fa688f7500fcd78a0b223e6a4571580a 277670.pdf 171a82b20398d8e21d9bfbb023e75c11f605058d 277670.pdf 30cc2f063fa7e4c4c806d6f3eb77ffc73e4e48882fd2d68cc2c35a50277cb53d 277670.pdf Title: Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome Subject: We aimed to analyze the role of the common genetic variants located in the PIN1 locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood–testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three PIN1 taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1058 controls from the Iberian Peninsula. The allelic frequency differences between cases and controls were analyzed by the means of logistic regression models. A subtype specific genetic association with the subset of NOA patients classified as suffering from the Sertoli cell-only (SCO) syndrome was observed with the minor alleles showing strong risk effects for this subset (ORaddrs2287839 = 1.85 (1.17–2.93), ORaddrs2233678 = 1.62 (1.11–2.36), ORaddrs62105751 = 1.43 (1.06–1.93)). The causal variants were predicted to affect the binding of key transcription factors and to produce an altered PIN1 gene expression and isoform balance. In conclusion, common non-coding single-nucleotide polymorphisms located in PIN1 increase the genetic risk to develop SCO. Keywords: severe spermatogenic failure; male infertility; PIN1; single-nucleotide polymorphism; Sertoli cell-only syndrome Author: Miriam Cerván-Martín, Lara Bossini-Castillo, Andrea Guzmán-Jimenez, Rocío Rivera-Egea, Nicolás Garrido, Saturnino Luján, Gema Romeu, Samuel Santos-Ribeiro, IVIRMA Group, Lisbon Clinical Group, José A. Castilla, M. Carmen Gonzalvo, Ana Clavero, F. Javier Vicente, Vicente Maldonado, Sara González-Muñoz, Inmaculada Rodríguez-Martín, Miguel Burgos, Rafael Jiménez, Maria Graça Pinto, Isabel Pereira, Joaquim Nunes, Josvany Sánchez-Curbelo, Olga López-Rodrigo, Iris Pereira-Caetano, Patricia Isabel Marques, Filipa Carvalho, Alberto Barros, Lluís Bassas, Susana Seixas, João Gonçalves, Sara Larriba, Alexandra M. Lopes, F. David Carmona and Rogelio J. Palomino-Morales Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Jun 13 11:05:07 2022 CEST ModDate: Mon Jun 13 11:12:58 2022 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2805933 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- YVDGZO+VnURWPalladioL Type 1 Custom yes yes no 10 0 IRUZXG+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 RREVLM+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 HUQVWV+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 OJYKSJ+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 UIJACC+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 46 0 BSDWLC+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 49 0 JNDUFU+CMSY10 Type 1 Builtin yes yes no 74 0 WBVKDJ+URWPalladioL-BoldItal Type 1 Custom yes yes no 98 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-07-15 02:43:06 CEST RepresentationInformation: 277670.