgaaataca tgtaacaaag tttcctttaa 132300
ctcggtcggt ttatctacca tagttacaga atttgtatcc ttatctataa tataataatc 132360
aaaatcgtat aaagttatat aattatcgcg ttcagattgg gatcttttca aatagactaa 132420
aaaccccatt tctctagtaa gtatcttatg tatatgtttg taaaatatct tcatggtggg 132480
aatatgctct accgcagtta gccattcctc attgacagcg gtagatgtat tagacaaaac 132540
tattccaatg tttaacaagg gccattttac gagattatta aatccttgtt tgataaatgt 132600
agccaatgag ggttcgagtt caacgacgat tgaattctct tcccgcggat gctgcatgat 132660
gaacgacggg atgttgttcg attgatttgg aattcttttt cgactttttg tttatattaa 132720
atattttaaa atttatagcg gatagcaatt catgtaccac ggataatgta gacgcgtatt 132780
gcgcatcgat atctttatta ttagataaat ttatcaataa atgtgagaag tttgcctcgt 132840
taaggtcttc catttaaata ttatataaac atttgtgttt gtatcttatt cgtcttttat 132900
ggaatagttt tttactagta aagctgcaat tacacacttt gtccgtaaaa cataaatata 132960
aacaccagct tttatcaatc gttccaaaaa gtcgacggcg gacattttta acatggcatc 133020
tattttaaat acacttaggt ttttggaaaa aacatcattt tataattgta acgattcaat 133080
aactaaagaa aagattaaga ttaaacataa gggaatgtca tttgtatttt ataagccaaa 133140
gcattctacc gttgttaaat acttgtctgg aggaggtata tatcatgatg atttggttgt 133200
attggggaag gtaacaatta atgatctaaa gatgatgcta ttttacatgg atttatcata 133260
tcatggagtg acaagtagtg gaacaattta caaattggga tcgtctatcg atagactttc 133320
tctaaatagg actattgtta caaaagttaa taattataat tatgatacat tttttgacga 133380
tgatgattga tcgctattgc acaattttgt ttttttactt tctaatatag cgtttagatt 133440
ctttttcatg tgcgaatatt gatttactaa aatatctatg tttaactttt gttctataac 133500
gtccttatcg gcggtatcgg tacatatacg taattcacct tcacaaaata cggagtcttc 133560
gataataata gccaatcgat tattggatct agctgtctgt atcatattca acatgtttaa 133620
tatatccttt cgtttcccct ttacaggcat cgatcgtagc atattttccg cgtctgagat 133680
ggaaatgtta aaactacaaa aatgcgtaat gttagcccgt cctaatattg gtacgtgtct 133740
ataagtttgg catagtagaa taatagacgt gtttaaatgc cttccaaagt ttaagaattc 133800
tattagagta ttgcattttg atagtttatc gcctacatca tcaaaaataa gtaaaaagtg 133860
tgctgatttt ttatgatttt gtgcgacagc aatacatttt tctatgttac ttttagttcg 133920
tatcagatta tattctagag attcctgact actaacgaaa ttaatatgat ttggccaaat 133980
gtatccatca taatctggat tataaacggg tgtaaacaag aatacatgtt tatatttttt 134040
aactagtgta gaaaacagag atagtaaata gatagttttt ccagatccag atcctcccgt 134100
taaaaccatt ctaaacggca tttttaataa attttctctt gaaaattgtt tttcttggaa 134160
acaattcata attatattta cagttactaa attaatttga taataaatca aaatatggaa 134220
aactaaggtc gttagtaggg aggagaacaa agaaggcaca tcgtgacata aataacattt 134280
attatcatga tgacaccaga aaacgacgaa gagcagacat ctgtgttctc cgctactgtt 134340
tacagagaca aaattcaggg aaagaataaa cgcaaacgcg tgattggtct atgtattaga 134400
atatctatgg ttatttcact actatctatg attaccatgt ccgcgtttct catagtgcgc 134460
ctaaatcaat gcatgtctgc taacgaggct gctattactg acgccgctgt tgccgttgct 134520
gctgcatcat ctactcatag aaaggttgcg tctagcacta cgcaatatga tcacaaagaa 134580
agctgtaatg gtttatatta ccagggttct tgttatatat tacattcaga ctaccagtta 134640
ttctcggatg ctaaagcaaa ttgcactgcg gaatcatcaa cactacccaa taaatccgat 134700
gtcttgacta cctggctcat tgattatgtt aaggatacat ggggatctga tggtaatcca 134760
attacaaaaa ctacatccga ttatcaagat tctgatgtat cacaagaagt tagaaagtat 134820
ttttgtgtta aaacaatgaa ctaatattta tttttgtaca ttaataaatg aaatcgctta 134880
atagacaaac tgtaagtagg tttaagaagt tgtcggtgcc ggtcgctata atgatgatac 134940
tctcaaccat tattagtggc ataggaacat ttctgcatta caaagaagaa ctgatgccta 135000
gtgcttgcgc caatggatgg atacaatacg ataaacattg ttatttagat actaacatta 135060
aaatgtctac agataatgcg gtttatcagt gtcgtaaatt acgagccaga ttgcctagac 135120
cggatactag acatctgaga gtattgttta gtatttttta taaagattat tgggtaagtt 135180
taaaaaagac caatgataaa tggttagata ttaataatga taaagatata gatattagta 135240
aattaacaaa ttttaaacaa ctaaacagta cgacggatgc tgaagcgtgt tatatataca 135300
agtctggaaa actggttaaa acagtatgta aaagtactca atctgtacta tgtgttaaaa 135360
aattctacaa gtgacaacaa aaaatgaatt aataataagt cgttaacgta cgccgccatg 135420
gacgccgcgt ttgttattac tccaatgggt gtgttgacta taacagatac attgtatgat 135480
gatctcgata tctcaatcat ggactttata ggaccataca ttataggtaa cataaaaact 135540
gtccaaatag atgtacggga tataaaatat tccgacatgc aaaaatgcta ctttagctat 135600
aagggtaaaa tagttcctca ggattctaat gatttggcta gattcaacat ttatagcatt 135660
tgtgccgcat acagatcaaa aaataccatc atcatagcat gcgactatga tatcatgtta 135720
gatatagaag ataaacatca gccattttat ctattcccat ctattgatgt ttttaacgct 135780
acaatcatag aagcgtataa cctgtataca gctggagatt atcatctaat catcaatcct 135840
tcagataatc tgaaaatgaa attgtcgttt aattcttcat tctgcatatc agacggcaat 135900
ggatggatca taattgatgg gaaatgcaat agtaattttt tatcataaaa gttgtaaagt 135960
aaataataaa acaataaata ttgaactagt agtacgtata ttgagcaatc agaaatgatg 136020
ctggtacctc ttatcacggt gaccgtagtt gcgggaacaa tattagtatg ttatatatta 136080
tatatttgta ggaaaaagat acgtactgtc tataatgaca ataaaattat catgacaaaa 136140
ttaaaaaaga taaagagttc taattccagc aaatctagta aatcaactga tagcgaatca 136200
gactgggagg atcactgtag tgctatggaa caaaacaatg acgtagataa tatttctagg 136260
aatgagatat tggacgatga tagcttcgct ggtagtttaa tatgggataa cgaatccaat 136320
gttatggcgc ctagcacaga acacatttac gatagtgttg ctggaagcac gctgctaata 136380
aataatgatc gtaatgaaca gactatttat cagaacacta cagtagtact taatgaagat 136440
accaaacaga atcctaacta ttcatccaat cctttcgtaa attataataa aaccagtatt 136500
tgtagcaagt caaatccgtt cattacagaa ctcaacaata aatttagtga gaataatccg 136560
tttagacgag cacatagcga tgattatctt aataagcaag aacaagatca tgaacacgat 136620
gatatagaat cattggtgtg attagtttcc tttttataaa attgaagtaa tatttagtat 136680
tattgctgcc gtcacgttgt acaaatggag atattccctg tattcggcat ttctaaaatt 136740
agcaatttta ttgctaataa tgactgtaga tattatatag atacagaaca tcaaaaaatt 136800
atatctgatg agatcaatag acagatggat gaaacggtac ttcttaccaa catcttaagc 136860
gtagaagttg taaatgacaa tgagatgtac catcttattc ctcatagatt atcgacgatt 136920
atactctgta ttagttctgt cggaggatgt gttatctcta tagataatga cgtcaatggc 136980
aaaaatattc taacctttcc cattgatcat gctgtaatca tatccccact gagtaaatgt 137040
gtcgtagtta gcaagggtcc tacaaccata ttggttgtta aagcggatat acctagcaaa 137100
cgattggtaa catcgtttac aaacgacata ctgtatgtaa acaatctatc actgattaat 137160
tattcgccgt tgtctgtatt cattattaga cgagttaccg actatttgga tagacacata 137220
tgcgatcaga tatttgcgaa taataagtgg tattccatta taaccatcga caataagcag 137280
tttcctattc catcaaactg tataggtatg tcctctgcca agtacataaa ttctagcatc 137340
gagcaagata ctttaataca tgtttgtaac ctcgagcatc cattcgactt agtatacaaa 137400
aaaatgcagt cgtacaattc tgtacctatc aaggaacaaa tattgtacgg tagaattgat 137460
aatataaata tgagcattag tatttctgtg gattaataga tttctagtat ggggatcatt 137520
aatcatctct aatctctaaa tacctcataa aacgaaaaaa aagctattat caaatactgt 137580
acggaatgga ttcattctct tctcttttta tgaaactctg ttgtatatct actgataaaa 137640
ctggaagcaa aaaatctgat aaaaagaata agaataagat caaggattat tataaaataa 137700
caatagttcc tggttcctct tccacgtcta ctagctcgtg gtattataca catgcctagt 137760
aatagtctct ttgcgttgac ggaaagcaga ctagaaataa caggctaaaa tgttcagaca 137820
ccataatagt tcccaaccca gataataaca gagtaccatc aacacattcc tttaaactca 137880
atcccaaacc caaaaccgtt aaaatgtatc cggccaattg atagtagata atgaggtgta 137940
cagcgcatga tgatttacac agtaaccaaa atgaaaatac tttagtaatt ataagaaata 138000
tagatggtaa cgtcatcatc aacaatccaa taatatgccg gagagtaaac attgacggat 138060
aaaacaaaaa tgctccgcat aactctatca tggcaataac acaaccaaat acttgtaaga 138120
ttcctaaatt agtagaaaat acaacggata tcgatgtata agtgatctcg agaaataata 138180
agaataaagt aatgcccgta aagataaaca tcaacattgt ttggtaatca ttaaaccaat 138240
tagtatgaag ttgaactaat ttcacagtag attttattcc agtattatcc ccgcatgtat 138300
aagtacctgg taagatatct ttatattcca taatcaatga gacatcacta tctgataacg 138360
aatgaagtct agcactagta tgccatttac ttaatattgt cgtcttggaa gttttattat 138420
aagttaaaat atcatggtta tccaatttcc atctaatata ctttgtcgga ttatctatag 138480
tacacggaat aatgatggta tcattacatg ctgtatactc tatggtcttt gtagttgtta 138540
taacaaccaa cgtatagagg tatatcaacg atattctaac tcttgacatt ttttatttat 138600
ttaaaatgat acctttgtta tttattttat tctattttgc taacggtatt gaatggcata 138660
agtttgaaac gagtgaagaa ataatttcta cttacttatt agacgacgta ttatacacgg 138720
gtgttaatgg ggcggtatac acattttcaa ataataaact aaacaaaact ggtttaacta 138780
ataataatta tataacaaca tctataaaag tagaggatgc ggaaccaata acggaaatcc 138840
caaatgttgg aaaatagacg gttcagacga cccaaaacat agaggtagag gatacgctcc 138900
ttatcaaaat agcaaagtaa cgataatcag tcacaacgga tgtgtactat ctgacataaa 138960
catatcaaaa gaaggaatta aacgatggag aagatttgac ggaccatgtg gttatgattt 139020
