b2012f92a8c0fb8416196fbeb8f7a809 cancers-18-01695-v3.pdf 59e7fbaf49fae589a023a054f0a57ea5f56d946b cancers-18-01695-v3.pdf 5f6c1bfdf7a2867fc35274372d2624b13208b7e986a9a011f24aee9e03bb8be8 cancers-18-01695-v3.pdf Title: Long-Term Risk of Residual or Recurrent CIN 2–3 After LLETZ in Immunosuppressed vs. Immunocompetent Women: A 20-Year Cohort Study Subject: Background: Immunosuppressed women are at increased risk of residual or recurrent high-grade cervical intraepithelial neoplasia (CIN 2–3) after excisional treatment, yet long-term comparative data remain limited. Previous studies are often small and heterogeneous, and they rarely compare outcomes directly with immunocompetent populations. This study evaluated the long-term incidence, timing and associated factors of CIN 2–3 recurrence after large loop excision of the transformation zone (LLETZ), stratified by immune status. Methods: We conducted a retrospective cohort study including 283 women treated with LLETZ for CIN 2–3 between 1996 and 2016 at Bellvitge University Hospital in Barcelona, Spain. Of these, 41 were immunosuppressed and 242 immunocompetent. Clinical, histopathological, virological, and immunological variables were extracted from hospital and pathology registries. Kaplan–Meier estimates and Cox proportional hazards models adjusted for immunosuppression status were used to evaluate time-to-recurrence and factors associated with recurrence. Results: At 36 months post-treatment, the probability of residual/recurrent CIN 2–3 was 44% in immunosuppressed women versus 5% in immunocompetent women (HR = 10.42, 95% CI 4.70–23.08, p < 0.001). Recurrence appeared earlier in immunosuppressed women (median 7 vs. 13 months). Persistent high-risk HPV infection at first follow-up (HR = 23.6, 95% CI 5.44–102, p < 0.001) and positive surgical margins (HR = 3.88, 95% CI 1.45–10.3, p = 0.007) were among the factors most strongly associated with recurrence, and advanced immunodeficiency (CD4+ < 200 cells/mm3 or detectable HIV viral load) was associated with earlier recurrences, though this association was not maintained after accounting for immunosuppression status in Cox models. Conclusions: Immunosuppressed women are at significantly higher and earlier risk of residual/recurrent CIN 2–3 after LLETZ. These findings support a risk-adapted, multidisciplinary follow-up integrating gynecologic, infectious disease, and immunologic care. Tailored surveillance and perioperative HPV vaccination may enhance secondary prevention in this high-risk population. Keywords: cervical intraepithelial neoplasia grade 2–3; immunosuppression; HIV; LLETZ; recurrence; associated factors; surgical margins; HPV persistence; long-term follow-up; immunovirological profile Author: Christian Leonardo Molina-Hinojosa, Ramón Carreras-Collado, María Saumoy-Linares, Judith Peñafiel, Fatima Heydari, Joan Climent Martí and María Eulalia Fernández-Montolí Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Mon Jun 1 11:04:03 2026 CEST ModDate: Mon Jun 1 11:10:18 2026 CEST Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 32 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3217335 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- SVSVJC+URWPalladioL-Ital Type 1 Custom yes yes yes 159 0 LRHRCY+VnURWPalladioL Type 1 Custom yes yes yes 160 0 DYNJQJ+URWPalladioL-Bold Type 1 Custom yes yes yes 161 0 OLIDPX+URWPalladioL-Roma Type 1 Custom yes yes yes 162 0 VBAQIR+CMSY10 Type 1 Builtin yes yes yes 304 0 JHYTSG+CMR10 Type 1 Builtin yes yes yes 327 0 WETGPF+PazoMath-Italic Type 1 Builtin yes yes yes 328 0 ZPGVCH+CMEX10 Type 1 Builtin yes yes yes 329 0 OVNEXW+EURM10 Type 1 Builtin yes yes yes 391 0 QLBIEB+URWPalladioL-BoldItal Type 1 Custom yes yes yes 405 0 OGBFMR+VnURWPalladioL-Italic Type 1 Custom yes yes yes 712 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-06-17 03:57:37 CEST RepresentationInformation: cancers-18-01695-v3.