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-07-14 12:15:10 CEST Size: 2805933 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 362 FreeObjects: 5 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Patients and Clinical Definition Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: SNP Selection and Genotyping Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Statistical Analyses Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: In Silico SNP Functional Characterization Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Children: Item: Title: Testing for Association with Idiopathic Spermatogenic Failure Overall Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: PIN1 Polymorphisms Have a Subtype-Specific Effect in SCO Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: In Silico Data from the GTEx Repository Suggest That the Genetic Variants in the PIN1 Locus Have Regulatory Functions on Gene and Isoform Expression Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Info: Title: Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome Author: Miriam Cerván-Martín, Lara Bossini-Castillo, Andrea Guzmán-Jimenez, Rocío Rivera-Egea, Nicolás Garrido, Saturnino Luján, Gema Romeu, Samuel Santos-Ribeiro, IVIRMA Group, Lisbon Clinical Group, José A. Castilla, M. Carmen Gonzalvo, Ana Clavero, F. Javier Vicente, Vicente Maldonado, Sara González-Muñoz, Inmaculada Rodríguez-Martín, Miguel Burgos, Rafael Jiménez, Maria Graça Pinto, Isabel Pereira, Joaquim Nunes, Josvany Sánchez-Curbelo, Olga López-Rodrigo, Iris Pereira-Caetano, Patricia Isabel Marques, Filipa Carvalho, Alberto Barros, Lluís Bassas, Susana Seixas, João Gonçalves, Sara Larriba, Alexandra M. Lopes, F. David Carmona and Rogelio J. Palomino-Morales Subject: We aimed to analyze the role of the common genetic variants located in the PIN1 locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three PIN1 taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1058 controls from the Iberian Peninsula. The allelic frequency differences between cases and controls were analyzed by the means of logistic regression models. A subtype specific genetic association with the subset of NOA patients classified as suffering from the Sertoli cell-only (SCO) syndrome was observed with the minor alleles showing strong risk effects for this subset (ORaddrs2287839 = 1.85 (1.17 2.93), ORaddrs2233678 = 1.62 (1.11 2.36), ORaddrs62105751 = 1.43 (1.06 1.93)). The causal variants were predicted to affect the binding of key transcription factors and to produce an altered PIN1 gene expression and isoform balance. In conclusion, common non-coding single-nucleotide polymorphisms located in PIN1 increase the genetic risk to develop SCO. Keywords: severe spermatogenic failure; male infertility; PIN1; single-nucleotide polymorphism; Sertoli cell-only syndrome Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Jun 13 11:05:07 CEST 2022 ModDate: Mon Jun 13 11:12:58 CEST 2022 ID: 0x8d9da7fb513222e66f871c23e43e50c2, 0x8d9da7fb513222e66f871c23e43e50c2 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: WBVKDJ+URWPalladioL-BoldItal FontSubset: true FirstChar: 112 LastChar: 112 FontDescriptor: FontName: WBVKDJ+URWPalladioL-BoldItal Flags: Symbolic FontBBox: -170, -300, 1073, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: RREVLM+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: RREVLM+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: HUQVWV+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 122 FontDescriptor: FontName: HUQVWV+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: YVDGZO+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 243 FontDescriptor: FontName: YVDGZO+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: JNDUFU+CMSY10 FontSubset: true FirstChar: 0 LastChar: 48 FontDescriptor: FontName: JNDUFU+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: OJYKSJ+VnURWPalladioL-Bold FontSubset: true FirstChar: 161 LastChar: 226 FontDescriptor: FontName: OJYKSJ+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: IRUZXG+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 241 FontDescriptor: FontName: IRUZXG+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 111, 323, 152, 332 Annotation: Subtype: Link Rect: 34, 311, 129, 320 Annotation: Subtype: Link Rect: 34, 164, 96, 186 Annotation: Subtype: Link Rect: 126, 90, 154, 99 Annotation: Subtype: Link Rect: 34, 78, 147, 87 Annotation: Subtype: Link Rect: 34, 756, 176, 792 Annotation: Subtype: Link Rect: 515, 756, 560, 792 Annotation: Subtype: Link Rect: 286, 660, 297, 674 Annotation: Subtype: Link Rect: 207, 648, 218, 661 Annotation: Subtype: Link Rect: 290, 648, 301, 661 Annotation: Subtype: Link Rect: 238, 635, 249, 649 Annotation: Subtype: Link Rect: 408, 623, 419, 636 Annotation: Subtype: Link Rect: 497, 623, 508, 636 Annotation: Subtype: Link Rect: 110, 610, 121, 624 Annotation: Subtype: Link Rect: 295, 610, 306, 624 Annotation: Subtype: Link Rect: 523, 610, 534, 624 Annotation: Subtype: Link Rect: 283, 585, 294, 599 Annotation: Subtype: Link Rect: 459, 585, 470, 599 Annotation: Subtype: Link Rect: 253, 572, 264, 586 Annotation: Subtype: Link Rect: 439, 572, 450, 586 Annotation: Subtype: Link Rect: 126, 17, 264, 28 Annotation: Subtype: Link Rect: 423, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 444, 87, 463 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 196, 425, 202, 434 ActionDest: 126 Annotation: Subtype: Link Rect: 203, 425, 210, 434 ActionDest: 126 Annotation: Subtype: Link Rect: 309, 413, 316, 422 ActionDest: 126 Annotation: Subtype: Link Rect: 364, 375, 371, 384 ActionDest: 126 Annotation: Subtype: Link Rect: 371, 375, 378, 384 ActionDest: 126 Annotation: Subtype: Link Rect: 384, 350, 391, 359 ActionDest: 126 Annotation: Subtype: Link Rect: 392, 350, 398, 359 ActionDest: 126 Annotation: Subtype: Link Rect: 327, 325, 334, 334 ActionDest: 126 Annotation: Subtype: Link Rect: 437, 300, 444, 309 ActionDest: 126 Annotation: Subtype: Link Rect: 526, 275, 533, 284 ActionDest: 126 Annotation: Subtype: Link Rect: 422, 250, 429, 258 ActionDest: 126 Annotation: Subtype: Link Rect: 269, 212, 275, 221 ActionDest: 126 Annotation: Subtype: Link Rect: 489, 174, 496, 183 ActionDest: 126 Annotation: Subtype: Link Rect: 549, 149, 556, 158 ActionDest: 126 Annotation: Subtype: Link Rect: 479, 136, 486, 146 ActionDest: 126 Annotation: Subtype: Link Rect: 323, 111, 330, 120 ActionDest: 126 Annotation: Subtype: Link Rect: 237, 74, 244, 83 ActionDest: 126 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 549, 735, 556, 744 ActionDest: 126 Annotation: Subtype: Link Rect: 243, 710, 250, 719 ActionDest: 126 Annotation: Subtype: Link Rect: 251, 710, 258, 719 ActionDest: 126 Annotation: Subtype: Link Rect: 272, 685, 279, 694 ActionDest: 126 Annotation: Subtype: Link Rect: 280, 685, 287, 694 ActionDest: 126 Annotation: Subtype: Link Rect: 350, 660, 357, 669 ActionDest: 126 Annotation: Subtype: Link Rect: 358, 660, 365, 669 ActionDest: 126 Annotation: Subtype: Link Rect: 289, 635, 296, 644 ActionDest: 126 