atacacggcg gataacgtaa ttccaaaaga tggtttacga ggagcattcg tcgataaaga 139080
tggtacttat gacaaagttt acattctttt cactgatact atcggctcaa agagaattgt 139140
caaaattccg tatatagcac aaatgtgcct aaacgacgaa ggtggtccat catcattgtc 139200
tagtcataga tggtcgacgt ttctcaaagt cgaattagaa tgtgatatcg acggaagaag 139260
ttatagacaa attattcatt ctagaactat aaaaacagat aatgatacga tactatatgt 139320
attcttcgat agtccttatt ccaagtccgc attatgtacc tattctatga ataccattaa 139380
acaatctttt tctacgtcaa aattggaagg atatacaaag caattgccgt ctccagctcc 139440
tggtatatgt ttaccagctg gaaaagttgt tccacatacc acgtttgaag tcatagaaaa 139500
atataatgta ctagatgata ttataaagcc tttatctaac caacctatct tcgaaggacc 139560
gtctggtgtt aaatggttcg atataaagga gaaggaaaat gaacatcggg aatatagaat 139620
atacttcata aaagaaaatt ctatatattc gttcgataca aaatctaaac aaactcgtag 139680
ctcgcaagtc gatgcgcgac tattttcagt aatggtaact tcgaaaccgt tatttatagc 139740
agatataggg ataggagtag gaatgccaca aatgaaaaaa atacttaaaa tgtaatctta 139800
atcgagtaca ccgcacgaca atgaacaaac ataagacaga ttatgctggt tatgcttgct 139860
gcgtaatatg cggtctaatt gttggaatta tttttacagc gacactatta aaagttgtag 139920
aacgtaaatt agttcataca ccatcaatag ataaaacgat aaaagatgca tatattagag 139980
aagattgtcc tactgactgg ataagctata ataataaatg tatccattta tctactgatc 140040
gaaaaacctg ggaggaagga cgtaatgcat gcaaagctct aaatccaaat tcggatctaa 140100
ttaagataga gactccaaac gagttaagtt ttttaagaag cattagacgc ggatattggg 140160
taggagaatc cgaaatatta aaccagacaa ccccatataa ttttatagct aaaaatgcca 140220
cgaagaatgg aactaaaaaa cggaaatata tttgtagtac aacgaatact cccaaactac 140280
atttttatca taccactact tcggttagat gttttagaaa aaaataaata tcgccgtacc 140340
gttcttgttt ttataaaaat aacaattaac aattatcaaa ttttttcttt aatattttac 140400
gtggttgacc attcttggtg gtaaaataat ctcttagtgt tggaatggaa tgctgtttaa 140460
tgtttccgca ctcatcgtat attttgacgt atgcagtcac atcgtttacg caatagtcag 140520
actgtagttc tatcatgctt cctacatcag aaggaggaac agttttaaag tctcttggtt 140580
ttaatctatt gccattagtt ttcatgaaat cctttgtttt atccacttca cattttaaat 140640
aaatgtccac tatacattct tctgttaatt ttactagatc gtcatgggtc atagaattta 140700
taggttccgt agtccatgga tccaaactag caaacttcgc gtatacggta tcgcgattag 140760
tgtatacacc aactgtatga aaattaagaa aacagtttaa taaatcaaca gaaatattta 140820
atcctccgtt tgatacagat gcgccatatt tatggatttc ggattcacac gttgtttgtc 140880
tgaggtgttc gtctagtgtt gcttctacgt aaacttcgat tcccatatat tctttattgt 140940
cagaatcgca taccgattta tcatcataca ctgtttgaaa actaaatggt atacacatca 141000
aaataataaa taataacgag tacattctgc aatattgtta tcgtaattgg aaaaatagtg 141060
ttcgagtgag ttggattatg tgagtattgg attgtatatt ttattttata ttttatattt 141120
tgtagtaaga atagaatgct aatgtcaagt ttattccaat agatgtctta ttaaaaaaca 141180
tatataataa ataacaatgg ctgaatggca taaaattatc gaggatatct caaaaaataa 141240
taagttcgag gatgccgcca tcgttgatta caagactaca aagaatgttc tagctgctat 141300
tcctaacaga acatttgcca agattaatcc tctcatcact aatcgtaata ttctaaaacc 141360
tcttattggt cagaaatatt gtattgtata tactaactct ctaatggatg agaacacgta 141420
tgctatggag ttgcttactg ggtacgcccc tgtatctccg atcgttatag cgagaactca 141480
taccgcactt atatttttga tgggtaagcc aacaacatcc agacgtgacg tgtatagaac 141540
gtgtagagat cacgctaccc gtgtacgtgc aactggtaat taaaataaaa agtaatattc 141600
atatgtagtg tcaattttaa atgatgatga tgaaatggat aatatccata ttgacgatgt 141660
caataatgcc ggtattggca tacagttcat cgatttttag atttcattca gaggatgtgg 141720
aattatgtta tgggcatttg tattttgata ggatctataa tgtagtaaat ataaaatata 141780
atccgcatat tccatataga tataatttta ttaatcgcac gttaaccgta gatgaactag 141840
acgataatgt cttttttaca catggttatt ttttaaaaca caaatatggt tcacttaatc 141900
ctagtttgat tgtctcatta tcaggaaact taaaatataa tgatatacaa tgctcagtaa 141960
atgtatcgtg tctcattaaa aatttggcaa cgagtacatc tactatatta acatctaaac 142020
ataagactta ttctctacat cggtccacgt gtattactat aataggatac gattctatta 142080
tatggtataa agatataaat gacatctatg attttactgc aatatgtatg ctaatagcgt 142140
ctacattgat agtgaccata tacgtgttta aaaaaataaa aatgaactct taattatgct 142200
atgctattag aaatggataa aatcaaaatt acggttgatt caaaaattgg taatgttgtt 142260
accatatcgt ataacttgga aaagataact attgatgtca cacctaaaaa gaaaaaagaa 142320
aaggatgtat tattagcgca atcagttgct gtcgaagagg caaaagatgt caaggtagaa 142380
gaaaaaaata ttatcgatat tgaagatgac gatgatatgg atgtagaaag cgcataatac 142440
gatctataaa aataagtata taaatacttt ttatttactg tactcttact gtgtagtggt 142500
gataccctac tcgattattt ttttaaaaaa aaatacttat tctgattctt ctagccattt 142560
ccgtgttcgt tcgaatgcca catcgacgtt aaagataggg gagtagttga aatctagttc 142620
tgcattgttg gtacgcacct caaatgtagt gttggatatc ttcaacgtat agttgttgag 142680
tagtgatggt tttctaaata gaattctctt catatcattc ttgcacgcgt acatttttag 142740
catccatctt ggaatcctag atccttgttc tattcccaat ggtttcatca atagaagatt 142800
aaacatatcg tacgaacacg atggagagta atcgtagcaa aagtaagcat ttcctttaat 142860
ctcagatccc ggatactgga tatattttgc agccaacacg tgcatccatg cagcatttcc 142920
tacatatacc cggctatgta ccgcgttatc atcgactgta cgatacataa tgttaccgtg 142980
ttgcttacat tgctcgtaaa agactttcat caatttgtct ccttctccgt aaattccagt 143040
gggtcttagg caacaagtat acaattttgc tccattcatg attacggaat tattggcttt 143100
cataaccagt tgctcggcca tacgtttact ttttgcgtat acatgtcctg gtgatatatc 143160
ataaagggta tgctcatggc cgatgaatgg atcaccgtgt ttattgggtc ctattgcttc 143220
catgctacta gtatagatca aatacttgat tcctaggtcc acacaagctg ccaatatagt 143280
ctgtgttcca taatagttta ctttcatgat ttcattatcg gtgtattttc caaatacatc 143340
cactagagca gctgtatgaa taatcagatt taccccatct agcgcttctc ttaccttatc 143400
aaagtcgttt atatcacatt gtatatagtt tataacctta actttcgagg ttattggttg 143460
tggatcttct acaatatcta tgactctgat ttcttgaaca tcatctgcac taattaacag 143520
ttttactata tacctgccta gaaatccggc accaccagta accgcgtaca cggccattgc 143580
tgccactcat aatatcagac tacttattct attttactaa ataatggctg tttgtataat 143640
agaccacgat aatatcagag gagttattta ctttgaacca gtccatggaa aagataaagt 143700
tattggatta aaatccggaa cgtatagttt gataattcat cgttacggag atattagtca 143760
aggatgtgat tccataggca gtccagaaat atttatcggt aacatctttg taaacagata 143820
tggtgtagca tatgtttatt tagatacaga tgtaaatata tctacaatta ttggaaaggc 143880
gttatctatt tcaaaaaatg atcagagatt agcgtgtgga gttattggta tttcttacat 143940
aaatgaaaag ataatacatt ttcttacaat taacgagaat ggcgtttgat atatcagtta 144000
atgcgtctaa aacaataaat gcattagttt acttttctac tcagcaaaat aaattagtca 144060
tacgtaatga agttaatgat acacactaca ctgtcgaatt tgatagggac aaagtagttg 144120
acacgtttat ttcatataat agacataatg actccataga gataagaggg gtgcttccag 144180
aggaaactaa tattggttgc gcggttaata cgccggttag tatgacttac ttgtataata 144240
agtatagttt taaactgatt ttagcagaat atataagaca cagaaatact atatccggca 144300
atatttattc ggcattgatg acactagatg atttggctat taaacagtat ggagacattg 144360
atctattatt taatgagaaa cttaaagtag actccgattc gggactattt gactttgtca 144420
actttgtaaa ggatatgata tgttgtgatt ctagaatagt agtagctcta tctagtctag 144480
tatctaaaca ttgggaattg acaaataaaa aatataggtg tatggcatta gccgaacata 144540
tatctgatag tattccaata tctgagctat ctagactacg atacaatcta tgtaagtatc 144600
tacgcgggca cactgagagc atagaggatg aatttgatta ttttgaagac gatgattcgt 144660
ctacatgttc tgccgtaacc gacagggaaa cggatgtata atttttttta tagcgtgaag 144720
gatatgataa aaaatataat tgttgtattt atcccattcc aatcacctta tatgattctg 144780
taacacaatg aaggagtctt atagatgtat agaggtcaga tactggtttg ataaactgtt 144840
tattccacat aagtatgttt gactttatgg ttagacccgc atactttaac aaatcactga 144900
aaattggagt taggtattga cctctcagaa tcagttgccg ttctggaaca ttaaatgtat 144960
tttttatgat atactccaac gcatttatgt gggcatacaa caagtcatta ctaatggagt 145020
attccaagag aagagatttc aacagactgt ttatgaactc gaatgccgcc tcattgtcgc 145080
ttatattgat gatgtcgaat tctcccaata tcatcaccga tgagtagctc atcttgttat 145140
cgggatccaa gttttctaaa gatgtcatta aaccctcgat catgaatgga tttatcatca 145200
tcgtttttat gttggacatg agcttagtcc gtttgtccac atctatagac gacgatttct 145260
gaattatttc atatatccct ctctttaact ccaggaactt gtcaggatgg tctactttaa 145320
tatgttctcg tctaagagat gaaaatcttt ggatggttgc acgcgacttt tctctaaagg 145380
atcctctctt aaatgaatcc atcttatcct tggacaagat ggacagtcta ttttccttag 145440
atggtttaat atttttgtta cccatgatct ataaaggtag acctaatcgt ctcggatgac 145500
catatattta ttttcagttt tattatacgc ataaattgta aaaaatatgt taggtttaca 145560
aaaatgtctc gtggggcatt aatcgttttt gaaggattgg acaaatctgg aaaaacaaca 145620
caatgtatga acatcatgga atctataccg gcaaacacga taaaatatct taactttcct 145680
cagagatcca ctgtcactgg aaagatgata gatgactatc taactcgtaa aaaaacctat 145740
aatgatcata tagttaatct attattttgt gcaaatagat gggagtttgc atcttttata 145800
