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Keywords: cancer-associated fibroblast (CAF), secretome, secreted factors, growth factors, cancer, tumor microenvironment (TME), metastasis, therapy Author: Alexandre Calon Creator: LaTeX with hyperref package + hypdvips Producer: dvips + MiKTeX GPL Ghostscript 9.0 CreationDate: Sun Jan 17 13:06:40 2021 CET ModDate: Sun Jan 17 13:17:22 2021 CET Custom Metadata: no Metadata Stream: yes Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 19 Encrypted: no Page size: 595.26 x 779.52 pts Page rot: 0 File size: 2087010 bytes Optimized: no PDF version: 1.6 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- TGNAGH+HelveticaNeueLTStd-Bd Type 1C Custom yes yes no 39 0 TJUNAG+HelveticaNeueLTStd-Lt Type 1C Custom yes yes no 44 0 PIAOFJ+HelveticaNeueLTStd-BdIt Type 1C WinAnsi yes yes no 57 0 CNSDIN+HelveticaNeueLTStd-LtIt Type 1C Custom yes yes no 59 0 WRBXGO+HelveticaNeueLTStd-MdIt Type 1C WinAnsi yes yes no 64 0 BWMFXN+MinionPro-Regular Type 1C Custom yes yes no 66 0 PPSKEF+MTGU Type 1C Custom yes yes no 107 0 TCJWTP+MinionPro-It Type 1C WinAnsi yes yes no 118 0 LUHOUN+HelveticaNeueLTStd-Md Type 1C WinAnsi yes yes no 88 0 NZZQTP+MinionPro-Bold Type 1C Custom yes yes no 91 0 QKTCQK+MTSY Type 1C Custom yes yes no 227 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-10-02 03:32:07 CEST RepresentationInformation: pmc_33553157.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 12:08:48 CEST Size: 2087010 Format: PDF Version: 1.6 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 1077 FreeObjects: 25 IncrementalUpdates: 1 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: UseOutlines Language: en Outlines: Item: Title: Determinants and Functions of CAFs Secretome During Cancer Progression and Therapy Destination: ariclecounter.1 Children: Item: Title: Introduction Destination: section*.2 Item: Title: Determinants of CAFS Secretome Destination: section*.3 Children: Item: Title: Crosstalk With Tumor Cells and TME Components Destination: section*.4 Children: Item: Title: Autocrine- and Paracrine-Secreted Factors Destination: section*.5 Item: Title: Extracellular Vesicles Destination: section*.6 Item: Title: Cell–Cell Contact and Mechanical Interactions Destination: section*.7 Item: Title: Spatial and Temporal Plasticity Destination: section*.8 Item: Title: Anti-cancer Therapy as a Determinant of CAFs Secretome Destination: section*.9 Children: Item: Title: Chemotherapy Destination: section*.10 Item: Title: Radiotherapy Destination: section*.11 Item: Title: Targeted Therapy Destination: section*.12 Item: Title: Epigenetic Regulation of CAFs Secretome Destination: section*.13 Item: Title: CAFS Secretome as Determinant of Tumor Development Destination: section*.14 Children: Item: Title: Cancer Cells Self-Renewal Destination: section*.15 Item: Title: Metastatic Cancer Cells Spreading Destination: section*.16 Item: Title: Immunomodulation Destination: section*.17 Item: Title: Angiogenesis Destination: section*.18 Item: Title: Resistance to Anti-cancer Therapy Destination: section*.19 Item: Title: Prognostic and Predictive Value of CAFS Secretome Destination: section*.20 Item: Title: CAF-Secreted Factors as a Therapeutic Target Destination: section*.21 Children: Item: Title: Targeting the CAFs Secretome Regulating Cancer Cells Proliferation Destination: section*.22 Item: Title: Overcoming CAFs-Induced Immunosuppression Destination: section*.23 Item: Title: Conclusions Destination: section*.24 Item: Title: Author Contributions Destination: section*.25 Item: Title: Acknowledgments Destination: section*.26 Item: Title: References Destination: section*.27 Info: Title: Determinants and Functions of CAFs Secretome During Cancer Progression and Therapy Author: Alexandre Calon Subject: Multiple lines of evidence are indicating that cancer development and malignant progression are not exclusively epithelial cancer cell-autonomous processes but may also depend on crosstalk with the surrounding tumor microenvironment (TME). 