Annotation: Subtype: Link Rect: 350, 610, 357, 619 ActionDest: 126 Annotation: Subtype: Link Rect: 425, 560, 437, 569 ActionDest: 126 Annotation: Subtype: Link Rect: 222, 509, 234, 519 ActionDest: 126 Annotation: Subtype: Link Rect: 235, 510, 247, 519 ActionDest: 126 Annotation: Subtype: Link Rect: 242, 484, 254, 493 ActionDest: 126 Annotation: Subtype: Link Rect: 313, 472, 325, 481 ActionDest: 126 Annotation: Subtype: Link Rect: 278, 459, 290, 468 ActionDest: 126 Annotation: Subtype: Link Rect: 418, 422, 430, 431 ActionDest: 126 Annotation: Subtype: Link Rect: 216, 295, 228, 304 ActionDest: 126 Annotation: Subtype: Link Rect: 228, 295, 240, 304 ActionDest: 126 Annotation: Subtype: Link Rect: 231, 232, 243, 241 ActionDest: 126 Annotation: Subtype: Link Rect: 525, 107, 537, 116 ActionDest: 126 Annotation: Subtype: Link Rect: 254, 81, 266, 91 ActionDest: 126 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 360, 647, 372, 657 ActionDest: 126 Annotation: Subtype: Link Rect: 372, 647, 384, 657 ActionDest: 126 Annotation: Subtype: Link Rect: 548, 607, 555, 619 ActionDest: 81 Annotation: Subtype: Link Rect: 314, 584, 326, 594 ActionDest: 126 Annotation: Subtype: Link Rect: 377, 532, 559, 544 Annotation: Subtype: Link Rect: 284, 522, 296, 531 ActionDest: 126 Annotation: Subtype: Link Rect: 333, 519, 340, 531 ActionDest: 81 Annotation: Subtype: Link Rect: 407, 469, 413, 481 ActionDest: 81 Annotation: Subtype: Link Rect: 427, 447, 439, 455 ActionDest: 126 Annotation: Subtype: Link Rect: 258, 419, 460, 431 Annotation: Subtype: Link Rect: 195, 409, 207, 418 ActionDest: 126 Annotation: Subtype: Link Rect: 438, 321, 450, 330 ActionDest: 126 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 448, 202, 560, 214 Annotation: Subtype: Link Rect: 165, 190, 196, 202 Annotation: Subtype: Link Rect: 293, 79, 305, 88 ActionDest: 126 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 281, 720, 505, 732 Annotation: Subtype: Link Rect: 225, 710, 237, 719 ActionDest: 126 Annotation: Subtype: Link Rect: 492, 585, 504, 594 ActionDest: 126 Annotation: Subtype: Link Rect: 251, 481, 440, 493 Annotation: Subtype: Link Rect: 194, 471, 205, 481 ActionDest: 126 Annotation: Subtype: Link Rect: 203, 419, 339, 431 Annotation: Subtype: Link Rect: 469, 421, 481, 430 ActionDest: 126 Annotation: Subtype: Link Rect: 490, 396, 502, 405 ActionDest: 126 Annotation: Subtype: Link Rect: 421, 306, 558, 318 Annotation: Subtype: Link Rect: 289, 296, 301, 305 ActionDest: 126 Annotation: Subtype: Link Rect: 359, 293, 560, 305 Annotation: Subtype: Link Rect: 165, 281, 274, 293 Annotation: Subtype: Link Rect: 395, 283, 407, 292 ActionDest: 126 Annotation: Subtype: Link Rect: 485, 281, 560, 293 Annotation: Subtype: Link Rect: 165, 268, 228, 280 Annotation: Subtype: Link Rect: 354, 271, 366, 280 ActionDest: 126 Annotation: Subtype: Link Rect: 544, 233, 556, 242 ActionDest: 126 Annotation: Subtype: Link Rect: 165, 180, 291, 192 Annotation: Subtype: Link Rect: 411, 183, 423, 192 ActionDest: 126 Annotation: Subtype: Link Rect: 423, 183, 435, 192 ActionDest: 126 Annotation: Subtype: Link Rect: 532, 120, 544, 129 ActionDest: 126 Annotation: Subtype: Link Rect: 544, 120, 556, 129 ActionDest: 126 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 480, 705, 487, 717 ActionDest: 95 Annotation: Subtype: Link Rect: 516, 263, 523, 