caagaacaac tagaacaggg aattacttta atagttgata gatacgcatt ctctggagta 145860
gcgtatgccg ccgctaaagg cgcgtcaatg actctcagta agagttatga atctggattg 145920
cctaaacccg acttagttat attcttggaa tctggtagca aagaaattaa tagaaacgtc 145980
ggcgaggaaa tttatgaaga tgttacattc caacaaaagg tattacaaga atataaaaaa 146040
atgattgaag aaggagatat tcattggcaa attatttctt ctgaattcga ggaagatgta 146100
aagaaggagt tgattaagaa tatagttata gaggctatac acacggttac tggaccagtg 146160
gggcaactgt ggatgtaata gtgaaattac attttttata aatggatgaa gcatattact 146220
ctggcaactt ggaatcagta ctcggatacg tgtccgatat gcataccgaa ctcgcatcaa 146280
tatctcaatt agttattgcc aagatagaaa ctatagataa tgatatatta aacaaggaca 146340
ttgtaaattt tatcatgtgt agatcaaact tggataatcc atttatctct ttcctagata 146400
ctgtatatac tattatagat caagagatct atcagaccga attgattaat tcattagacg 146460
acaatgaaat tatcgattgt atagttaaca agtttatgag cttttataag gataacctag 146520
aaaatatagt agatgctatc attactctaa aatatataat gaataatcca gattttaaaa 146580
ctacgtatgc cgaagtactc ggttccagaa tagcggatat agatattaaa caagtgatac 146640
gtgagaatat actacaattg tctaataata tccgcgaacg atatttgtga aaatattaaa 146700
aaaaaatact ttttttatta aatgacgtcg cttcgcgaat ttagaaaatt atgctgtgat 146760
atatatcacg catcaggata taaagaaaaa tctaaattaa ttagagactt tataacagat 146820
agggatgata aatatttgat cattaagcta ttgcttcccg gattagacga tagaatttat 146880
aacatgaacg ataaacaaat tataaaatta tatagtataa tatttaaaca atctcaggaa 146940
gatatgctac aagatttagg atacggatat ataggagaca ctattaggac tttcttcaaa 147000
gagaacacag aaatccgtcc acgagataaa agcattttaa ctttagaaga agtggatagt 147060
tttttaacta cgttatcatc cgtaactaaa gaatcgcatc aaataaaatt attgactgat 147120
atcgcatccg tttgtacatg taatgattta aaatgtgtag tcatgcttat tgataaagat 147180
ctaaaaatta aagcgggccc tcggtacgta cttaacgcta ttagtcctca tgcctatgat 147240
gtgtttagaa aatctaataa cttgaaagag ataatagaaa atgcatctaa acaaaatcta 147300
gactctatat ctatttctgt tatgactcca attaatccca tgttagcgga atcgtgtgat 147360
tctgtcaata aggcgtttaa aaaatttcca tcaggaatgt ttgcggaagt caaatacgat 147420
ggtgaaagag tacaagttca taaaaataat aacgagtttg ccttctttag tagaaacatg 147480
aaaccagtac tctctcataa agtggattat ctcaaagaat acataccgaa agcatttaaa 147540
aaagctacgt ctatcgtatt ggattctgaa attgttcttg tagacgaaca taatgtaccg 147600
ctcccgtttg gaagtttagg tatacacaaa aagaaagaat ataaaaactc taacatgtgt 147660
ttgttcgtgt ttgactgttt gtactttgat ggattcgata tgacggacat tccattgtac 147720
gaacgaagat cttttctcaa agatgttatg gttgaaatac ccaatagaat agtattctca 147780
gagttgacga atattagtaa cgagtctcag ttaactgacg tattggatga tgcactaacg 147840
agaaaattag aaggattggt cttaaaagat attaatggag tatacgaacc gggaaagaga 147900
agatggttaa aaataaagcg agactatttg aacgagggtt ccatggcaga ttctgccgat 147960
ttagtagtac taggtgctta ctatggtaaa ggagcaaagg gtggtatcat ggcagtcttt 148020
ctaatgggtt gttacgacga tgaatccggt aaatggaaga cggttaccaa gtgttcagga 148080
cacgatgata atacgttaag ggagttgcaa gaccaattaa agatgattaa aattaacaag 148140
gatcccaaaa aaattccaga gtggttagta gttaataaaa tctatattcc cgattttgta 148200
gtagaggatc caaaacaatc tcagatatgg gaaatttcag gagcagagtt tacatcttcc 148260
aagtcccata ccgcaaatgg aatatccatt agatttccta gatttactag gataagagag 148320
gataaaacgt ggaaagaatc tactcatcta aacgatttag taaacttgac taaatcttaa 148380
tagttacata caaattaaaa taacactatt tagttggtgg tcgccatgga tggtgttatt 148440
gtatactgtc taaacgcgtt agtaaaacat ggcgaggaaa taaatcatat aaaaaatgat 148500
ttcatgatta aaccatgttg tgaaaaagtc aagaacgttc acattggcgg acaatctaaa 148560
aacaatacag tgattgcaga tttgccatat atggataatg cggtatccga tgtatgcaat 148620
tcactgtata aaaagaatgt atcaagaata tccagatttg ctaatttgat aaagatagat 148680
gacgatgaca agactcctac tggtgtatat aattatttta aacctaaaga tgccattcct 148740
gttattatat ccataggaaa ggatagagat gtttgtgaac tattaatctc atctgataaa 148800
gcgtgtgcgt gtatagagtt aaattcatat aaagtagcca ttcttcccat ggatgtttcc 148860
ttttttacca aaggaaatgc atcattgatt attctcctgt ttgatttctc tatcgatgcg 148920
gcacctctct taagaagtgt aaccgataat aatgttatta tatctagaca ccagcgtcta 148980
catgacgagc ttccgagttc caattggttc aagttttaca taagtataaa gtccgactat 149040
tgttctatat tatatatggt tgttgatgga tctgtgatgc atgcaatagc tgataataga 149100
acttacgcaa atattagcaa aaatatatta gacaatacta caattaacga tgagtgtaga 149160
tgctgttatt ttgaaccaca gattaggatt cttgatagag atgagatgct caatggatca 149220
tcgtgtgata tgaacagaca ttgtattatg atgaatttac ctgatgtagg cgaatttgga 149280
tctagtatgt tggggaaata tgaacctgac atgattaaga ttgctctttc ggtggctggt 149340
atttggaaag ttttataggt agttgataga acaaaataca taattttgta aaaataaatc 149400
actttttata ctaatatgac acgattacca atacttttgt tactaatatc attagtatac 149460
gctacacctt ttcctcagac atctaaaaaa ataggtgatg atgcaacttt atcatgtaat 149520
cgaaataata caaatgacta cgttgttatg agtgcttggt ataaggagcc caattccatt 149580
attcttttag ctgctaaaag cgacgtcttg tattttgata attataccaa ggataaaata 149640
tcttacgact ctccatacga tgatctagtt acaactatca caattaaatc attgactgct 149700
agagatgccg gtacttatgt atgtgcattc tttatgacat cgcctacaaa tgacactgat 149760
aaagtagatt atgaagaata ctccacagag ttgattgtaa atacagatag tgaatcgact 149820
atagacataa tactatctgg atctacacat tcaccggaaa ctagttctga gaaacctgat 149880
tatatagata attctaattg ctcgtcggta ttcgaaatcg cgactccgga accaattact 149940
gataatgtag aagatcatac agacaccgtc acatacacta gtgatagcat taatacagta 150000
agtgcatcat ctggagaatc cacaacagac gagactccgg aaccaattac tgataaagaa 150060
gaagatcata cagttacaga cactgtctca tacactacag taagtacatc atctggaatt 150120
gtcactacta aatcaaccac cgatgatgcg gatctttatg atacgtacaa tgataatgat 150180
acagtaccat caactactgt aggcggtagt acaacctcta ttagcaatta taaaaccaag 150240
gactttgtag aaatatttgg tattaccgca ttaattatat tgtcggccgt ggcaatattc 150300
tgtattacat attatatata taataaacgt tcacgtaaat acaaaacaga gaacaaagtc 150360
tagatttttg acttacataa atgtctggga tagtaaaatc tatcatattg agcgggccat 150420
ctggtttagg aaagacagcc atagccaaaa gactatggga atatatttgg atttgtggtg 150480
tcccatacca ctagatttcc tcgtcctatg gaacgagaag gtgtcgatta ccattacgtt 150540
aacagagagg ccatctggaa gggaatagcc gccggaacat actgagtttt taggaaatat 150600
ttacggaact tctaaaactg ctgtgaatac agcggctatt aataatcgta tttgtgtgat 150660
ggatctaaac atcgacggtg ttagaagttt taaaaatact tacctaatgc cttactcggt 150720
gtatataaga cctacctctc ttaaaatggt tgagaccaag cttcgttgta gaaacactga 150780
agcggatgat gagattcatc gtcgtgtgat gttggcaaaa actgacatgg atgaggcagg 150840
tgaagccggt ctattcgaca ctattatcat tgaagatgat gtgaatttag catatagtaa 150900
gttaattcag atactacagg accgtattag aatgtatttt aacactaatt agagacttaa 150960
gacttaaaac ttgataatta ataatataac tcgtttttat atgtggctat ttcaacgtct 151020
aatgtattag ttaaatatta aaacttacca cgtaaaactt aaaatttaaa atgatatttc 151080
attgacagat agatcacaca ttatgaactt tcaaggactt gtgttaactg acaattgcaa 151140
aaatcaatgg gtcgttggac cattaatagg aaaaggtgga tttggtagta tttatactac 151200
taatgacaat aattatgtag taaaaataga gcccaaagct aacggatcat tatttaccga 151260
acaggcattt tatactagag tacttaaacc atccgttatc gaagaatgga aaaaatctca 151320
caatataaag cacgtaggtc ttatcacgtg caaggcattt ggtctataca aatccattaa 151380
tgtggaatat cgattcttgg taattaatag attaggtgca gatctagatg cggtgatcag 151440
agccaataat aatagattac caaaaaggtc ggtgatgttg atcggaatcg aaatcttaaa 151500
taccatacaa tttatgcacg agcaaggata ttctcacgga gatattaaag cgagtaatat 151560
agtcttggat caaatagata agaataaatt atatctagtg gattacggat tggtttctaa 151620
attcatgtct aatggcgaac atgttccatt tataagaaat ccaaataaaa tggataacgg 151680
tactctagaa tttacaccta tagattcgca taaaggatac gttgtatcta gacgtggaga 151740
tctagaaaca cttggatatt gtatgattag atggttggga ggtatcttgc catggactaa 151800
gatatctgaa acaaagaatt gtgcattagt aagtgccaca aaacagaaat atgttaacaa 151860
tactgcgact ttgttaatga ccagtttgca atatgcacct agagaattgc tgcaatatat 151920
taccatggta aactctttga catattttga ggaacccaat tacgacaagt ttcggcacat 151980
attaatgcag ggtgtatatt attaagtgtg gtgtttggtt gatgtaaaat ttttgtcgat 152040
aaaaattaaa aaataactta atttattatt gatctcgtgt gtacaaccga aatcatggcg 152100
atgttttacg cacacgctct cggtgggtac gacgagaatc ttcatgcctt tcctggaata 152160
tcatcgactg ttgccaatga tgtcagttta taataacaag tatgacattg taaaagacaa 152220
atatatgtgg tgttacagtc aggtgaacaa gagatatatt ggagcactgc tgcctatgtt 152280
tgagtgcaat gaatatctac aaattggaga tccgatccat gatcaagaag gaaatcacat 152340
atcgccacaa aaactactat gctctaagcg gaatcgggta cgagagtcta gacttgtgtt 152400
tggaaggagt agggattcat catcacgtac ttgaaacaga aaacgctgta tatggaaaag 152460
ttcaacatga ttattctact atcaaagaga aggccaaaga aatgaatgca ctcagttcag 152520
gacctatcat cgattaccac gtctggatag gagattgtat ctgtcaagtt actgctgtgg 152580