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-06-16 14:06:37 CEST Size: 3217335 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 1040 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Item: Title: Materials and Methods Children: Item: Title: Study Design and Setting Item: Title: Participants Item: Title: Objective Item: Title: Procedures and Data Collection Item: Title: Type of Excision, Specimen Measurements, and Volume Estimation Item: Title: Post-Treatment Follow-Up Item: Title: Outcomes Item: Title: Statistical Analysis Item: Title: Ethical Approval Item: Title: Results Children: Item: Title: Study Population Item: Title: Descriptive Statistics Children: Item: Title: Demographic and Immunological Data Item: Title: Surgical Specimen Findings Item: Title: HPV Detection and Viral Load Item: Title: Incidence and Timing of Residual or Recurrent CIN 2–3 Item: Title: Overview of Factors Evaluated for Recurrence Item: Title: Univariable Cox Regression in the Overall Cohort Item: Title: Cox Models Adjusted for Immunosuppression for Factors Associated with Residual/Recurrent CIN 2–3 Item: Title: Exploratory Analysis in Immunosuppressed Women Item: Title: Discussion Item: Title: Conclusions Item: Title: Appendix A Item: Title: Appendix B Item: Title: References Info: Title: Long-Term Risk of Residual or Recurrent CIN 2–3 After LLETZ in Immunosuppressed vs. Immunocompetent Women: A 20-Year Cohort Study Author: Christian Leonardo Molina-Hinojosa, Ramón Carreras-Collado, María Saumoy-Linares, Judith Peñafiel, Fatima Heydari, Joan Climent Martí and María Eulalia Fernández-Montolí Subject: Background: Immunosuppressed women are at increased risk of residual or recurrent high-grade cervical intraepithelial neoplasia (CIN 2–3) after excisional treatment, yet long-term comparative data remain limited. Previous studies are often small and heterogeneous, and they rarely compare outcomes directly with immunocompetent populations. This study evaluated the long-term incidence, timing and associated factors of CIN 2–3 recurrence after large loop excision of the transformation zone (LLETZ), stratified by immune status. Methods: We conducted a retrospective cohort study including 283 women treated with LLETZ for CIN 2–3 between 1996 and 2016 at Bellvitge University Hospital in Barcelona, Spain. Of these, 41 were immunosuppressed and 242 immunocompetent. Clinical, histopathological, virological, and immunological variables were extracted from hospital and pathology registries. Kaplan–Meier estimates and Cox proportional hazards models adjusted for immunosuppression status were used to evaluate time-to-recurrence and factors associated with recurrence. Results: At 36 months post-treatment, the probability of residual/recurrent CIN 2–3 was 44% in immunosuppressed women versus 5% in immunocompetent women (HR = 10.42, 95% CI 4.70–23.08, p < 0.001). Recurrence appeared earlier in immunosuppressed women (median 7 vs. 13 months). Persistent high-risk HPV infection at first follow-up (HR = 23.6, 95% CI 5.44–102, p < 0.001) and positive surgical margins (HR = 3.88, 95% CI 1.45–10.3, p = 0.007) were among the factors most strongly associated with recurrence, and advanced immunodeficiency (CD4+ < 200 cells/mm3 or detectable HIV viral load) was associated with earlier recurrences, though this association was not maintained after accounting for immunosuppression status in Cox models. Conclusions: Immunosuppressed women are at significantly higher and earlier risk of residual/recurrent CIN 2–3 after LLETZ. These findings support a risk-adapted, multidisciplinary follow-up integrating gynecologic, infectious disease, and immunologic care. Tailored surveillance and perioperative HPV vaccination may enhance secondary prevention in this high-risk population. Keywords: cervical intraepithelial neoplasia grade 2–3; immunosuppression; HIV; LLETZ; recurrence; associated factors; surgical margins; HPV persistence; long-term follow-up; immunovirological profile Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Mon Jun 01 11:04:03 CEST 2026 ModDate: Mon Jun 01 11:10:18 CEST 2026 ID: 0x26e801549a6a7ff30f90439a7e01df77, 0x5caeb68334440a569f4faf39f43d56d8 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: LRHRCY+VnURWPalladioL FontSubset: true FirstChar: 160 LastChar: 225 FontDescriptor: FontName: LRHRCY+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: VBAQIR+CMSY10 FontSubset: true FirstChar: 0 LastChar: 21 FontDescriptor: FontName: VBAQIR+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true ToUnicode: true Font: BaseFont: DYNJQJ+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 243 FontDescriptor: FontName: DYNJQJ+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: OLIDPX+URWPalladioL-Roma FontSubset: true FirstChar: 1 LastChar: 252 FontDescriptor: FontName: OLIDPX+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: QLBIEB+URWPalladioL-BoldItal FontSubset: true FirstChar: 110 LastChar: 112 FontDescriptor: FontName: QLBIEB+URWPalladioL-BoldItal Flags: Symbolic FontBBox: -170, -300, 1073, 935 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: JHYTSG+CMR10 FontSubset: true FirstChar: 61 LastChar: 61 FontDescriptor: FontName: JHYTSG+CMR10 Flags: Symbolic FontBBox: -40, -250, 1009, 750 FontFile: true ToUnicode: true Font: BaseFont: OVNEXW+EURM10 FontSubset: true FirstChar: 22 LastChar: 22 FontDescriptor: FontName: OVNEXW+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true ToUnicode: true Font: BaseFont: WETGPF+PazoMath-Italic FontSubset: true FirstChar: 112 LastChar: 112 FontDescriptor: FontName: WETGPF+PazoMath-Italic Flags: Symbolic FontBBox: -70, -277, 902, 733 FontFile: true ToUnicode: true Font: BaseFont: OGBFMR+VnURWPalladioL-Italic FontSubset: true FirstChar: 211 LastChar: 211 FontDescriptor: FontName: OGBFMR+VnURWPalladioL-Italic Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ZPGVCH+CMEX10 FontSubset: true FirstChar: 18 LastChar: 19 FontDescriptor: FontName: ZPGVCH+CMEX10 Flags: Symbolic FontBBox: -24, -2960, 1454, 772 FontFile: true ToUnicode: true Font: BaseFont: SVSVJC+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 243 FontDescriptor: FontName: SVSVJC+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 34, 216, 124, 235 Annotation: Subtype: Link Rect: 89, 77, 152, 84 Annotation: Subtype: Link Rect: 34, 64, 120, 72 Annotation: Subtype: Link Rect: 34, 773, 130, 809 Annotation: Subtype: Link Rect: 515, 773, 560, 809 Annotation: Subtype: Link Rect: 210, 643, 221, 656 Annotation: Subtype: Link Rect: 459, 643, 470, 656 Annotation: Subtype: Link Rect: 211, 629, 222, 642 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 280, 301, 287, 310 ActionDest: 126 Annotation: Subtype: Link Rect: 290, 301, 297, 310 ActionDest: 126 Annotation: Subtype: Link Rect: 341, 273, 348, 282 ActionDest: 126 Annotation: Subtype: Link Rect: 352, 273, 359, 282 ActionDest: 126 Annotation: Subtype: Link Rect: 402, 245, 409, 254 ActionDest: 126 Annotation: Subtype: Link Rect: 410, 245, 417, 254 ActionDest: 126 Annotation: Subtype: Link Rect: 349, 231, 361, 240 ActionDest: 126 Annotation: Subtype: Link Rect: 364, 231, 376, 240 ActionDest: 126 Annotation: Subtype: Link Rect: 425, 203, 437, 212 ActionDest: 126 Annotation: Subtype: Link Rect: 437, 203, 449, 212 ActionDest: 236 Annotation: Subtype: Link Rect: 452, 203, 464, 212 ActionDest: 236 Annotation: Subtype: Link Rect: 262, 161, 274, 170 ActionDest: 126 Annotation: Subtype: Link Rect: 275, 162, 287, 170 ActionDest: 236 Annotation: Subtype: Link Rect: 287, 161, 299, 170 ActionDest: 236 Annotation: Subtype: Link Rect: 444, 147, 456, 157 ActionDest: 236 Annotation: Subtype: Link Rect: 337, 120, 349, 129 ActionDest: 236 Annotation: Subtype: Link Rect: 411, 106, 423, 115 ActionDest: 236 Annotation: Subtype: Link Rect: 387, 78, 399, 87 ActionDest: 236 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 407, 759, 419, 767 ActionDest: 236 Annotation: Subtype: Link Rect: 402, 730, 414, 740 ActionDest: 236 Annotation: Subtype: Link Rect: 465, 717, 477, 726 ActionDest: 236 Annotation: Subtype: Link Rect: 477, 717, 489, 726 ActionDest: 236 Annotation: Subtype: Link Rect: 529, 703, 541, 712 ActionDest: 236 Annotation: Subtype: Link Rect: 544, 703, 556, 712 ActionDest: 236 Annotation: Subtype: Link Rect: 208, 661, 220, 670 ActionDest: 236 Annotation: Subtype: Link Rect: 277, 633, 289, 642 ActionDest: 236 Annotation: Subtype: Link Rect: 292, 633, 304, 642 ActionDest: 268 Annotation: Subtype: Link Rect: 338, 619, 350, 628 ActionDest: 236 Annotation: Subtype: Link Rect: 351, 619, 363, 628 ActionDest: 268 Annotation: Subtype: Link Rect: 366, 619, 378, 628 ActionDest: 268 Annotation: Subtype: Link Rect: 384, 605, 396, 614 ActionDest: 268 Annotation: Subtype: Link Rect: 396, 605, 408, 614 ActionDest: 268 Annotation: Subtype: Link Rect: 429, 577, 436, 586 ActionDest: 126 Annotation: Subtype: Link Rect: 436, 577, 448, 586 ActionDest: 268 Annotation: Subtype: Link Rect: 220, 549, 232, 559 ActionDest: 268 Annotation: Subtype: Link Rect: 274, 522, 286, 531 ActionDest: 268 Annotation: Subtype: Link Rect: 289, 522, 301, 531 ActionDest: 268 Annotation: Subtype: Link Rect: 321, 508, 333, 517 ActionDest: 268 Annotation: Subtype: Link Rect: 316, 494, 327, 503 ActionDest: 268 Annotation: Subtype: Link Rect: 529, 480, 541, 489 ActionDest: 268 Annotation: Subtype: Link Rect: 544, 480, 556, 489 ActionDest: 268 Annotation: Subtype: Link Rect: 334, 466, 345, 475 ActionDest: 268 Annotation: Subtype: Link Rect: 518, 424, 530, 433 ActionDest: 268 Annotation: Subtype: Link Rect: 204, 410, 215, 419 ActionDest: 268 Annotation: Subtype: Link Rect: 309, 410, 321, 419 ActionDest: 285 Annotation: Subtype: Link Rect: 383, 396, 395, 405 ActionDest: 285 Annotation: Subtype: Link Rect: 395, 396, 407, 405 ActionDest: 285 Annotation: Subtype: Link Rect: 284, 299, 291, 308 ActionDest: 126 Annotation: Subtype: Link Rect: 292, 299, 303, 308 ActionDest: 285 Annotation: Subtype: Link Rect: 287, 271, 299, 280 ActionDest: 285 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 432, 358, 444, 367 ActionDest: 285 Annotation: Subtype: Link Rect: 445, 358, 457, 367 ActionDest: 285 Annotation: Subtype: Link Rect: 364, 317, 376, 326 ActionDest: 285 Annotation: Subtype: Link Rect: 353, 303, 365, 312 ActionDest: 285 Annotation: Subtype: Link Rect: 403, 261, 415, 270 ActionDest: 285 Annotation: Subtype: Link Rect: 416, 261, 428, 270 ActionDest: 285 Annotation: Subtype: Link Rect: 491, 161, 501, 173 ActionDest: 116 Annotation: Subtype: Link Rect: 527, 161, 542, 173 ActionDest: 116 Annotation: Subtype: Link Rect: 335, 94, 346, 103 ActionDest: 285 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 544, 758, 556, 767 ActionDest: 285 Annotation: Subtype: Link Rect: 285, 717, 297, 726 ActionDest: 285 Annotation: Subtype: Link Rect: 209, 605, 220, 614 ActionDest: 285 Annotation: Subtype: Link Rect: 228, 495, 239, 504 ActionDest: 268 Annotation: Subtype: Link Rect: 370, 495, 382, 504 ActionDest: 285 Annotation: Subtype: Link Rect: 245, 384, 257, 393 ActionDest: 268 Annotation: Subtype: Link Rect: 345, 384, 357, 393 ActionDest: 285 Annotation: Subtype: Link Rect: 276, 239, 288, 247 ActionDest: 285 Annotation: Subtype: Link Rect: 291, 171, 303, 180 ActionDest: 285 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 248, 744, 260, 754 ActionDest: 285 Annotation: Subtype: Link Rect: 271, 717, 283, 726 ActionDest: 268 Annotation: Subtype: Link Rect: 283, 717, 295, 726 ActionDest: 268 Annotation: Subtype: Link Rect: 492, 648, 504, 657 ActionDest: 285 Annotation: Subtype: Link Rect: 504, 648, 516, 657 ActionDest: 285 Annotation: Subtype: Link Rect: 531, 317, 543, 326 ActionDest: 285 Annotation: Subtype: Link Rect: 543, 317, 555, 326 ActionDest: 365 Annotation: Subtype: Link Rect: 384, 261, 396, 270 ActionDest: 365 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 443, 401, 449, 413 ActionDest: 78 Annotation: Subtype: Link Rect: 441, 376, 453, 385 ActionDest: 268 Annotation: Subtype: Link Rect: 209, 362, 221, 371 ActionDest: 268 Annotation: Subtype: Link Rect: 201, 251, 213, 260 ActionDest: 268 Annotation: Subtype: Link Rect: 213, 251, 225, 260 ActionDest: 268 Annotation: Subtype: Link Rect: 388, 221, 402, 233 ActionDest: 116 Annotation: Subtype: Link Rect: 245, 68, 260, 80 ActionDest: 116 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 392, 276, 407, 288 ActionDest: 116 Annotation: Subtype: Link Rect: 428, 248, 434, 260 ActionDest: 381 Annotation: Subtype: Link Rect: 265, 182, 277, 191 ActionDest: 268 Annotation: Subtype: Link Rect: 277, 182, 289, 191 ActionDest: 268 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 294, 437, 304, 444 ActionDest: 268 Annotation: Subtype: Link Rect: 547, 425, 556, 432 ActionDest: 285 Annotation: Subtype: Link Rect: 438, 413, 448, 420 ActionDest: 285 Annotation: Subtype: Link Rect: 194, 103, 201, 115 ActionDest: 381 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 423, 641, 430, 653 ActionDest: 381 Annotation: Subtype: Link Rect: 420, 559, 427, 571 ActionDest: 82 Annotation: Subtype: Link Rect: 243, 517, 250, 529 ActionDest: 94 Annotation: Subtype: Link Rect: 469, 462, 476, 474 ActionDest: 82 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 432, 271, 439, 283 ActionDest: 440 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 382, 115, 392, 123 ActionDest: 268 Annotation: Subtype: Link Rect: 467, 104, 477, 111 ActionDest: 285 Annotation: Subtype: Link Rect: 366, 91, 376, 99 ActionDest: 285 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 194, 699, 201, 711 ActionDest: 99 Annotation: Subtype: Link Rect: 333, 267, 343, 279 ActionDest: 116 Annotation: Subtype: Link Rect: 373, 267, 387, 279 ActionDest: 116 Annotation: Subtype: Link Rect: 227, 239, 235, 251 ActionDest: 121 Annotation: Subtype: Link Rect: 263, 239, 278, 251 ActionDest: 121 Annotation: Subtype: Link Rect: 194, 115, 208, 126 ActionDest: 121 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 323, 521, 335, 530 ActionDest: 365 Annotation: Subtype: Link Rect: 338, 521, 350, 530 ActionDest: 365 Annotation: Subtype: Link Rect: 209, 381, 221, 390 ActionDest: 365 Annotation: Subtype: Link Rect: 222, 381, 233, 390 ActionDest: 365 Annotation: Subtype: Link Rect: 531, 381, 543, 390 ActionDest: 365 Annotation: Subtype: Link Rect: 544, 381, 556, 390 ActionDest: 365 Annotation: Subtype: Link Rect: 344, 353, 356, 363 ActionDest: 268 Annotation: Subtype: Link Rect: 357, 353, 369, 363 ActionDest: 365 Annotation: Subtype: Link Rect: 369, 353, 381, 363 ActionDest: 497 Annotation: Subtype: Link Rect: 384, 353, 401, 363 ActionDest: 497 Annotation: Subtype: Link Rect: 271, 340, 283, 349 ActionDest: 365 Annotation: Subtype: Link Rect: 284, 340, 301, 349 ActionDest: 497 Annotation: Subtype: Link Rect: 474, 326, 491, 335 ActionDest: 497 Annotation: Subtype: Link Rect: 413, 312, 430, 321 ActionDest: 497 Annotation: Subtype: Link Rect: 430, 312, 447, 321 ActionDest: 497 Annotation: Subtype: Link Rect: 522, 298, 534, 307 ActionDest: 268 Annotation: Subtype: Link Rect: 328, 284, 340, 293 ActionDest: 268 Annotation: Subtype: Link Rect: 340, 284, 357, 293 ActionDest: 497 Annotation: Subtype: Link Rect: 358, 284, 375, 293 ActionDest: 497 Annotation: Subtype: Link Rect: 378, 284, 395, 293 ActionDest: 497 Annotation: Subtype: Link Rect: 382, 186, 394, 195 ActionDest: 268 Annotation: Subtype: Link Rect: 394, 186, 411, 195 ActionDest: 497 Annotation: Subtype: Link Rect: 412, 186, 428, 195 ActionDest: 497 Annotation: Subtype: Link Rect: 355, 131, 367, 140 ActionDest: 268 Annotation: Subtype: Link Rect: 368, 131, 385, 140 ActionDest: 497 Annotation: Subtype: Link Rect: 388, 131, 405, 140 ActionDest: 497 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 444, 661, 461, 670 ActionDest: 497 Annotation: Subtype: Link Rect: 464, 661, 481, 670 ActionDest: 538 Annotation: Subtype: Link Rect: 423, 563, 435, 572 ActionDest: 268 Annotation: Subtype: Link Rect: 435, 563, 447, 572 ActionDest: 268 Annotation: Subtype: Link Rect: 448, 563, 460, 572 ActionDest: 365 Annotation: Subtype: Link Rect: 460, 563, 477, 572 ActionDest: 538 Annotation: Subtype: Link Rect: 480, 563, 497, 572 ActionDest: 538 Annotation: Subtype: Link Rect: 379, 522, 396, 531 ActionDest: 538 Annotation: Subtype: Link Rect: 399, 522, 416, 531 ActionDest: 538 Annotation: Subtype: Link Rect: 474, 424, 486, 433 ActionDest: 268 Annotation: Subtype: Link Rect: 486, 424, 498, 433 ActionDest: 268 Annotation: Subtype: Link Rect: 428, 396, 440, 405 ActionDest: 268 Annotation: Subtype: Link Rect: 440, 396, 452, 405 ActionDest: 285 Annotation: Subtype: Link Rect: 453, 396, 470, 405 ActionDest: 538 Annotation: Subtype: Link Rect: 473, 396, 490, 405 ActionDest: 538 Annotation: Subtype: Link Rect: 290, 327, 302, 336 ActionDest: 268 Annotation: Subtype: Link Rect: 539, 299, 556, 308 ActionDest: 538 Annotation: Subtype: Link Rect: 343, 243, 360, 252 ActionDest: 538 Annotation: Subtype: Link Rect: 371, 146, 388, 155 ActionDest: 538 Annotation: Subtype: Link Rect: 388, 146, 405, 155 ActionDest: 550 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 199, 744, 211, 754 ActionDest: 268 Annotation: Subtype: Link Rect: 211, 745, 228, 754 ActionDest: 550 Annotation: Subtype: Link Rect: 539, 703, 556, 712 ActionDest: 550 Annotation: Subtype: Link Rect: 435, 619, 452, 628 ActionDest: 550 Annotation: Subtype: Link Rect: 455, 619, 472, 628 ActionDest: 550 Annotation: Subtype: Link Rect: 504, 605, 521, 614 ActionDest: 497 Annotation: Subtype: Link Rect: 522, 605, 538, 614 ActionDest: 550 Annotation: Subtype: Link Rect: 539, 605, 556, 614 ActionDest: 550 Annotation: Subtype: Link Rect: 514, 494, 526, 503 ActionDest: 268 Annotation: Subtype: Link Rect: 526, 494, 538, 503 ActionDest: 268 Annotation: Subtype: Link Rect: 539, 494, 556, 503 ActionDest: 550 Annotation: Subtype: Link Rect: 485, 466, 497, 475 ActionDest: 285 Annotation: Subtype: Link Rect: 497, 466, 514, 475 ActionDest: 550 Annotation: Subtype: Link Rect: 309, 396, 326, 405 ActionDest: 550 Annotation: Subtype: Link Rect: 329, 396, 346, 405 ActionDest: 550 Annotation: Subtype: Link Rect: 283, 341, 295, 350 ActionDest: 268 Annotation: Subtype: Link Rect: 296, 341, 313, 350 ActionDest: 550 Annotation: Subtype: Link Rect: 210, 299, 222, 308 ActionDest: 268 Annotation: Subtype: Link Rect: 293, 201, 305, 210 ActionDest: 285 Annotation: Subtype: Link Rect: 305, 201, 322, 210 ActionDest: 550 Annotation: Subtype: Link Rect: 322, 201, 339, 210 ActionDest: 550 Annotation: Subtype: Link Rect: 197, 159, 214, 169 ActionDest: 550 Annotation: Subtype: Link Rect: 427, 159, 444, 169 ActionDest: 550 Annotation: Subtype: Link Rect: 228, 90, 235, 99 ActionDest: 126 