276 ActionDest: 95 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 273, 619, 280, 631 ActionDest: 95 Annotation: Subtype: Link Rect: 410, 569, 417, 581 ActionDest: 95 Annotation: Subtype: Link Rect: 505, 532, 512, 544 ActionDest: 95 Annotation: Subtype: Link Rect: 255, 507, 262, 519 ActionDest: 95 Annotation: Subtype: Link Rect: 530, 318, 537, 330 ActionDest: 81 Annotation: Subtype: Link Rect: 283, 119, 290, 131 ActionDest: 81 Annotation: Subtype: Link Rect: 243, 82, 250, 94 ActionDest: 105 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 229, 723, 241, 732 ActionDest: 126 Annotation: Subtype: Link Rect: 209, 708, 358, 720 Annotation: Subtype: Link Rect: 502, 710, 514, 719 ActionDest: 126 Annotation: Subtype: Link Rect: 511, 295, 518, 307 ActionDest: 105 Annotation: Subtype: Link Rect: 392, 283, 399, 295 ActionDest: 105 Annotation: Subtype: Link Rect: 333, 135, 345, 144 ActionDest: 129 Annotation: Subtype: Link Rect: 403, 135, 415, 144 ActionDest: 129 Annotation: Subtype: Link Rect: 334, 59, 346, 69 ActionDest: 129 Annotation: Subtype: Link Rect: 346, 59, 358, 69 ActionDest: 129 Annotation: Subtype: Link Rect: 426, 59, 438, 69 ActionDest: 129 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 382, 695, 393, 704 ActionDest: 126 Annotation: Subtype: Link Rect: 531, 670, 543, 679 ActionDest: 129 Annotation: Subtype: Link Rect: 544, 670, 556, 679 ActionDest: 129 Annotation: Subtype: Link Rect: 243, 632, 255, 641 ActionDest: 126 Annotation: Subtype: Link Rect: 371, 579, 379, 591 ActionDest: 81 Annotation: Subtype: Link Rect: 549, 517, 556, 528 ActionDest: 95 Annotation: Subtype: Link Rect: 448, 481, 460, 490 ActionDest: 129 Annotation: Subtype: Link Rect: 521, 456, 533, 465 ActionDest: 129 Annotation: Subtype: Link Rect: 376, 115, 383, 127 ActionDest: 105 Annotation: Subtype: Link Rect: 345, 92, 357, 101 ActionDest: 129 Annotation: Subtype: Link Rect: 544, 92, 556, 101 ActionDest: 129 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 482, 660, 494, 669 ActionDest: 129 Annotation: Subtype: Link Rect: 310, 610, 322, 619 ActionDest: 129 Annotation: Subtype: Link Rect: 228, 560, 240, 569 ActionDest: 129 Annotation: Subtype: Link Rect: 223, 497, 235, 506 ActionDest: 129 Annotation: Subtype: Link Rect: 462, 497, 474, 506 ActionDest: 129 Annotation: Subtype: Link Rect: 548, 484, 555, 493 ActionDest: 126 Annotation: Subtype: Link Rect: 364, 472, 371, 481 ActionDest: 126 Annotation: Subtype: Link Rect: 458, 459, 465, 468 ActionDest: 126 Annotation: Subtype: Link Rect: 517, 447, 529, 456 ActionDest: 129 Annotation: Subtype: Link Rect: 544, 434, 556, 443 ActionDest: 129 Annotation: Subtype: Link Rect: 226, 384, 238, 393 ActionDest: 129 Annotation: Subtype: Link Rect: 485, 283, 497, 292 ActionDest: 129 Annotation: Subtype: Link Rect: 498, 283, 510, 292 ActionDest: 129 Annotation: Subtype: Link Rect: 396, 208, 408, 217 ActionDest: 126 Annotation: Subtype: Link Rect: 536, 182, 560, 193 Annotation: Subtype: Link Rect: 165, 170, 378, 181 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 208, 675, 219, 684 ActionDest: 126 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 59, 708, 96, 718 Annotation: Subtype: Link Rect: 102, 708, 138, 718 Annotation: Subtype: Link Rect: 407, 696, 444, 707 Annotation: Subtype: Link Rect: 450, 696, 486, 707 Annotation: Subtype: Link Rect: 