acgtacatgg aaaggaaatt atgagaatga gattcaaaaa gggtgcggtg cttccgatcc 152640
caaatctggt aaaagttaaa cttggggaga atgatacaga aaatctttct tctactatat 152700
cggcggcacc atcgaggtaa ccacctctct ggaagacagt gtgaatcatg tactcatgaa 152760
acgtttggaa tctatacgcc atatgtggtc tgttgtatat gatcattttg atattgtgaa 152820
tggtaaagaa tgctgttatg tgcatacgca tttgtctaat caaaatctta taccgagtac 152880
tgtaaaaaca aatttgtaca tgaagactat gggatcatgc attcaaatga gtatcttagc 152940
gaactgaagg aatcaggtgg atggagtccc agaccagaaa tgcaggaatt tgaatatcca 153000
gatggagtgg aagacactga atcaattgag agattggtag aggagttctt caatagatca 153060
gaacttcagg ctggtaaatc tattaatgtt aaacatacat ctgtttcagc taagcaacta 153120
agaacacgta tactctcatc ttttgccaac acagagggtg gatatttgtt cattggagtt 153180
gataataata cacacaaagt atttggattc acggtgggtt acgactacct cagactgata 153240
gagaatgata tagaaaagca tatcaaaaga ctttgtgttg tgtatttctg tgagaagaaa 153300
gaggacatca agtacacgtg tcgattcatc aaggtatata aacctgggga tgaggctacc 153360
tcgacatacg tgtgcgctat caaagtggaa agatgctgtt gtgctgtgtt tgcagattgg 153420
ccagaatcat ggtatcaaga agtattctcc agatgaatag gtgtcacata taaaatttta 153480
attaatgtaa ctatagagaa caaataatag gttgtaatat catatagaca ataactaaca 153540
attaattagt aactgttatc tctttttaac taactaacta tacctattaa tacatcgtaa 153600
ttatagttct taacatctat taatcattga ttcgcttctt taatttttta taaaccaaca 153660
ttgttaattg aaaagggata acatgttaca gaatataaat tatatatgga ttttttttaa 153720
aaaggaaata cttgactgga gtgtatattt atctcttcat tatatagcac gcgtgttttc 153780
caatttttcc acatcccata taatacagga ttataatctc gttcgaacat acgagaaagt 153840
ggataaaaca atagttgatt ttttatctag gttgccaaat ttattccata ttttagaata 153900
tggggaaaat attctacata tttattctat ggatgatgct aatacgaata ttataatttt 153960
ttttctagat agagtattaa atattaataa gaacgggtca tttatacaca atctcaggtt 154020
atcatcatcc attaatataa aagaatatgt atatcaatta gttaataatg atcatccaga 154080
taataggata agactaatgc ttgaaaatgg acgtagaaca agacattttt tgtcctatat 154140
atcagataca gttaatatct atatatgtat tttatataga tgccgaagac agttacggtt 154200
gtacattatt acatagatgt atatatcact ataagaaatc agaatcagaa tcagaatcat 154260
acaatgaatt aattaagata ttgttaaata atggatcaga tgtagataaa aaagatacgt 154320
acggaaacac accttttatc ctattatgta aacacgatat caacaacgtg gaattgtttg 154380
agatatgttt agagaatgct aatatagact ctgtagactt taatagatat acacctcttc 154440
attatgtctc atgtcgtaat aaatatgatt ttgtaaagtt attaatttct aaaggagcaa 154500
atgttaatgc gcgtaataaa ttcggaacta ctccatttta ttgtggaatt atacacggta 154560
tctcgcttat aaaactatat ttggaatcag acacagagtt agaaatagat aatgaacata 154620
tagttcgtca tttaataatt tttgatgctg ttgaatcttt agattatcta ttatccagag 154680
gagttattga tattaactat cgtactattt acgacgctgt cagttataat gcgtataata 154740
cgttggtcta tctattaaac agaaatggtg attttgagac gattactact agtggatgta 154800
catgtatttc ggaagcagtc gcaaacaaca acaaaataat aatggaagta ctattgtcta 154860
aacgaccatc tttgaaaatt atgatacagt ctatgatagc aattactaaa cataaacagc 154920
ataatgcaga tttattgaaa atgtgtataa aatatactgc gtgtatgacc gattatgata 154980
ctcttataga tgtacaatca ctacagcaat ataaatggta tattttaaga tgtttcgatg 155040
aaatagatat catgaagaga tgttatataa aaaataaaac tgtattccaa ttagtttttt 155100
gtatcaaaga cattaatact ttaatgagat acggtaaaca tccttctttc gtgaagtgca 155160
ctagtctcga cgtatacgga agtcgtgtac gtaatatcat agcatctatt agatatcgtc 155220
agagattaat tagtctatta tccaagaagc tggatcctgg agataaatgg tcgtgttttc 155280
ctaacgaaat aaaatataac gataacgaac tgtccacata tctaaaaatc ttataaacac 155340
tattaaaata taaaatcaca ctacatcatt gtttcctttt agtgctcgac agtgtatact 155400
atttttaacg ctcataaata aaaatgaaaa cgatttccgt tgttacgttg ttatgcgtac 155460
tacctgctgt tgtttattca acatgtactg tacccactat gaataacgct aaattaacgt 155520
ctaccgaaac atcgtttaat aataaccaga aagttacgtt tacatgtgat cagggatatc 155580
attcttcgga tccaaatgct gtctgcgaaa cagataaatg gaaatacgaa aatccatgca 155640
aaaaaatgtg cacagtttct gattacatct ctgaactata taataaaccg ctatacgaag 155700
tgaattccac catgacacta agttgcaacg gcgaaacaaa atattttcgt tgcgaagaaa 155760
aaaatggaaa tacttcttgg aatgatactg ttacgtgtcc taatgcggaa tgtcaacctc 155820
ttcaattaga acacggatcg tgtcaaccag ttaaagaaaa atactcattt ggggaatata 155880
taactatcaa ctgtgatgtt ggatatgagg ttattggtgc ttcgtacata agttgtacag 155940
ctaattcttg gaatgttatt ccatcatgtc aacaaaaatg tgatataccg tctctatcta 156000
atggattaat ttccggatct acattttcta tcggtggcgt tatacatctt agttgtaaaa 156060
gtggttttat actaacggga tctccatcat ccacatgtat cgacggtaaa tggaatccca 156120
tactcccaac atgtgtacga tctaacgaaa aatttgatcc agtggatgat ggtcccgacg 156180
atgagacaga tttgagcaaa ctctcgaaag acgttgtaca atatgaacaa gaaatagaat 156240
cgttagaagc aacttatcat ataatcatag tggcgttaac aattatgggc gtcatatttt 156300
taatctccgt tatagtatta gtttgttcct gtgacaaaaa taatgaccaa tataagttcc 156360
ataaattgct accgtgaata taaatccgtt aaaataatga ataattaata attaataatt 156420
taataacaaa caagtatcaa aagattaaag acttatagct agaatcaatt gagatgtctt 156480
cttcagtgga tgttgatatc tacgatgccg ttagagcatt tttactcagg cactattata 156540
acaagagatt tattgtgtat ggaagaagta acgccatatt acataatata tacaggctat 156600
ttacaagatg cgccgttata ccgttcgatg atatagtacg tactatgcca aatgaatcac 156660
gtgttaaaca atgggtgatg gatacactta atggtataat gatgaatgaa cgcgatgttt 156720
ctgtaagcgt tggcaccgga atactattca tggaaatgtt tttcgattac aataaaaata 156780
gtatcaacaa tcaactaatg tatgatataa ttaatagcgt atctataatt ctagctaatg 156840
agagatatag aagcgctttt aacgacgatg gtatatacat ccgtagaaat atgattaaca 156900
agttgtacgg atacgcatct ctaactacta ttggcacgat cgctggaggt gtttgttatt 156960
atctgttgat gcatctagtt agtttgtata aataattatt tcaatatact agttaaaatt 157020
ttaagatttt aaatgtataa aaaactaata acgtttttat ttgtaatagg tgcattagca 157080
tcctattcga ataatgagta cactccgttt aataaactga gtgtaaaact ctatatagat 157140
ggagtagata atatagaaaa ttcatatact gatgataata atgaattggt gttaaatttt 157200
aaagagtaca caatttctat tattacagag tcatgcgacg tcggatttga ttccatagat 157260
atagatgtta taaacgacta taaaattatt gatatgtcta ctattcaacg cagaggtcac 157320
acgtgtagaa tatctaccaa attatcatgc cattatgata agtaccctta tattcacaaa 157380
tatgatggtg atgagcgaca atattctatt actgcagagg gaaaatgcta taaaggaata 157440
aaatatgaaa taagtatgat caacgatgat actctattga gaaaacatac tcttaaaatt 157500
ggatctactt atatatttga tcgtcatgga catagtaata catattattc aaaatatgat 157560
ttttaaaaat ttaaaatata ttatcacttc agtgacagta gtcaaataac aaacaacacc 157620
atgagatata ttataattct cgcagttttg ttcattaata gtatacacgc taaaataact 157680
agttataagt ttgaatccgt caattttgat tccaaaattg aatggactgg ggatggtcta 157740
tacaatatat cccttaaaaa ttatggcatc aagacgtggc aaacaatgta tacaaatgta 157800
ccagaaggaa catacgacat atccgcattt ccaaagaatg atttcgtatc tttctgggtt 157860
aaatttgaac aaggcgatta taaagtggaa gagtattgta cgggaccacc gactgtaaca 157920
ttaactgaat acgacgacca tccgtatgct actagaggta gcaaaaagat tcctatttac 157980
aaacgcggtg acatgtgtga tatctacttg ttgtatacgg ctaacttcac attcggagat 158040
tctaaagaac cagtaccata tgatatcgat gactacgatt gcacgtctac aggttgcagc 158100
atagactttg tcacaacaga aaaagtgtgc gtgacagcac agggagccac agaagggttt 158160
ctcgaaaaaa ttactccatg gagttcgaaa gtatgtctga cacctaaaaa gagtgtatat 158220
acatgcgcaa ttagatccaa agaagatgtt cccaatttca aggacaaaat ggccagagtt 158280
atcaagagaa aatttaacta aatttctcgg tagcacatca aatgatgtta ccacttttct 158340
tagcatgctt aacttgacta aatattcata actaattttt attaatgata caaaaacgaa 158400
ataaaactgc atattataca ctggttaacg cccttatagg ctctaaccat tttcaagatg 158460
aggtccctga ttatagtcct tctgttcccc tctatcatct actccatgtc tattagacga 158520
tgtgagaaga ctgaagagga aacatgggga ttgaaaatag ggttgtgtat aattgccaaa 158580
gatttctatc ccgaaagaac tgattgcagt gttcatctcc caactgcaag tgaaggcaat 158640
ggattcaggg atatacgaaa caccgataaa ttataaaaaa agcaatgtgt ccgctgtttc 158700
cgttaataat actattttcg taactggcgg attattcata aataactcta atagcacgat 158760
cgtggttaac aatatggaaa aacttgacat ttataaagac aaacaatggt cgattataga 158820
aatgcctatg gctagggtat atcacggcat cgactcgaca tttggaatgt tatattttgc 158880
cggaggtcta tccgttaccg aacaatatgg taatttagag aaaaacaacg agatatcttg 158940
ttacaatcct agaacgaata agtggtttga tatttcatat actatttata agatatccat 159000
atcatcattg tgtaaactaa ataacgtctt ctatgtattt agtaaggaca ttggatatgt 159060
ggaaaagtat gatggtctcc ccgctataaa ggcattatca acttctcctt attgattgaa 159120
aatgaaaata taaatagttt ttatgtatag cagtattacc ctatagtttt attgcttact 159180
actaacatgg atacagatac agatgttaca aatgtagaag atatcatgaa tgaaatagat 159240
agagagaaag aagaaatact aaaaaatgta gaaattgaaa ataataaaaa cattaacaag 159300
aatcatccca atgaatatat tagagaagca ctcgttatta atacaagtag taatagtgat 159360