Annotation: Subtype: Link Rect: 296, 90, 308, 99 ActionDest: 285 Annotation: Subtype: Link Rect: 355, 90, 367, 99 ActionDest: 236 Annotation: Subtype: Link Rect: 492, 90, 509, 99 ActionDest: 550 Annotation: Subtype: Link Rect: 243, 76, 260, 85 ActionDest: 550 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 214, 717, 231, 726 ActionDest: 550 Annotation: Subtype: Link Rect: 521, 689, 538, 698 ActionDest: 550 Annotation: Subtype: Link Rect: 539, 689, 556, 698 ActionDest: 550 Annotation: Subtype: Link Rect: 424, 549, 436, 559 ActionDest: 285 Annotation: Subtype: Link Rect: 481, 271, 498, 280 ActionDest: 617 Annotation: Subtype: Link Rect: 261, 257, 273, 266 ActionDest: 365 Annotation: Subtype: Link Rect: 273, 257, 290, 266 ActionDest: 617 Annotation: Subtype: Link Rect: 293, 257, 310, 266 ActionDest: 617 Annotation: Subtype: Link Rect: 485, 243, 497, 252 ActionDest: 268 Annotation: Subtype: Link Rect: 498, 243, 515, 252 ActionDest: 617 Annotation: Subtype: Link Rect: 518, 243, 535, 252 ActionDest: 617 Annotation: Subtype: Link Rect: 391, 229, 408, 238 ActionDest: 617 Annotation: Subtype: Link Rect: 410, 229, 427, 238 ActionDest: 625 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 377, 351, 392, 360 ActionDest: 625 Annotation: Subtype: Link Rect: 234, 336, 383, 347 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 20 Annotations: Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 21 Annotations: Annotation: Subtype: Link Rect: 319, 221, 329, 228 ActionDest: 268 Annotation: Subtype: Link Rect: 546, 192, 556, 200 ActionDest: 285 Annotation: Subtype: Link Rect: 168, 164, 178, 172 ActionDest: 285 Annotation: Subtype: Link Rect: 178, 164, 188, 172 ActionDest: 285 Annotation: Subtype: Link Rect: 469, 152, 479, 160 ActionDest: 285 Annotation: Subtype: Link Rect: 366, 140, 376, 148 ActionDest: 285 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 22 Annotations: Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 23 Annotations: Annotation: Subtype: Link Rect: 307, 577, 317, 585 ActionDest: 268 Annotation: Subtype: Link Rect: 465, 549, 475, 556 ActionDest: 285 Annotation: Subtype: Link Rect: 438, 530, 447, 538 ActionDest: 285 Annotation: Subtype: Link Rect: 447, 530, 457, 538 ActionDest: 285 Annotation: Subtype: Link Rect: 168, 506, 178, 513 ActionDest: 285 Annotation: Subtype: Link Rect: 456, 506, 466, 513 ActionDest: 285 Annotation: Subtype: Link Rect: 304, 434, 342, 444 Annotation: Subtype: Link Rect: 348, 434, 384, 444 Annotation: Subtype: Link Rect: 210, 409, 248, 419 Annotation: Subtype: Link Rect: 254, 409, 290, 419 Annotation: Subtype: Link Rect: 59, 370, 96, 381 Annotation: Subtype: Link Rect: 125, 344, 332, 355 Annotation: Subtype: Link Rect: 56, 306, 183, 317 Annotation: Subtype: Link Rect: 270, 268, 307, 278 Annotation: Subtype: Link Rect: 160, 204, 198, 215 Annotation: Subtype: Link Rect: 290, 140, 327, 151 Annotation: Subtype: Link Rect: 59, 102, 96, 112 Annotation: Subtype: Link Rect: 450, 76, 487, 87 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 24 Annotations: Annotation: Subtype: Link Rect: 412, 743, 449, 754 Annotation: Subtype: Link Rect: 456, 743, 492, 754 Annotation: Subtype: Link Rect: 160, 718, 198, 729 Annotation: Subtype: Link Rect: 243, 692, 281, 703 Annotation: Subtype: Link Rect: 440, 667, 477, 678 Annotation: Subtype: Link Rect: 483, 667, 519, 678 Annotation: Subtype: Link Rect: 233, 629, 270, 639 Annotation: Subtype: Link Rect: 276, 629, 312, 639 Annotation: Subtype: Link Rect: 305, 565, 343, 576 Annotation: Subtype: Link Rect: 104, 527, 142, 537 Annotation: Subtype: Link Rect: 478, 513, 515, 524 Annotation: Subtype: Link Rect: 521, 513, 557, 524 Annotation: Subtype: Link Rect: 135, 476, 173, 486 Annotation: Subtype: Link Rect: 195, 450, 232, 461 Annotation: Subtype: Link Rect: 156, 424, 193, 435 Annotation: Subtype: Link Rect: 358, 399, 396, 410 Annotation: Subtype: Link Rect: 445, 347, 483, 358 Annotation: Subtype: Link Rect: 113, 323, 150, 333 Annotation: Subtype: Link Rect: 301, 296, 339, 307 Annotation: Subtype: Link Rect: 345, 296, 381, 307 Annotation: Subtype: Link Rect: 492, 258, 529, 269 Annotation: Subtype: Link Rect: 424, 233, 462, 244 Annotation: Subtype: Link Rect: 59, 195, 96, 205 Annotation: Subtype: Link Rect: 56, 169, 170, 180 Annotation: Subtype: Link Rect: 318, 105, 355, 116 Annotation: Subtype: Link Rect: 312, 79, 350, 90 Annotation: Subtype: Link Rect: 356, 79, 392, 90 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 25 Annotations: Annotation: Subtype: Link Rect: 59, 731, 96, 742 Annotation: Subtype: Link Rect: 102, 731, 138, 742 Annotation: Subtype: Link Rect: 366, 718, 404, 729 Annotation: Subtype: Link Rect: 96, 693, 133, 703 Annotation: Subtype: Link Rect: 139, 693, 175, 703 Annotation: Subtype: Link Rect: 353, 667, 391, 678 Annotation: Subtype: Link Rect: 203, 641, 240, 652 Annotation: Subtype: Link Rect: 341, 603, 378, 614 Annotation: Subtype: Link Rect: 384, 603, 420, 614 Annotation: Subtype: Link Rect: 491, 577, 529, 588 Annotation: Subtype: Link Rect: 110, 552, 560, 563 Annotation: Subtype: Link Rect: 56, 539, 172, 550 Annotation: Subtype: Link Rect: 451, 513, 489, 524 Annotation: Subtype: Link Rect: 135, 476, 173, 486 Annotation: Subtype: Link Rect: 184, 437, 221, 448 Annotation: Subtype: Link Rect: 227, 437, 263, 448 Annotation: Subtype: Link Rect: 59, 399, 96, 410 Annotation: Subtype: Link Rect: 363, 360, 400, 371 Annotation: Subtype: Link Rect: 259, 322, 297, 333 Annotation: Subtype: Link Rect: 469, 296, 506, 307 Annotation: Subtype: Link Rect: 369, 258, 406, 269 Annotation: Subtype: Link Rect: 90, 221, 128, 231 Annotation: Subtype: Link Rect: 134, 221, 170, 231 Annotation: Subtype: Link Rect: 95, 182, 132, 193 Annotation: Subtype: Link Rect: 138, 182, 174, 193 Annotation: Subtype: Link Rect: 166, 131, 204, 141 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 26 Annotations: Annotation: Subtype: Link Rect: 104, 743, 560, 754 Annotation: Subtype: Link Rect: 56, 731, 247, 742 Annotation: Subtype: Link Rect: 95, 693, 133, 703 Annotation: Subtype: Link Rect: 322, 667, 360, 678 Annotation: Subtype: Link Rect: 56, 616, 412, 627 Annotation: Subtype: Link Rect: 95, 553, 133, 563 Annotation: Subtype: Link Rect: 113, 527, 151, 537 Annotation: Subtype: Link Rect: 455, 475, 493, 486 Annotation: Subtype: Link Rect: 471, 450, 509, 461 Annotation: Subtype: Link Rect: 56, 411, 482, 422 Annotation: Subtype: Link Rect: 449, 360, 487, 371 Annotation: Subtype: Link Rect: 59, 285, 96, 295 Annotation: Subtype: Link Rect: 491, 233, 528, 244 Annotation: Subtype: Link Rect: 407, 194, 445, 205 Annotation: Subtype: Link Rect: 59, 144, 96, 154 Annotation: Subtype: Link Rect: 479, 92, 516, 103 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 27 Annotations: Annotation: Subtype: Link Rect: 510, 705, 548, 716 Annotation: Subtype: Link Rect: 437, 679, 475, 690 Annotation: Subtype: Link Rect: 258, 641, 296, 652 Annotation: Subtype: Link Rect: 139, 604, 176, 614 Annotation: Subtype: Link Rect: 511, 565, 548, 576 Annotation: Subtype: Link Rect: 301, 540, 339, 550 Annotation: Subtype: Link Rect: 253, 501, 290, 512 Annotation: Subtype: Link Rect: 361, 463, 399, 473 Annotation: Subtype: Link Rect: 253, 399, 291, 410 Annotation: Subtype: Link Rect: 433, 373, 471, 384 Annotation: Subtype: Link Rect: 59, 336, 96, 346 Annotation: Subtype: Link Rect: 102, 336, 138, 346 Annotation: Subtype: Link Rect: 221, 296, 259, 307 Annotation: Subtype: Link Rect: 153, 272, 191, 282 Annotation: Subtype: Link Rect: 127, 246, 164, 256 Annotation: Subtype: Link Rect: 442, 220, 480, 231 Annotation: Subtype: Link Rect: 324, 182, 361, 193 Annotation: Subtype: Link Rect: 299, 156, 336, 167 Annotation: Subtype: Link Rect: 86, 119, 124, 129 Annotation: Subtype: Link Rect: 130, 119, 166, 129 Annotation: Subtype: Link Rect: 451, 92, 488, 103 Annotation: Subtype: Link Rect: 494, 92, 530, 103 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 28 Annotations: Annotation: Subtype: Link Rect: 59, 731, 96, 742 Annotation: Subtype: Link Rect: 477, 705, 515, 716 Annotation: Subtype: Link Rect: 521, 705, 557, 716 Annotation: Subtype: Link Rect: 197, 667, 234, 678 Annotation: Subtype: Link Rect: 90, 642, 128, 652 Annotation: Subtype: Link Rect: 95, 604, 133, 614 Annotation: Subtype: Link Rect: 104, 578, 142, 588 Annotation: Subtype: Link Rect: 299, 552, 336, 563 Annotation: Subtype: Link Rect: 86, 514, 124, 524 Annotation: Subtype: Link Rect: 520, 488, 557, 499 Annotation: Subtype: Link Rect: 368, 462, 406, 473 Annotation: Subtype: Link Rect: 412, 462, 448, 473 Annotation: Subtype: Link Rect: 204, 424, 242, 435 Annotation: Subtype: Link Rect: 248, 424, 284, 435 Annotation: Subtype: Link Rect: 59, 387, 96, 397 Annotation: Subtype: Link Rect: 354, 360, 392, 371 Annotation: Subtype: Link Rect: 247, 322, 284, 333 Annotation: Subtype: Link Rect: 290, 322, 326, 333 Annotation: Subtype: Link Rect: 365, 284, 402, 295 Annotation: Subtype: Link Rect: 474, 258, 511, 269 Annotation: Subtype: Link Rect: 517, 258, 553, 269 Annotation: Subtype: Link Rect: 471, 233, 509, 244 Annotation: Subtype: Link Rect: 367, 207, 405, 218 Annotation: Subtype: Link Rect: 86, 170, 124, 180 Annotation: Subtype: Link Rect: 130, 170, 166, 180 Annotation: Subtype: Link Rect: 307, 143, 345, 154 Annotation: Subtype: Link Rect: 59, 106, 96, 116 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 29 Annotations: Annotation: Subtype: Link Rect: 313, 743, 351, 754 Annotation: Subtype: Link Rect: 95, 706, 132, 716 Annotation: Subtype: Link Rect: 431, 679, 469, 690 Annotation: Subtype: Link Rect: 475, 679, 511, 690 Annotation: Subtype: Link Rect: 475, 641, 513, 652 Annotation: Subtype: Link Rect: 184, 603, 222, 614 Annotation: Subtype: Link Rect: 181, 565, 217, 576 Annotation: Subtype: Link Rect: 200, 539, 238, 550 Annotation: Subtype: Link Rect: 500, 501, 538, 512 Annotation: Subtype: Link Rect: 196, 462, 234, 473 Annotation: Subtype: Link Rect: 240, 462, 276, 473 Annotation: Subtype: Link Rect: 402, 437, 440, 448 Annotation: Subtype: Link Rect: 95, 399, 132, 410 Annotation: Subtype: Link Rect: 138, 399, 174, 410 Annotation: Subtype: Link Rect: 478, 361, 515, 371 Annotation: Subtype: Link Rect: 521, 361, 557, 371 Annotation: Subtype: Link Rect: 397, 322, 434, 333 Annotation: Subtype: Link Rect: 415, 296, 453, 307 Annotation: Subtype: Link Rect: 59, 259, 96, 269 Annotation: Subtype: Link Rect: 472, 207, 510, 218 Annotation: Subtype: Link Rect: 516, 207, 552, 218 Annotation: Subtype: Link Rect: 118, 170, 155, 180 Annotation: Subtype: Link Rect: 229, 131, 266, 141 Annotation: Subtype: Link Rect: 487, 106, 525, 116 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 30 Annotations: Annotation: Subtype: Link Rect: 223, 718, 260, 729 Annotation: Subtype: Link Rect: 59, 680, 96, 690 Annotation: Subtype: Link Rect: 227, 641, 264, 652 Annotation: Subtype: Link Rect: 474, 616, 511, 627 Annotation: Subtype: Link Rect: 135, 591, 173, 601 Annotation: Subtype: Link Rect: 241, 565, 279, 576 Annotation: Subtype: Link Rect: 500, 539, 538, 550 Annotation: Subtype: Link Rect: 193, 501, 231, 512 Annotation: Subtype: Link Rect: 343, 475, 381, 486 Annotation: Subtype: Link Rect: 421, 462, 560, 473 Annotation: Subtype: Link Rect: 56, 450, 333, 461 Annotation: Subtype: Link Rect: 449, 424, 486, 435 Annotation: Subtype: Link Rect: 481, 399, 519, 410 Annotation: Subtype: Link Rect: 207, 361, 245, 371 Annotation: Subtype: Link Rect: 440, 335, 478, 346 Annotation: Subtype: Link Rect: 59, 297, 96, 307 Annotation: Subtype: Link Rect: 104, 259, 142, 269 Annotation: Subtype: Link Rect: 359, 220, 396, 231 Annotation: Subtype: Link Rect: 298, 194, 336, 205 Annotation: Subtype: Link Rect: 475, 130, 513, 141 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 31 Annotations: Annotation: Subtype: Link Rect: 422, 731, 459, 742 Annotation: Subtype: Link Rect: 361, 705, 398, 716 Annotation: Subtype: Link Rect: 519, 679, 557, 690 Annotation: Subtype: Link Rect: 59, 668, 95, 678 Annotation: Subtype: Link Rect: 282, 641, 319, 652 Annotation: Subtype: Link Rect: 222, 604, 259, 614 Annotation: Subtype: Link Rect: 127, 578, 164, 588 Annotation: Subtype: Link Rect: 519, 552, 557, 563 Annotation: Subtype: Link Rect: 59, 540, 95, 550 Annotation: Subtype: Link Rect: 59, 502, 96, 512 Annotation: Subtype: Link Rect: 438, 462, 475, 473 Annotation: Subtype: Link Rect: 375, 424, 413, 435 Annotation: Subtype: Link Rect: 175, 387, 213, 397 Annotation: Subtype: Link Rect: 272, 348, 310, 358 Annotation: Subtype: Link Rect: 260, 322, 298, 333 Annotation: Subtype: Link Rect: 245, 297, 283, 307 Annotation: Subtype: Link Rect: 289, 297, 325, 307 Annotation: Subtype: Link Rect: 183, 259, 220, 269 Annotation: Subtype: Link Rect: 226, 259, 262, 269 Annotation: Subtype: Link Rect: 56, 220, 270, 231 Annotation: Subtype: Link Rect: 277, 194, 314, 205 Annotation: Subtype: Link Rect: 320, 194, 356, 205 Annotation: Subtype: Link Rect: 148, 169, 440, 180 Annotation: Subtype: Link Rect: 56, 130, 353, 141 Annotation: Subtype: Link Rect: 392, 105, 560, 116 Annotation: Subtype: Link Rect: 56, 92, 188, 103 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Page: Sequence: 32 Annotations: Annotation: Subtype: Link Rect: 86, 718, 379, 729 Annotation: Subtype: Link Rect: 188, 692, 521, 703 Annotation: Subtype: Link Rect: 409, 27, 560, 37 Checksum: 6db2321b Type: CRC32 Checksum: b2012f92a8c0fb8416196fbeb8f7a809 Type: MD5 Checksum: 59e7fbaf49fae589a023a054f0a57ea5f56d946b Type: SHA-1 Checksum: 5f6c1bfdf7a2867fc35274372d2624b13208b7e986a9a011f24aee9e03bb8be8 Type: SHA-256