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Alexandre Calon Determinants and Functions of CAFs Secretome During Cancer Progression and Therapy cancer-associated fibroblast (CAF) secretome secreted factors growth factors cancer tumor microenvironment (TME) metastasis therapy cancer-associated fibroblast (CAF), secretome, secreted factors, growth factors, cancer, tumor microenvironment (TME), metastasis, therapy dvips + MiKTeX GPL Ghostscript 9.0 uuid:5a6cb9db-669e-46a6-9449-f1046dd3666b uuid:4b26aeda-ed7b-4edd-8041-06facd535963 Pages: Page: Label: 1 Annotations: Annotation: Subtype: Link Rect: 43, 719, 270, 755 Annotation: Subtype: Link Rect: 522, 736, 551, 744 Annotation: Subtype: Link Rect: 465, 728, 508, 736 Annotation: Subtype: Link Rect: 508, 728, 533, 736 Annotation: Subtype: Link Rect: 533, 728, 551, 736 Annotation: Subtype: Link Rect: 454, 720, 551, 728 Annotation: Subtype: Link Rect: 521, 678, 551, 709 Annotation: Subtype: Link Rect: 43, 30, 175, 38 Annotation: Subtype: Link Rect: 179, 30, 239, 38 Annotation: Subtype: 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Rect: 498, 273, 326, 273 Destination: External Annotation: Subtype: Link Rect: 331, 261, 351, 273 Destination: External Annotation: Subtype: Link Rect: 356, 261, 410, 273 Destination: External Annotation: Subtype: Link Rect: 415, 261, 435, 273 Destination: External Annotation: Subtype: Link Rect: 350, 204, 404, 216 Destination: External Annotation: Subtype: Link Rect: 411, 204, 431, 216 Destination: External Annotation: Subtype: Link Rect: 437, 204, 502, 216 Destination: External Annotation: Subtype: Link Rect: 508, 204, 528, 216 Destination: External Annotation: Subtype: Link Rect: 534, 204, 350, 204 Destination: External Annotation: Subtype: Link Rect: 355, 193, 375, 204 Destination: External Annotation: Subtype: Link Rect: 386, 158, 451, 170 Destination: External Annotation: Subtype: Link Rect: 454, 158, 474, 170 Destination: External Annotation: Subtype: Link Rect: 476, 158, 504, 170 Destination: External Annotation: Subtype: Link Rect: 507, 158, 527, 170 Destination: External Annotation: Subtype: Link Rect: 523, 90, 328, 90 Destination: External Annotation: Subtype: Link Rect: 334, 78, 354, 90 Destination: External Annotation: Subtype: Link Rect: 43, 29, 175, 38 Annotation: Subtype: Link Rect: 179, 29, 239, 37 Annotation: Subtype: Link Rect: 425, 29, 551, 38 Page: Label: 7 Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 153, 685, 197, 697 Destination: External Annotation: Subtype: Link Rect: 202, 685, 222, 697 Destination: External Annotation: Subtype: Link Rect: 248, 674, 65, 674 Destination: External Annotation: Subtype: Link Rect: 69, 662, 90, 674 Destination: External Annotation: Subtype: Link Rect: 158, 640, 224, 651 Destination: External Annotation: Subtype: Link Rect: 226, 640, 246, 651 Destination: External Annotation: Subtype: Link Rect: 47, 408, 81, 419 Destination: External Annotation: Subtype: Link Rect: 223, 388, 266, 399 Destination: External Annotation: Subtype: Link Rect: 268, 388, 289, 399 Destination: External Annotation: Subtype: Link Rect: 43, 376, 79, 388 Destination: External Annotation: Subtype: Link Rect: 84, 376, 104, 388 Destination: External Annotation: Subtype: Link Rect: 141, 353, 182, 365 Destination: External Annotation: Subtype: Link Rect: 185, 353, 205, 365 Destination: External Annotation: Subtype: Link Rect: 232, 307, 289, 319 Destination: External Annotation: Subtype: Link Rect: 43, 296, 64, 307 Destination: External Annotation: Subtype: Link Rect: 265, 284, 64, 284 Destination: External Annotation: Subtype: Link Rect: 67, 273, 88, 284 Destination: External Annotation: Subtype: Link Rect: 79, 250, 132, 261 Destination: External Annotation: Subtype: Link Rect: 