tccattgata aagaagttat agaatgtatc agtcacgatg taggaatata gatcatatct 159420
actaattttt ataatcaata caaaacataa aaaacaactc gttattacat agcaggcatg 159480
gaatccttca agtattgttt tgataacgat ggcaagaaat ggattatcgg aaatacttta 159540
tattctggta attcaatact ctataaggtc agaaaaaatt tcactagttc gttctacaat 159600
tacgtaatga agatagatca caaatcacac aagccattgt tgtctgaaat acgattctat 159660
atatctgtat tggatccttt gactatcgac aactggacac gggaacgtgg tataaagtat 159720
ttggctattc cagatctgta tggaattgga gaaaccgatg attatatgtt cttcgttata 159780
aagaatttgg gaagagtatt cgccccaaag gatactgaat cagtcttcga agcatgcgtc 159840
actatgataa acacgttaga gtttatacac tctcgaggat ttacccatgg aaaaatagaa 159900
ccgaggaata tactgattag aaataaacgt ctttcactaa ttgactattc tagaactaac 159960
aaactataca agagtggaaa ctcacatata gattacaacg aggacatgat aacttcagga 160020
aatatcaatt atatgtgtgt agacaatcat cttggagcaa cagtttcaaa acgaggagat 160080
ttagaaatgt tgggatattg catgatagaa tggttcggtg gcaaacttcc atggaaaaac 160140
gaaagtagta taaaagtaat aaaacaaaaa aaagaatata aaaaatttat agctactttc 160200
tttgaggact gttttcctga aggaaatgaa cctctggaat tagttagata tatagaatta 160260
gtatacacgt tagattattc tcaaactcct aattatgaca gactacgtag actgtttata 160320
caagattgaa atattctttt tttatagagt gtggtagtgt tacggatatc taatattaat 160380
attagactat ctctatcgcg ctacacgacc aatatcgatt actatggata tcttctatga 160440
aaggagagaa tgtattcatt tctccagcgt caatctcgtc agtattgaca atactgtatt 160500
atggagctaa tggatccact gctgaacagc tatcaaaata tgtagaaaag gaggagaaca 160560
cggataaggt tagcgctcag aatatctcat tcaaatccat gaataaagta tatgggcgat 160620
attctgccgt gtttaaagat tcctttttga gaaaaattgg cgataagttt caaactgttg 160680
acttcactga ttgtcgcact atagatgcaa tcaacaagtg tgtagatatc tttactgagg 160740
ggaaaatcaa tccactattg gatgaacaat tgtctcctag caattagtgc cgtatacttt 160800
aaagcaaaat ggttgacgcc attcgaaaag gaatttacca gtgattatcc cttttacgta 160860
tcaccaacgg aaatggtaga cgtaagtatg atgtctatgt acggcgagct atttaatcac 160920
gcatctgtaa aagaatcatt cggtaacttt tcaatcatag aactgccata tgttggagat 160980
actagtatga tggtcattct tccagacaag attgatggat tagaatccat agaacaaaat 161040
ctaacagata caaattttaa gaaatggtgt aactctctgg aagctacgtt tatcgatgtt 161100
cacattccca agtttaaggt aacaggctcg tataatctgg tggatactct agtaaagtca 161160
ggactgacag aggtgttcgg ttcaactgga gattatagca atatgtgtaa tttagatgtg 161220
agtgtcgacg ctatgatcca caaaacgtat atagatgtca atgaagagta tacagaagca 161280
gctgcagcaa cttgtgcact ggtgtcagac tgtgcatcaa caattacaaa tgagttctgt 161340
gtagatcatc cgttcatcta tgtgattagg catgttgatg gaaaaatttt tttcgttggt 161400
agatattgct ctccgacaac taattgttaa ccattttttt taaaaaaata gaaaaaacat 161460
gtggtattag tgcaggtcgt tattcttcca attgcaattg gtaagatgac ggccaacttt 161520
agtacccacg tcttttcacc acagcactgt ggatgtgaca gactgaccag tattgatgac 161580
gtcaaacaat gtttgactga atatatttat tggtcgtcct atgcataccg caacaggcaa 161640
tgcgctggac aattgtattc cacactcctc tcttttagag atgatgcgga attagtgttc 161700
atcgacattc gcgagctggt aaaaaatatg ccgtgggatg atgtcaaaga ttgtgtagaa 161760
atcatccgtt gttatatacc ggatgagcaa aaaaccatca tcggactttg tgcatatgct 161820
gctacttact ggggaggtga agaccatccc actagtaaca gtctgaacgc attgtttgtg 161880
atgcttgaga tgctaaatta cgtggattat aacatcatat tccggcgtat gaattgatga 161940
gttgtacatc ttgacatttt cttctttctt ctcttctccc tttcccagaa acaaactttt 162000
tttacccact ataaaataaa atgagtatac tacctgttat atttctttct atattttttt 162060
attcttcatt cgttcagact tttaacgcgc ctgaatgtat cgacaaaggg caatattttg 162120
catcattcat ggagttagaa aacgagccag taatcttacc atgtcctcaa ataaatacgc 162180
tatcatccgg atataatata ttagatattt tatgggaaaa acgaggagcg gataatgata 162240
gaattatacc gatagataat ggtagcaata tgctaattct gaacccgaca caatcagact 162300
ctggtattta tatatgcatt accacgaacg aaacctactg tgacatgatg tcgttaaatt 162360
tgacaatcgt gtctgtctca gaatcaaata tagatcttat ctcgtatcca caaatagtaa 162420
atgagagatc tactggcgaa atggtatgtc ccaatattaa tgcatttatt gctagtaacg 162480
taaacgcaga tattatatgg agcgggcatc gacgccttag aaataagaga cttaaacaac 162540
ggacacctgg aattattacc atagaagatg ttagaaaaaa tgatgctggt tattatacat 162600
gtgttttaga atatatatac ggtggcaaaa catataacgt aaccagaatt gtaaaattag 162660
aggtacggga taaaataata ccttctacta tgcaattacc agaaggtgtt gtaacttcaa 162720
taggtagtaa tttgactatt gcgtgtagag tatcgttgag acctcccaca acggatgcag 162780
acgtcttttg gataagtaat ggtatgtatt acgaagaaga tgatggggac ggagacggta 162840
gaataagtgt agcaaataaa atctatatga ccgataagag acgtgttatt acatcccggt 162900
taaacattaa tcctgtcaag gaagaagatg ctacaacgtt tacgtgtatg gcgtttacta 162960
ttcctagcat cagcaaaaca gttactgtta gtataacgtg aatgtatgtt gttacatttc 163020
catgtcaatt gagtttataa gaatttttat acattatctt ccaacaaaca attgacgaac 163080
gtattgctat gattaactcc cacgatacta tgcatattat taatcattaa cttgcagact 163140
atacctagtg ctattttgac atactcatgt tcttgtgtaa ttgcggtatc tatattatta 163200
aagtacgtaa atctagctat agttttatta tttaatttta gataatatac cgtctcctta 163260
tttttaaaaa ttgccacatc ctttattaaa tcatgaatgg gaatttctat gtcatcgtta 163320
atatattgtg aacaacaaga gcagatatct ataggaaagg gtggaatgcg atacattgat 163380
ctatgtagtt ttaaaacaca cgcgaacttt gaagaattta tataaatcat tccatcgata 163440
catccttcta tgttgacatg tatatatcca ggaattcttt tattaatgtc aggaaatgta 163500
taaactaaaa cattgcccga aagcggtgcc tctatctgcg ttatatccgt tcttaactta 163560
caaaatgtaa ccaatacctt tgcatgactt gttttgttcg gcaacgttag tttaaacttg 163620
acgaatggat taattacaat agcatgatcc gcgcatctat taagtttttt tactttaacg 163680
cccttgtatg tttttacaga gactttatct aaatttctag tgcttgtatg tgttataaat 163740
ataacgggat atagaactga atcacctacc ttagataccc aattacattt tatcagatcc 163800
agataataaa caaattttgt cgccctaact aattctatat tgttatatat tttacaattg 163860
gttatgatat catgtaataa cttggagtct aacgcgcatc gtcgtacgtt tatacaattg 163920
tgatttagtg tagtatatct acacatgtat ttttccgcac tatagtattc tggactagtg 163980
ataaaactat cgttatatct gtcttcaatg aactcatcga gatattgctc tctgtcatat 164040
tcatacacct gcataaactt tctagacatc ttacaatccg tgttatttta ggatcatatt 164100
tacatattta cgggtatatc aaagatgtta gattagttaa tgggaatcgt ctataataat 164160
gaatattaaa caattatatg aggactttta ccacaaagca tcataaaaat gagtcgtcgt 164220
ctgatttatg ttttaaatat caaccgcgaa tcaactcata aaatacaaga gaatgaaata 164280
tatacatatt ttagtcattg caatatagac catacttcta cagaacttga ttttgtagtt 164340
aaaaactatg atctaaacag acgacaacct gtaactgggt atactgcact acactgctat 164400
ttgtataata attactttac aaacgatgta ctgaagatat tattaaatca tggagtggat 164460
gtaacgatga aaaccagtag cggacgtatg cctgtttata tattgcttac tagatgttgt 164520
aatatttcac atgatgtagt gatagatatg atagacaaag ataaaaacca cttatcgcat 164580
agagactatt ccaacctact actagagtat ataaaatctc gttacatgtt attgaaggaa 164640
gaggatatcg atgagaacat agtatccact ttattagata agggaatcga tcctaacttt 164700
aaacaagacg gatatacagc gttacattat tattatttgt gtctcgcaca cgtttataaa 164760
ccaggtgagt gtagaaaacc gataacgata aaaaaggcca agcgaattat ttctttgttt 164820
atacaacatg gagctaatct aaacgcgtta gataattgtg gtaatacacc attccatttg 164880
tatcttagta ttgaaatgtg taataatatt catatgacta aaatgctgtt gacttttaat 164940
ccgaatttca aaatatgtaa taatcatgga ttaacgccta tactatgtta tataacttcc 165000
gactacatac aacacgatat tcttgttatg ttaatacatc actatgaaac aaatgttgga 165060
gaaatgccga tagatgagcg tcgtataatc gtattcgagt ttatcaaaac atattctaca 165120
cgtccggcag attcgataac ttatttgatg aataggttta aaaatataga tatttatacc 165180
cgctatgaag gaaagacatt attacacgta gcatgtgaat ataataatac acacgtaata 165240
gattatctta tacgtatcaa cggagatata aatgcgttaa ccgacaataa caaacacgct 165300
acacaactca ttatagataa caaagaaaat tccccatata ccattaattg tttactgtat 165360
atacttagat atattgtaga taagaatgtg ataagatcgt tggtggatca acttccatct 165420
ctacctatct tcgatataaa atcatttgag aaattcatat cctactgtat acttttagat 165480
gacacatttt acaatagaca cgttaggaat cgcaattcta aaacgtatcg atacgcattt 165540
tcaaaataca tgtcgtttga taaatacgat ggtataataa ctaaatgtca taaagaaaca 165600
atattgctca aactatccac tgttctagac actacactat atgcagtttt aagatgccat 165660
aattcgaaaa agttaagaag atacctcaac gagttaaaaa aatataataa cgataagtcc 165720
tttaaaatat attctaatat tatgaatgag agatacctta atgtatatta taaagatatg 165780
tacgtgtcaa aggtatatga taaactattt cctgttttca cagataaaaa ttgtctacta 165840
acattactac cttcagaaat tatatacgaa atattataca tgctgacaat taacgatctt 165900
tataatatat cgtatccacc taccaaagta tagttgtatt tttctcatgc gatgtgtgta 165960
aaaaaactga tattatataa atattttagt gccgtataat gaagatgacg atgaaaatga 166020
tggtacatat atatttcgta tcattattgt tattgctatt ccacagttac gccatagaca 166080
tcgaaaatga aatcacagaa ttcttcaata aaatgagaga tactctacca gctaaagact 166140