150, 673, 188, 684 Annotation: Subtype: Link Rect: 194, 673, 230, 684 Annotation: Subtype: Link Rect: 122, 650, 159, 661 Annotation: Subtype: Link Rect: 166, 650, 202, 661 Annotation: Subtype: Link Rect: 421, 638, 458, 649 Annotation: Subtype: Link Rect: 400, 615, 438, 626 Annotation: Subtype: Link Rect: 519, 603, 557, 614 Annotation: Subtype: Link Rect: 59, 593, 95, 603 Annotation: Subtype: Link Rect: 516, 569, 554, 580 Annotation: Subtype: Link Rect: 253, 546, 290, 557 Annotation: Subtype: Link Rect: 109, 524, 146, 534 Annotation: Subtype: Link Rect: 520, 500, 557, 511 Annotation: Subtype: Link Rect: 59, 489, 95, 499 Annotation: Subtype: Link Rect: 423, 477, 461, 488 Annotation: Subtype: Link Rect: 467, 477, 503, 488 Annotation: Subtype: Link Rect: 306, 454, 344, 465 Annotation: Subtype: Link Rect: 350, 454, 386, 465 Annotation: Subtype: Link Rect: 59, 420, 96, 430 Annotation: Subtype: Link Rect: 430, 396, 468, 407 Annotation: Subtype: Link Rect: 182, 351, 219, 361 Annotation: Subtype: Link Rect: 174, 305, 212, 315 Annotation: Subtype: Link Rect: 389, 281, 426, 292 Annotation: Subtype: Link Rect: 520, 270, 557, 281 Annotation: Subtype: Link Rect: 59, 259, 95, 269 Annotation: Subtype: Link Rect: 59, 236, 96, 246 Annotation: Subtype: Link Rect: 102, 236, 138, 246 Annotation: Subtype: Link Rect: 192, 213, 230, 223 Annotation: Subtype: Link Rect: 250, 189, 288, 200 Annotation: Subtype: Link Rect: 294, 189, 330, 200 Annotation: Subtype: Link Rect: 448, 178, 486, 189 Annotation: Subtype: Link Rect: 492, 178, 528, 189 Annotation: Subtype: Link Rect: 350, 155, 387, 166 Annotation: Subtype: Link Rect: 394, 155, 430, 166 Annotation: Subtype: Link Rect: 475, 132, 513, 143 Annotation: Subtype: Link Rect: 356, 109, 393, 120 Annotation: Subtype: Link Rect: 264, 86, 302, 97 Annotation: Subtype: Link Rect: 493, 63, 531, 74 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 401, 722, 439, 733 Annotation: Subtype: Link Rect: 445, 722, 481, 733 Annotation: Subtype: Link Rect: 418, 699, 455, 710 Annotation: Subtype: Link Rect: 461, 699, 497, 710 Annotation: Subtype: Link Rect: 59, 665, 96, 675 Annotation: Subtype: Link Rect: 102, 665, 138, 675 Annotation: Subtype: Link Rect: 155, 642, 192, 652 Annotation: Subtype: Link Rect: 193, 619, 231, 629 Annotation: Subtype: Link Rect: 237, 619, 273, 629 Annotation: Subtype: Link Rect: 297, 595, 335, 606 Annotation: Subtype: Link Rect: 113, 561, 151, 571 Annotation: Subtype: Link Rect: 188, 537, 225, 548 Annotation: Subtype: Link Rect: 59, 515, 96, 525 Annotation: Subtype: Link Rect: 415, 491, 452, 502 Annotation: Subtype: Link Rect: 108, 469, 146, 479 Annotation: Subtype: Link Rect: 152, 469, 188, 479 Annotation: Subtype: Link Rect: 144, 446, 182, 456 Annotation: Subtype: Link Rect: 188, 446, 224, 456 Annotation: Subtype: Link Rect: 117, 412, 155, 422 Annotation: Subtype: Link Rect: 161, 412, 197, 422 Annotation: Subtype: Link Rect: 126, 377, 164, 387 Annotation: Subtype: Link Rect: 170, 377, 206, 387 Annotation: Subtype: Link Rect: 263, 353, 301, 364 Annotation: Subtype: Link Rect: 307, 353, 343, 364 Annotation: Subtype: Link Rect: 263, 330, 300, 341 Annotation: Subtype: Link Rect: 306, 330, 342, 341 Checksum: 071fb274 Type: CRC32 Checksum: fa688f7500fcd78a0b223e6a4571580a Type: MD5 Checksum: 171a82b20398d8e21d9bfbb023e75c11f605058d Type: SHA-1