134, 250, 155, 261 Destination: External Annotation: Subtype: Link Rect: 129, 204, 198, 216 Destination: External Annotation: Subtype: Link Rect: 202, 204, 222, 216 Destination: External Annotation: Subtype: Link Rect: 227, 204, 289, 216 Destination: External Annotation: Subtype: Link Rect: 43, 193, 64, 204 Destination: External Annotation: Subtype: Link Rect: 66, 193, 99, 204 Destination: External Annotation: Subtype: Link Rect: 101, 193, 121, 204 Destination: External Annotation: Subtype: Link Rect: 206, 158, 289, 170 Destination: External Annotation: Subtype: Link Rect: 43, 147, 64, 158 Destination: External Annotation: Subtype: Link Rect: 67, 147, 99, 158 Destination: External Annotation: Subtype: Link Rect: 102, 147, 122, 158 Destination: External Annotation: Subtype: Link Rect: 103, 113, 157, 124 Destination: External Annotation: Subtype: Link Rect: 162, 113, 182, 124 Destination: External Annotation: Subtype: Link Rect: 187, 113, 237, 124 Destination: External Annotation: Subtype: Link Rect: 242, 113, 262, 124 Destination: External Annotation: Subtype: Link Rect: 267, 113, 66, 113 Destination: External Annotation: Subtype: Link Rect: 71, 101, 91, 113 Destination: External Annotation: Subtype: Link Rect: 96, 101, 155, 113 Destination: External Annotation: Subtype: Link Rect: 160, 101, 180, 113 Destination: External Annotation: Subtype: Link Rect: 403, 697, 451, 708 Destination: External Annotation: Subtype: Link Rect: 453, 697, 473, 708 Destination: External Annotation: Subtype: Link Rect: 356, 637, 390, 648 Destination: External Annotation: Subtype: Link Rect: 420, 594, 469, 605 Destination: External Annotation: Subtype: Link Rect: 474, 594, 494, 605 Destination: External Annotation: Subtype: Link Rect: 335, 559, 391, 571 Destination: External Annotation: Subtype: Link Rect: 396, 559, 416, 571 Destination: External Annotation: Subtype: Link Rect: 504, 536, 549, 548 Destination: External Annotation: Subtype: Link Rect: 304, 525, 324, 536 Destination: External Annotation: Subtype: Link Rect: 328, 491, 377, 502 Destination: External Annotation: Subtype: Link Rect: 381, 491, 401, 502 Destination: External Annotation: Subtype: Link Rect: 505, 468, 549, 479 Destination: External Annotation: Subtype: Link Rect: 304, 456, 324, 468 Destination: External Annotation: Subtype: Link Rect: 398, 433, 440, 445 Destination: External Annotation: Subtype: Link Rect: 443, 433, 463, 445 Destination: External Annotation: Subtype: Link Rect: 356, 353, 434, 365 Destination: External Annotation: Subtype: Link Rect: 438, 353, 459, 365 Destination: External Annotation: Subtype: Link Rect: 386, 319, 426, 330 Destination: External Annotation: Subtype: Link Rect: 430, 319, 450, 330 Destination: External Annotation: Subtype: Link Rect: 448, 296, 486, 307 Destination: External Annotation: Subtype: Link Rect: 489, 296, 510, 307 Destination: External Annotation: Subtype: Link Rect: 501, 273, 549, 284 Destination: External Annotation: Subtype: Link Rect: 304, 261, 324, 273 Destination: External Annotation: Subtype: Link Rect: 307, 168, 341, 178 Destination: External Annotation: Subtype: Link Rect: 387, 135, 445, 147 Destination: External Annotation: Subtype: Link Rect: 449, 135, 469, 147 Destination: External Annotation: Subtype: Link Rect: 472, 135, 549, 147 Destination: External Annotation: Subtype: Link Rect: 304, 124, 324, 135 Destination: External Annotation: Subtype: Link Rect: 43, 29, 175, 38 Annotation: Subtype: Link Rect: 179, 29, 239, 37 Annotation: Subtype: Link Rect: 425, 29, 551, 38 Page: Label: 8 Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 245, 319, 289, 331 Destination: External Annotation: Subtype: Link Rect: 43, 308, 64, 319 Destination: External Annotation: Subtype: Link Rect: 212, 285, 266, 296 Destination: External Annotation: Subtype: Link Rect: 268, 285, 289, 296 Destination: External Annotation: Subtype: Link Rect: 43, 