ctaaatggtt gaatccagca tgtatgttcg gaggcacaat gaatgatata gccgctctag 166200
gagagccatt cagcgcaaag tgtcctccta ttgaagacag tcttttatcg cacagatata 166260
aagactatgt ggttaaatgg gagaggctag aaaaaaatag acggcgacag gtttctaata 166320
aacgtgttaa acatggtgat ttatggatag ccaactatac atctaaattc agtaaccgta 166380
ggtatttgtg taccgtaact acaaagaatg gtgactgtgt tcagggtata gttagatctc 166440
atattaaaaa acctccttca tgcattccaa aaacatatga actaggtact catgataagt 166500
atggcataga cttatactgt ggaattcttt acgcaaaaca ttataataat ataacttggt 166560
ataaagataa taaggaaatt aatatcgacg atattaagta ttcacaaacg ggaaagaaat 166620
taattattca taatccagag ttagaagata gtggaagata caactgttac gttcattacg 166680
acgacgttag aatcaagatg taaaatactt acggttatac cgtcgcaaga ccacaggttt 166740
aaactaatac tagatccaaa aatcaacgta acgataggag aacctgccaa tataacatgc 166800
actgctgtgt caacgtcatt attgattgac gatgtactga ttgaatggga aaatccatcc 166860
ggatggctta taggattcga ttttgatgta tactctgttt taactagtag aggcggtatc 166920
accgaggcga ccttgtactt tgaaaatgtt actgaagaat atataggtaa tacatataaa 166980
tgtcgtggac acaactatta ttttgaaaaa acccttacaa ctacagtagt attggagtaa 167040
atacacaatg catttttata tacattactg aataattatt attattattt atatcgtatt 167100
tgtgctataa cgcgactatc taggtatttg tatctcaccg atagagaaca tataaatgta 167160
gactctatta aacagttgtg taaaatatca gatcctaata gatgtggatg tacggcttta 167220
gaaatgagtt cattaaaata tgtgatatca acggaacata tttatataat tatactattg 167280
ctgttagtat aattattgat tccacggaag aactaccaac agttactcca attacaacaa 167340
catataatta tactatcgat gatagcacta ctgaagaact acaagtgact cctcatatgg 167400
atctccatcg atgatacatg tattaaaata ctttccgaat aagtctttta aatattgtat 167460
taattatgaa aaactatgct atgcgagtat gatacgatac tagattttat ctctagcgag 167520
agatgtcgtt agaatcattt atcaacgaat atcgataaca tgtgtcattt atacgttaaa 167580
gtctgtccgt cttctctatt gtttagactg tttgtagaat gctgtgatat aaacaaacta 167640
gtagacacaa atatttaact catgatgaag ttgagaatga tatgctttag ctaatataaa 167700
aatatattaa tccactatat attctagact tgatttaaaa ccgataaact actactacgt 167760
actgtataag ttaggagcag accctaatta tgtagatgat agaggtaata cttctgcatc 167820
tatatgtcca cttatgagaa aacgtcattt aataagatgc atcgtgaaaa gaaatttatt 167880
aaagagttgg taaaatatga aaccgaaagt aaataatata ggaaatacac ctctacataa 167940
ctacgtatct caatatgata tcactctcat tcctcatcca caacccatta aaaaatggaa 168000
attaaagccc tctattagca taaacggcta caggtctacc tttacaatgg cctttccttg 168060
tgcccagttc agaccctgtc attgccacgc tactaaggac tccctgaata ccgtggccga 168120
cgtcagacat tgtctgactg aatacatcct gtgggtttct catagatgga cccatagaga 168180
aagcgcaggg tctctctaca ggcttctcat ctctttcaga actgatgcaa cggagctctt 168240
tggtggtgag ttgaaggatt cacttccgtg gagatcatta aatgactcca tgaaaaccgc 168300
cgaagaactt cgtgcaatca ttggactttg tactcaatca gctatcgtct ctggaagagt 168360
cttcaacgat aagtatatcg acatactact tatgctgcga aagattctga acgagaacga 168420
ctatctcacc ctcttggatc atatccgcac tgctaaatac taaatctcct tcatgctctc 168480
tcactacact ttttatcatc ttatgaggaa taattagcac cagaatagct atggattgca 168540
catgtattct atgtcgtcta ctggatgaag atgtgacgta caaaaaaata aaactagaaa 168600
ttgaaacgtg tcacaactta tcaaaacata tagatagacg aggaaacaat gcgctacatt 168660
gttacgtctc caataaatgc gatacagaca ttaagattgt tcgactgtta ctctctcgcg 168720
gagtcgagag actttgtaga aacaacgaag gattaactcc gctaggagca tacagtaagc 168780
atagatacgt aaaatctcag attgtgcatc tactgatatc cagctattcg aattcctcta 168840
acgaactcaa gtcgaatata aatgatttcg acttacgtct gctaaaatac ctaattgtgg 168900
ataaacggat acgtccgtcc aagaatacga attatgcaat caatggtctc ggattggtgg 168960
atatatacgt aacgacgcct aatccgagac cagaagtatt gctatggctt cttaaatcag 169020
aatgttacag caccggttac gtatttcgta cctgtatgta caacagtgat atgtgtaaga 169080
actctcttca ttactatata tcgtctcata gagaatctct atccaaggat gtaattaaat 169140
gtttgatcga taacaatgtt tccatccaat actactggtc ttgctcaacc atagatatag 169200
agattattaa taaaggatgt ggacacgtgt agagtatacg acgtcagccc tatattagag 169260
gcgtattatc taaacaagcg atttagagta accccatata atgtagacat ggaaatcgtt 169320
aatcttctta ttgagagacg tcatactctt gtcgacgtaa tgcgtagtat tacttcgtac 169380
gattccagag aatataacca ctacatcatc gataacattc taaagagatt tagacaacag 169440
gatgaatcca tcgtacaagc catactgata aactacttac attacggcga tatggtaagt 169500
atacctatca ttcaatgcat gttggataag acgacggaca acaactttgt taataataat 169560
ctcgtcgatg taaacgtcgt aaggtttatc gtggaaaata tggacacgcg gctgtaaatc 169620
acatatctaa caatggccgt ctatgtatgt acggtctgat attatcgaga tttaataatt 169680
gcgggtatca ctgttatgaa gatgtatttg atatactaag caagtacatg gatgatatag 169740
atatgatcga taactctact atattacgcg gtcgatgtca ataatataca atttgcaaag 169800
cggttattgg aatatggagc gagtgtcacg ctcgataatc aatacggcca tccagaaaag 169860
cagttaccaa agagaagcta gttgatttat tactgagtta ccatcccact ctagagacta 169920
tgattgacgc atttaataga gatatacgct atctatatcc tgaaccatta ttcgcctgta 169980
tcagatacgc cttaatccta gatgatgatt ttccttctaa agtaagtatg atatcgccgg 170040
tcgtcataag gaactaaagc gctatagagc agacattaat agaatgaaga atgcctacat 170100
atcaggcgtc tccatgtttg atatattatt taaacgaagc aaacgccaca gattgagata 170160
cgcaaagaac aatgagagga tcgactccat taaataattt atcatggagt gataatgtcc 170220
tgtttccatg gcatattaca aaatcgattc cgtccaagat gataaaaaca tttaccggca 170280
tcataaacac ggagtttatt ttatatgtct cgcataaaca ttactaaaaa aatatattgt 170340
tcggttttct ttcacatctt taattatgaa aaagtaaatc attatgagat ggacgcatcg 170400
ttcgcgacag tatgtggtac atacctaacg tatttatgga cgacggtaag aatgaaggtc 170460
acgtttctgt caacaatgtc gacgcgatcg tgtaacacga ctcacaatag aatctgtgaa 170520
tgctctcccg atcatggatg caaggcatgt gtttcccaaa caaaatgtgg aataggatac 170580
ggagtatccg gagacgtcat ctgttctccg tgtggtctcg gaacatattc tcacaccgtc 170640
tcttccgcag ataaatgcga acccgtaccc agaaatacct ttaactatat cgatgtggaa 170700
attaacctgt atccagttaa cgacacatcg tgtactcgga cgaccactac cggtctcagc 170760
gaatccatct caacgtcgga actaactatt actatgaatc ataaagactg cgatcccgtc 170820
ttcttaataa ggtagcgact tcaggtttct ttacaggaga aaggtgtgca ctctgaattt 170880
cgagattaaa tgcaataaca aagattcttc ctccaaacag ttaacgaaag caaagaatga 170940
tactatcatg ccgcattcgg agacagtaac tctagcgtcg acatctatat actatatagt 171000
aataccaata ctcaagacta cgaaactgat acaatctctt atcatgtggg taatgtagcc 171060
atatgcccgg tagttgcgat atacataaac tgatcactaa ttccaaaccc acccgctttt 171120
tatagtaagt ttttcaccca taaatacaat aattaatttc tcgtaaaagt agaaaatata 171180
ttctaattta ttgcacggta aggaagtaga atcataaaga acagtactca atcaatagca 171240
atcatgaaac aatatatcgt actggcatgc atgtgcctgc cagtcttcag caatcatcct 171300
catcgtgtac ggaagaagaa aacaaacatc atatgggaat cgatgttatt atcaaagtca 171360
caaagcaaga ccaaacaccg accgatgata agatttgcca atccgtaacg gaaattacag 171420
agtccgagtc agatccagat cccgaggtgg aatcagtcga ggatgtagat cctcctacca 171480
cttattactc catcatcggt ggaggtctga gaatgaactt tggattcacc aaatgtcctc 171540
agattaaatc catctcagaa tccgctgatg gaaagactgt gaggtgtcta tcgacatcag 171600
atgtagcgaa gaagagaaag acagcgacat caagacccat ccagtactcg ggtctaacat 171660
ctctcataag aaagtgagtt acgaagatat catcggttca acgatcgtcg atacaaaatg 171720
tgtcaagaat ctagagttta gcgttcgtat cggagacatg tgcaaggaat catctgaact 171780
tgaggtcaag tatgtcgacg gatcggcatc tgaaggtgca accgatgata cttcactcat 171840
cgattcaaca aaactcaaag cgtgtgtctg aatcgataac tctattcatc tgaaattgga 171900
tgagtagggt taatcgaacg attcaggcac accacgaatt aaaaaagtgt accggacact 171960
atattccggt ttgcaaaaca aaaagttacc tctcgcgact tcttcttttt ctgtctcaat 172020
agtgtgatac gattatgaca ctattcctat ttcctttcag ggtatcacaa aaatattaaa 172080
cctctttctg atggtctcat acaaaaatat ttttattctc tttctctctt tgatggtctc 172140
ataaaaaata tttttattct ctttctctct ttgatggtct cataaaatat ttttattctc 172200
tttctctctt tgatggtctc ataaaaaata tttttattct ctttctctct ttgatggtct 172260
cataaaatat ttttattctc tttctctctt tgatggtctc ataaaaaata tttttattct 172320
ctttctctct ttgatggtct cataaaaaat attaaacctc tttctgatgg tgtcactaaa 172380
atatttttat tctctttctc tcttcaatgg agtcataaaa tatttttatt ctctttctct 172440
cttcgatggt ctcacaaaaa tattaaacct ctttctgatg gtgtcactaa aatattttta 172500
ttctctttct ctcttcaatg gagtcataaa atatttttat tctctttctc tctttgatgg 172560
tctcacaaaa atatttttat tctctttctc tctttgatgg tctcacaaaa atatttttat 172620
tctctttctc tctttgatgg tctcacaaaa atatttttat tctctttctc tctttgatgg 172680
tctcataaaa aaagttttac aaaaatattt ttattctctt tctctctttg atggtctcat 172740
aaaaaaagtt ttacaaaaat atttttattc tctttctctc tttgatggtc tcataaaaaa 172800
agttttacaa aaatattttt attctctttc tctctttgat ggtctcataa aaaatattaa 172860
acctctttct gatggtgtca ctaaaatatt tttattctca ttctctcttc aatggagtca 172920
taaaatattt ttattctctt tctctcttcg atggtctcac aaaaatatta aacctctttc 172980
tgatggtgtc actaaaatat ttttattctc attctctctt caatggagtc ataaaatatt 173040
tttattctct ttctctcttc gatggtctca caaaaatatt aaacctcttt ctgatggtgt 173100
cactaaaata tttttattct cattctctct tcaatggagt cataaaatat ttttattctc 173160
tttctctctt tgatggtctc ataaaaaaag ttttacaaaa atatttttat tctctttctc 173220
tctttgatgg tctcataaaa aatattaaac ctctttctga tggtgtcact aaaatatttt 173280
tattctcttt ctctcttcaa tggagtcata aaatattttt attctctttc tctcttcgat 173340
ggtctcacaa aaatattaaa cctctttctg atggtgtcac taaaatattt ttattctcat 173400
tctctcttca atggagtcat aaaatatttt tattctcttt ctctctttga tggtctcata 173460
aaaaaagttt tacaaaaata tttttattct ctttctctct ttgatggtct cataaaaaaa 173520
gttttacaaa aatattttta ttctctttct ctctttgatg gtctcataaa aaaagtttta 173580
caaaaatatt tttattctct ttctctcttt gatggtctca taaaaaaagt tttacaaaaa 173640
tatttttatt ctctttctct ctttgatggt ctcataaaaa atattaaacc tctttctgat 173700
ggtgtcacta aaatattttt attctcattc tctcttcaat ggagtcataa aatattttta 173760
ttctctttct ctcttcgatg gtctcacaaa aatattaaac ctctttctga tggtgtcact 173820
aaaatatttt tattctcatt ctctcttcaa tggagtcata aaatattttt attctctttc 173880
tctctttgat ggtctcataa aaaaagtttt acaaaaatat ttttattctc tttctctctt 173940
tgatggtctc ataaaaaaag ttttacaaaa atatttttat tctctttctc tctttgatgg 174000
tctcataaaa aaagttttac aaaaatattt ttattctctt tctctctttg atggtctcat 174060
aaaaaaagtt ttacaaaaat atttttattc tctttctctc tttgatggtc tcacaaaaat 174120
attaaacctc tttctgatgg agtcgtaaaa aagttttatc tctttctcct tcgatggtct 174180
cacaaaaata ttaaacctct ttctgatgga gtcgtaaaaa agttttatct ctttctctct 174240
tcgatggtct cacaaaaata ttaaacctct ttctgatgga gtcgtaaaaa agttttatct 174300
ctttctctct tcgatggtct cactaaaata ttttttattc tctttctgat gcatcaacta 174360
tttcttaaac aataacgtcc aacaacatat actcgtcgag cttatcaaca tcccctatgc 174420
ccatctaggt taccagacaa ttgtatatca taaaataatg tttataattt ttacaaaaat 174480
atttttattc tctttctctc tttgatggtc tcataaaaaa agttttacaa aaatattttt 174540
attctctttc tctctttgat ggtctcataa aaaatattaa acctctttct gatggtgtca 174600
ctaaaatatt tttattctca ttctctcttc aatggagtca taaaatattt ttattctctt 174660
tctctcttcg atggtctcac aaaaatatta aacctctttc tgatggtgtc actaaaatat 174720
ttttattctc attctctctt caatggagtc ataaaatatt tttattctct ttctctcttt 174780
gatggtctca taaaaaaagt tttacaaaaa tatttttatt ctctttctct ctttgatggt 174840
ctcataaaaa aagttttaca aaaatatttt tattctcttt ctctctttga tggtctcata 174900
aaaaaagttt tacaaaaata tttttattct ctttctctct ttgatggtct cataaaaaaa 174960
gttttacaaa aatattttta ttctctttct ctctttgatg gtctcataaa aaaagtttta 175020
caaaaatatt tttattctct ttctctcttt gatggtctca taaaaaaagt tttacaaaaa 175080
tatttttatt ctctttctct ctttgatggt ctcataaaaa aagttttaca aaaatatttt 175140
tattctcttt ctctctttga tggtctcata aaaaatatta aacctctttc tgatggtgtc 175200
actaaaatat ttttattctc tttctctctt caatggagtc ataaaatatt tttattctct 175260
ttctctcttc gatggtctca caaaaatatt aaacctcttt ctgatggtgt cactaaaata 175320
tttttattct cattctctct tcaatggagt cataaaatat ttttattctc tttctctctt 175380
tgatggtctc ataaaaaaag ttttacaaaa atatttttat tctctttctc tctttgatgg 175440
tctcataaaa aaagttttac aaaaatattt ttattctctt tctctctttg atggtctcat 175500
aaaaaaagtt ttacaaaaat atttttattc tctttctctc tttgatggtc tcataaaaaa 175560
agttttacaa aaatattttt attctctttc tctctttgat ggtctcataa aaaaagtttt 175620
acaaaaatat ttttattctc tttctctctt tgatggtctc ataaaaaata ttaaacctct 175680
ttctgatggt gtcactaaaa tatttttatt ctctttctct cttcaatgga gtcataaaat 175740
atttttattc tctttctctc ttcgatggtc tcacaaaaat attaaacctc tttctgatgg 175800
tgtcactaaa atatttttat tctctttctc tcttcaatgg agtcataaaa tatttttatt 175860
ctctttctct ctttgatggt ctcataaaaa aagttttaca aaaatatttt tattctcttt 175920
ctctctttga tggtctcata aaaaaagttt tacaaaaata tttttattct ctttctctct 175980
ttgatggtct cataaaaaaa gttttacaaa aatattttta ttctctttct ctctttgatg 176040
gtctcataaa aaaagtttta caaaaatatt tttattctct ttctctcttt gatggtctca 176100
taaaaaaagt tttacaaaaa tatttttatt ctctttctct ctttgatggt ctcataaaaa 176160
aagttttaca aaaatatttt tattctcttt ctctctttga tggtctcata aaaaaagttt 176220
tacaaaaata tttttattct ctttctctct ttgatggtct cataaaaaat attaaacctc 176280
tttctgatgg tgtcactaaa atatttttat tctcattttc tctttctctc ttcaatggag 176340
tcataaaata tttttattct ctttctctct ttgatggtct cataaaaaat attaaacctc 176400
tttctgatgg tgtcactaaa atatttttat tctcattctc tcttcaatgg agtcataaaa 176460
aagttttatc tctttctctc ttcgatggtc tcacaaaaat attaaacctc tttctgatgg 176520
agtcgtaaaa aagttttatc tctttctctc ttcgatggtc tcacaaaaat attaaacctc 176580
tttctgatgc atcaactatt tcttaaacaa taacgtccaa caacatatac tcatccccta 176640
tgcccatcta ggttaccaga caattgtata tcataaaata atgtttataa tttacacgtt 176700
aaaatcatat aataaaacgt agatcgtata atattttttg gtatataaat gatctagtaa 176760
aatccatgta ggggatactg ctcacatttt ttctttggta caaaatttca cacaagtttt 176820
tatacagaca aattcttgtc catatatttt aaaacattga cttttgtact aagaaaaata 176880
tctagactaa ctatctcttt ctctttctct cttcgatggt ctttctgatg gagtcgtaaa 176940
aaagttttat ctctttctct cttcgatggt ctcacaaaaa tattaaacct ctttctgatg 177000
gagtcgtaaa aaagttttat ctctttctct cttcgatggt ctcacaaaaa tattaaacct 177060
ctttctgatg gagtcgtaaa aaagttttat ctctttctcc ttcgatggtc tcacaaaaat 177120
attaaacctc tttctgatgg agtcgtaaaa aagttttatc tctttctctc ttcgatggtc 177180
tcacaaaaat attaaacctc tttctgatgg tgtcactaaa atatttttat tctctttctc 177240
tcttcgatgg tctcacaaaa atattaaacc tctttctgat ggagtcgtaa aaaagtttta 177300
tctctttctc cttcgatggt ctcacaaaaa tattaaacct ctttctgatg gagtcgtaaa 177360
aaagttttat ctctttctct cttcgatggt ctcacaaaaa tattaaacct ctttctgatg 177420
gagtcgtaaa aaagttttat ctctttctcc ttcgatggtc tcacaaaaat attaaacctc 177480
tttctgatgg agtcgtaaaa aagttttatc tctttctcct tcgatggtct cacaaaaata 177540
ttaaacctct ttctgatgga gtcgtaaaaa agttttatct ctttctcctt cgatggtctc 177600
acaaaaatat taaacctctt tctgatggag tcgtaaaaaa gttttatctc tttctctctt 177660
cgatggtctc acaaaaatat taaacctctt tctgatggag tcgtaaaaaa gttttatctc 177720
tttctctctt cgatggtctc acaaaaatat taaacctctt tctgatggag tcgtaaaaaa 177780
gttttatctc tttctccttc gatggtctca caaaaatatt aaacctcttt ctgatggtct 177840
ctataaagcg attgattttt cttaccctct agagtttcct acggtcgttg gtcacacatt 177900
tttttctaga cactaaataa ata 177923
<210> 3
<211> 150
<212> PRT
<213> 牛痘病毒
<400> 3
Met Gly Ile Gln His Glu Phe Asp Ile Ile Ile Asn Gly Asp Ile Ala
1 5 10 15
Leu Arg Asn Leu Gln Leu His Lys Gly Asp Asn Tyr Gly Cys Lys Leu
20 25 30
Lys Ile Ile Ser Asn Asp Tyr Lys Lys Leu Lys Phe Arg Phe Ile Ile
35 40 45
Arg Pro Asp Trp Ser Glu Ile Asp Glu Val Lys Gly Leu Thr Val Phe
50 55 60
Ala Asn Asn Tyr Ala Val Lys Val Asn Lys Val Asp Asp Thr Phe Tyr
65 70 75 80
Tyr Val Ile Tyr Glu Ala Val Ile His Leu Tyr Asn Lys Lys Thr Glu
85 90 95
Ile Leu Ile Tyr Ser Asp Asp Glu Asn Glu Leu Phe Lys His Tyr Tyr
100 105 110
Pro Tyr Ile Ser Leu Asn Met Ile Ser Lys Lys Tyr Lys Val Lys Glu
115 120 125
Glu Asn Tyr Ser Ser Pro Tyr Ile Glu His Pro Leu Ile Pro Tyr Arg
130 135 140
Asp Tyr Glu Ser Met Asp
145 150
<210> 4
<211> 4445
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多核苷酸
<400> 4
gcggccgcct tcttgttgta ctgtaacttc tcgttttgtt agatgtttgc atcgtgcttt 60
aacatcaatg gtacaaattt tatcctcgct ttgtgtatca tattcgtccc tactataaaa 120
ttgtatattc agattatcat gagatgtgta tacgctaacg gtatcaataa acggagcaca 180
ccatttagtc ataaccgtaa tccaaaaatt tttaaagtat atcttaacga aagaagttgt 240
gtcattgtct acggtgtatg gtactagatc ctcataagtg tatatatcta cagtaatgtt 300
taatttatca aatggttgat aatatggatc ctcatgacaa tttccgaaga tggaaatgag 360
atatagacat gcaataaatc taattgcgga catggttact ccttaaaaaa atacgaataa 420
tcaccttggc tatttagtaa gtgtcattta acactatact catagcggcc gccgcgcgta 480
atacgactca ctatagggcg aattggagct ctttttatct gcgcggttaa ccgccttttt 540
atccatcagg tgatctgttt ttattgtgga gtctagaact agtggatccc ccgggctgca 600
ggaattcgat atcaagctca ggcctagatc tgtcgacttc gagcttattt atattccaaa 660
aaaaaaaaat aaaatttcaa tttttaagct ttcactaatt ccaaacccac ccgcttttta 720
tagtaagttt ttcacccata aataataaat acaataatta atttctcgta aaagtagaaa 780
atatattcta atttattgca cggtaaggaa gtagatcata actcgaggaa ttggggatct 840
ctataatctc gcgcaaccta ttttcccctc gaacactttt taagccgtag ataaacaggc 900
tgggacactt cacacgcgta tggtcagtaa aggtgaggag ctttttacag gagttgtgcc 960
aatacttgtg gagttagacg gagatgtaaa tggtcataag ttttctgttt cgggagaggg 1020
tgaaggtgac gcaacttatg gaaagttaac tttaaagttc atctgcacaa cgggtaaatt 1080
gccagttccc tggcctacat tagtaaccac gttgacttac ggagtccaat gcttttcacg 1140
ataccctgat cacatgaagc aacacgattt ctttaaatcg gcaatgcccg agggttacgt 1200
gcaggagaga acaatctttt ttaaggacga cggaaactat aaaacccgag ccgaagtaaa 1260
atttgaaggt gacacattag taaatcgaat tgaattgaaa ggtattgact ttaaagaaga 1320
tggtaacatt ttgggacaca agcttgagta caactacaac agtcacaacg tatatatcat 1380
ggccgataag cagaagaatg gaatcaaagt gaatttcaag atccgacata atatagaaga 1440
tggatcagtt caattagccg accactacca acagaacact cctattggag acggacccgt 1500
tttgttaccg gataatcact acctaagtac acagtccgct ttgagtaaag accccaacga 1560
gaaacgagac catatggtgc ttttggagtt cgttacggca gccggaatta cgttaggtat 1620
ggatgaatta tataagtaaa cgcgttcttt tcaacgcctg gcactgccgg gcgttgttct 1680
ttttaacttc aggcgggtta caatagtttc cagtaagtat tctggaggct gcatccatga 1740
cacaggcaaa cctgcggatc ccagcttttg ttccctttag tgagggttaa ttgcgcgcgc 1800
atgcactgaa tggatgaacg aataccgacg gcgttaatag taatttactt tttcatcttt 1860
acatattggg tactagtttt actatcataa gtttataaat tccacaagct actatggaat 1920
aagccaacca tcttagtata acacacatgt cttaaagttt attaattaat tacatgttgt 1980
tttatatatc gctacgaatt taaacagaga aatcagttta ggaaaaaaaa atatctatct 2040
acatcatcac gtctctgtat tctacgatag agtgctactt taagatgaga catatccgtg 2100
tcatcaaaaa tatactccat taaaatgatt attccggcag cgaacttgat attggatata 2160
tcacaacctt tgttaatatc tacgacaata gacagcagtc ccatggttcc ataaacagtg 2220
agtttatctt tctttgaaga gatattttgt agagatctta taaaactgtc gaatggcatg 2280
ctaggccgcg ttgctggcgt ttttccatag gctccgcccc cctgacgagc atcacaaaaa 2340
tcgacgctca agtcagaggt ggcgaaaccc gacaggacta taaagatacc aggcgtttcc 2400
ccctggaagc tccctcgtgc gctctcctgt tccgaccctg ccgcttaccg gatacctgtc 2460
cgcctttctc ccttcgggaa gcgtggcgct ttctcaatgc tcacgctgta ggtatctcag 2520
ttcggtgtag gtcgttcgct ccaagctggg ctgtgtgcac gaaccccccg ttcagcccga 2580
ccgctgcgcc ttatccggta actatcgtct tgagtccaac ccggtaagac acgacttatc 2640
gccactggca gcagccactg gtaacaggat tagcagagcg aggtatgtag gcggtgctac 2700
agagttcttg aagtggtggc ctaactacgg ctacactaga aggacagtat ttggtatctg 2760
cgctctgctg aagccagtta ccttcggaaa aagagttggt agctcttgat ccggcaaaca 2820
aaccaccgct ggtagcggtg gtttttttgt ttgcaagcag cagattacgc gcagaaaaaa 2880
aggatctcaa gaagatcctt tgatcttttc tacggggtct gacgctcagt ggaacgaaaa 2940
ctcacgttaa gggattttgg tcatgagatt atcaaaaagg atcttcacct agatcctttt 3000
aaattaaaaa tgaagtttta aatcaatcta aagtatatat gagtaaactt ggtctgacag 3060
ttaccaatgc ttaatcagtg aggcacctat ctcagcgatc tgtctatttc gttcatccat 3120
agttgcctga ctccccgtcg tgtagataac tacgatacgg gagggcttac catctggccc 3180
cagtgctgca atgataccgc gagacccacg ctcaccggct ccagatttat cagcaataaa 3240
ccagccagcc ggaagggccg agcgcagaag tggtcctgca actttatccg cctccatcca 3300
gtctattaat tgttgccggg aagctagagt aagtagttcg ccagttaata gtttgcgcaa 3360
cgttgttgcc attgctgcag gcatcgtggt gtcacgctcg tcgtttggta tggcttcatt 3420
cagctccggt tcccaacgat caaggcgagt tacatgatcc cccatgttgt gcaaaaaagc 3480
ggttagctcc ttcggtcctc cgatcgttgt cagaagtaag ttggccgcag tgttatcact 3540
catggttatg gcagcactgc ataattctct tactgtcatg ccatccgtaa gatgcttttc 3600
tgtgactggt gagtactcaa ccaagtcatt ctgagaatag tgtatgcggc gaccgagttg 3660
ctcttgcccg gcgtcaacac gggataatac cgcgccacat agcagaactt taaaagtgct 3720
catcattgga aaacgttctt cggggcgaaa actctcaagg atcttaccgc tgttgagatc 3780
cagttcgatg taacccactc gtgcacccaa ctgatcttca gcatctttta ctttcaccag 3840
cgtttctggg tgagcaaaaa caggaaggca aaatgccgca aaaaagggaa taagggcgac 3900
acggaaatgt tgaatactca tactcttcct ttttcaatat tattgaagca tttatcaggg 3960
ttattgtctc atgagcggat acatatttga atgtatttag aaaaataaac aaataggggt 4020
tccgcgcaca tttccccgaa aagtgccacc tgacgtctaa gaaaccatta ttatcatgac 4080
attaacctat aaaaataggc gtatcacgag gccctttcgt cttcgaataa atacctgtga 4140
cggaagatca cttcgcagaa taaataaatc ctggtgtccc tgttgatacc gggaagccct 4200
gggccaactt ttggcgaaaa tgagacgttg atcggcacgt aagaggttcc aactttcacc 4260
ataatgaaat aagatcacta ccgggcgtat tttttgagtt atcgagattt tcaggagcta 4320
aggaagctaa aatggagaaa aaaatcactg gatataccac cgttgatata tcccaatggc 4380
atcgtaaaga acattttgag gcatttcagt cagttgctca atgtacctat aaccagaccg 4440
ttcag 4445
<210> 5
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成
引物
<400> 5
atgggtatac agcacgaatt c 21
<210> 6
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成
引物
<400> 6
ttaatccatg gactcataat c 21

Claims (53)

1.一种工程化的改良安卡拉牛痘(MVA)病毒株，其包含C7L基因的破坏。
2.根据权利要求1所述的工程化的MVA病毒株，其中所述经破坏的C7L基因不编码全长野生型基因产物。
3.根据权利要求1所述的工程化的MVA病毒株，其中所述经破坏的C7L基因包含异源核酸序列到C7L基因的编码序列的插入。
4.根据权利要求1所述的工程化的MVA病毒株，其中所述经破坏的C7L基因包含一个或多个基因盒的插入。
5.根据权利要求1所述的工程化的MVA毒株，其中所述经破坏的C7L基因包含一个或多个基因盒对至少一部分基因的替换。
6.根据权利要求1所述的工程化的MVA病毒，其中所述经破坏的C7L基因包含一个或多个基因盒对整个C7L基因的替换。
7.根据权利要求4所述的工程化的MVA毒株，其中所述一个或多个基因盒包含编码人Fms样酪氨酸激酶3配体(hFlt3L)的核苷酸序列。
8.根据权利要求4所述的工程化的MVA毒株，其中所述一个或多个基因盒包含编码可选择标记的核苷酸序列。
9.根据权利要求1所述的工程化的MVA毒株，其中所述MVA毒株展现出以下特征中的一种或多种：
与感染相应的野生型毒株的树突细胞和THP-1细胞相比，诱导树突细胞和THP-1细胞中干扰素β(IFNB)表达水平升高；
与感染相应的野生型毒株的树突细胞相比，诱导树突细胞中TBK1和IRF3磷酸化水平升高；
与感染相应的野生型毒株的树突细胞相比，诱导树突细胞中ISG表达水平升高；
与感染相应的野生型毒株的癌细胞相比，诱导癌细胞中IFNB、CCL4、CCL5、CXCL10中的至少一种水平升高；以及
与感染相应的野生型毒株的肿瘤相比，减小与所述工程化的MVA毒株接触的肿瘤的肿瘤体积。
10.根据权利要求9所述的工程化的MVA毒株，其中所述癌细胞包含黑素瘤细胞。
11.根据权利要求9所述的工程化的MVA毒株，其中所述肿瘤包含恶性黑素瘤。
12.一种免疫原性组合物，其包含根据权利要求1所述的工程化的改良安卡拉牛痘(MVA)病毒株。
13.根据权利要求12所述的免疫原性组合物，其还包含药学上可接受的载体。
14.根据权利要求12所述的免疫原性组合物，其还包含药学上可接受的佐剂。
15.一种工程化的减毒牛痘病毒(VACV)株，其包含C7L基因的破坏。
16.根据权利要求15所述的工程化的减毒VACV毒株，其中所述经破坏的C7L基因不编码全长野生型基因产物。
17.根据权利要求15所述的工程化的减毒VACV毒株，其中所述经破坏的C7L基因包含异源核酸序列到C7L基因的编码序列的插入。
18.根据权利要求15所述的工程化的减毒VACV毒株，其中所述经破坏的C7L基因包含一个或多个基因盒的插入。
19.根据权利要求15所述的工程化的减毒VACV毒株，其中所述经破坏的C7L基因包含一个或多个基因盒对至少一部分基因的替换。
20.根据权利要求19所述的工程化的减毒VACV毒株，其中所述一个或多个基因盒包含编码人Fms样酪氨酸激酶3配体(hFlt3L)的核苷酸序列。
21.根据权利要求19所述的工程化的减毒VACV毒株，其中所述一个或多个基因盒包含编码可选择标记的核苷酸序列。
22.根据权利要求15所述的工程化的减毒VACV毒株，其中与感染相应的野生型毒株的小鼠相比，感染所述工程化的VACV毒株的小鼠具有增加的感染后寿命。
23.一种免疫原性组合物，其包含根据权利要求15所述的工程化的牛痘病毒(VACV)株。
24.根据权利要求23所述的免疫原性组合物，其还包含药学上可接受的载体。
25.根据权利要求23所述的免疫原性组合物，其还包含药学上可接受的佐剂。
26.一种重组牛痘病毒(VACV)核酸序列，其中在SEQ ID NO:1的位置15,716和16,168之间的核酸序列被包含编码可选择标记的开放阅读框的异源核酸序列替换。
27.根据权利要求26所述的重组VACV核酸序列，其中所述异源核酸序列的开放阅读框与能够指导所述可选择标记表达的启动子可操作地连接。
28.根据权利要求26所述的重组VACV核酸序列，其中所述可选择标记是生物发光蛋白、荧光蛋白、化学发光蛋白、黄嘌呤-鸟嘌呤磷酸核糖基转移酶基因(gpt)或其任何组合。
29.根据权利要求26所述的重组VACV核酸序列，其中所述可选择标记是绿色荧光蛋白(GFP)。
30.根据权利要求26所述的重组VACV核酸序列，其中所述异源核酸序列还包含编码人Fms样酪氨酸激酶3配体(hFlt3L)的开放阅读框。
31.一种重组改良安卡拉牛痘(MVA)病毒核酸序列，其中在SEQ ID NO:2的位置18,407和18,859之间的核酸序列被包含编码可选择标记的开放阅读框的异源核酸序列替换。
32.根据权利要求31所述的重组MVA核酸序列，其中所述异源核酸序列的开放阅读框与能够指导所述可选择标记表达的启动子可操作地连接。
33.根据权利要求31所述的重组牛痘病毒核酸序列，其中所述可选择标记是生物发光蛋白、荧光蛋白、化学发光蛋白、黄嘌呤-鸟嘌呤磷酸核糖基转移酶基因(gpt)或其任何组合。
34.根据权利要求31所述的重组牛痘病毒核酸序列，其中所述可选择标记是绿色荧光蛋白(GFP)。
35.根据权利要求31所述的重组牛痘病毒核酸序列，其中所述异源核酸序列还包含编码人Fms样酪氨酸激酶3配体(hFlt3L)的开放阅读框。
36.一种用于治疗有需要的受试者的实体瘤的方法，所述方法包括将包含有效量的包含C7L基因的破坏的工程化的改良安卡拉牛痘(MVA)病毒株(MVAΔC7L)和/或基因工程化以表达hFlt3L的MVAΔC7L病毒(MVAΔC7L-hFlt3L)的组合物递送至肿瘤。
37.根据权利要求36所述的方法，其中所述破坏包含C7L基因的缺失。
38.根据权利要求36所述的方法，其中治疗包含以下中的一种或多种：在所述受试者体内诱导针对所述肿瘤的免疫应答或者在所述受试者体内增强或促进针对所述肿瘤的正在进行的免疫应答、减小所述肿瘤的大小、根除所述肿瘤、抑制所述肿瘤的生长、抑制所述肿瘤的转移性生长、诱导肿瘤细胞的凋亡或延长所述受试者的存活期。
39.根据权利要求36所述的方法，其中所述免疫应答的诱导、增强或促进包含以下中的一种或多种：
与感染相应的野生型毒株的树突细胞和THP-1细胞相比，树突细胞和THP-1细胞中干扰素β(IFNB)表达的水平升高；
与感染相应的野生型毒株的树突细胞相比，树突细胞中TBK1和IRF3磷酸化的水平升高；
与感染相应的野生型毒株的树突细胞相比，树突细胞中ISG表达的水平升高；以及
与感染相应的野生型毒株的肿瘤细胞相比，肿瘤细胞中IFNB、CCL4、CCL5和CXCL10中的至少一种的水平升高。
40.根据权利要求36所述的方法，其中所述组合物通过瘤内或静脉内注射或者瘤内和静脉内注射的同时或顺序组合来给予。
41.根据权利要求36所述的方法，其中所述肿瘤是黑素瘤、结肠癌、乳腺癌或前列腺癌。
42.根据权利要求36所述的方法，其中所述组合物还包含一种或多种免疫检查点阻断剂。
43.根据权利要求42所述的方法，其中所述免疫检查点阻断剂选自：CTLA-4、CD80、CD86、PD-1、PDL1、PDL2、LAG3、B7-H3、B7-H4、TIM3、ICOS、IIDLBCL抑制剂、BTLA、伊匹单抗、纳武单抗、派姆单抗、皮地利珠单抗、AMP-224、MPDL3280A、BMS-936559、MED14736、MSB00107180及其任何组合。
44.一种用于治疗有需要的受试者的实体瘤的方法，所述方法包括将包含有效量的包含C7L基因的破坏的工程化的减毒牛痘病毒(VACV)株(VACVΔC7L)、基因工程化以表达hFlt3L的VACVΔC7L病毒(VACVΔC7L-hFlt3L)或其组合的组合物递送至肿瘤。
45.根据权利要求44所述的方法，其中所述破坏包含C7L基因的缺失。
46.根据权利要求44所述的方法，其中治疗包含以下中的一种或多种：在所述受试者体内诱导针对所述肿瘤的免疫应答或者在所述受试者体内增强或促进针对所述肿瘤的正在进行的免疫应答、减小所述肿瘤的大小、根除所述肿瘤、抑制所述肿瘤的生长、抑制所述肿瘤的转移性生长、诱导肿瘤细胞的凋亡或延长所述受试者的存活期。
47.根据权利要求44所述的方法，其中所述免疫应答的诱导、增强或促进包含以下中的一种或多种：
与感染相应的野生型毒株的树突细胞和THP-1细胞相比，树突细胞和THP-1细胞中干扰素β(IFNB)表达的水平升高；
与感染相应的野生型毒株的树突细胞相比，树突细胞中TBK1和IRF3磷酸化的水平升高；
与感染相应的野生型毒株的树突细胞相比，树突细胞中ISG表达的水平升高；以及
与感染相应的野生型毒株的肿瘤细胞相比，肿瘤细胞中IFNB、CCL4、CCL5和CXCL10中的至少一种的水平升高。
48.根据权利要求44所述的方法，其中所述组合物通过瘤内或静脉内注射或者瘤内和静脉内注射的同时或顺序组合来给予。
49.根据权利要求44所述的方法，其中所述肿瘤是黑素瘤、结肠癌、乳腺癌或前列腺癌。
50.根据权利要求44所述的方法，其中所述组合物还包含一种或多种免疫检查点阻断剂。
51.根据权利要求50所述的方法，其中所述免疫检查点阻断剂选自：CTLA-4、CD80、CD86、PD-1、PDL1、PDL2、LAG3、B7-H3、B7-H4、TIM3、ICOS、IIDLBCL抑制剂、BTLA、伊匹单抗、纳武单抗、派姆单抗、皮地利珠单抗、AMP-224、MPDL3280A、BMS-936559、MED14736、MSB00107180及其任何组合。
52.一种刺激免疫应答的方法，其包括：
向受试者给予根据权利要求12所述的免疫原性组合物。
53.一种刺激免疫应答的方法，其包括：
向受试者给予根据权利要求23所述的免疫原性组合物。
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