273, 85, 285 Destination: External Annotation: Subtype: Link Rect: 89, 273, 109, 285 Destination: External Annotation: Subtype: Link Rect: 109, 239, 147, 250 Destination: External Annotation: Subtype: Link Rect: 149, 239, 169, 250 Destination: External Annotation: Subtype: Link Rect: 171, 239, 227, 250 Destination: External Annotation: Subtype: Link Rect: 230, 239, 250, 250 Destination: External Annotation: Subtype: Link Rect: 202, 193, 240, 205 Destination: External Annotation: Subtype: Link Rect: 243, 193, 264, 205 Destination: External Annotation: Subtype: Link Rect: 267, 193, 65, 193 Destination: External Annotation: Subtype: Link Rect: 68, 182, 88, 193 Destination: External Annotation: Subtype: Link Rect: 274, 170, 67, 170 Destination: External Annotation: Subtype: Link Rect: 73, 159, 93, 170 Destination: External Annotation: Subtype: Link Rect: 143, 113, 241, 124 Destination: External Annotation: Subtype: Link Rect: 244, 113, 264, 124 Destination: External Annotation: Subtype: Link Rect: 268, 113, 65, 113 Destination: External Annotation: Subtype: Link Rect: 69, 102, 89, 113 Destination: External Annotation: Subtype: Link Rect: 199, 67, 261, 79 Destination: External Annotation: Subtype: Link Rect: 265, 67, 285, 79 Destination: External Annotation: Subtype: Link Rect: 307, 296, 350, 308 Destination: External Annotation: Subtype: Link Rect: 353, 296, 373, 308 Destination: External Annotation: Subtype: Link Rect: 375, 296, 415, 308 Destination: External Annotation: Subtype: Link Rect: 418, 296, 438, 308 Destination: External Annotation: Subtype: Link Rect: 533, 262, 326, 262 Destination: External Annotation: Subtype: Link Rect: 331, 250, 351, 262 Destination: External Annotation: Subtype: Link Rect: 356, 250, 407, 262 Destination: External Annotation: Subtype: Link Rect: 412, 250, 432, 262 Destination: External Annotation: Subtype: Link Rect: 450, 205, 504, 216 Destination: External Annotation: Subtype: Link Rect: 507, 205, 527, 216 Destination: External Annotation: Subtype: Link Rect: 529, 205, 323, 205 Destination: External Annotation: Subtype: Link Rect: 326, 193, 346, 205 Destination: External Annotation: Subtype: Link Rect: 526, 170, 324, 170 Destination: External Annotation: Subtype: Link Rect: 327, 159, 347, 170 Destination: External Annotation: Subtype: Link Rect: 350, 159, 430, 170 Destination: External Annotation: Subtype: Link Rect: 433, 159, 454, 170 Destination: External Annotation: Subtype: Link Rect: 307, 113, 380, 124 Destination: External Annotation: Subtype: Link Rect: 384, 113, 404, 124 Destination: External Annotation: Subtype: Link Rect: 43, 29, 175, 38 Annotation: Subtype: Link Rect: 179, 29, 239, 37 Annotation: Subtype: Link Rect: 425, 29, 551, 38 Page: Label: 9 Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 47, 708, 121, 720 Destination: External Annotation: Subtype: Link Rect: 125, 708, 145, 720 Destination: External Annotation: Subtype: Link Rect: 150, 708, 210, 720 Destination: External Annotation: Subtype: Link Rect: 215, 708, 235, 720 Destination: External Annotation: Subtype: Link Rect: 245, 685, 289, 697 Destination: External Annotation: Subtype: Link Rect: 43, 674, 64, 685 Destination: External Annotation: Subtype: Link Rect: 82, 640, 121, 651 Destination: External Annotation: Subtype: Link Rect: 127, 640, 147, 651 Destination: External Annotation: Subtype: Link Rect: 153, 640, 209, 651 Destination: External Annotation: Subtype: Link Rect: 215, 640, 235, 651 Destination: External Annotation: Subtype: Link Rect: 112, 523, 147, 533 Destination: External Annotation: Subtype: Link Rect: 154, 525, 219, 536 Destination: External Annotation: Subtype: Link Rect: 222, 525, 242, 536 Destination: External Annotation: Subtype: Link Rect: 246, 525, 289, 536 Destination: External Annotation: Subtype: Link Rect: 43, 514, 64, 525 Destination: External Annotation: Subtype: Link Rect: 47, 491, 94, 502 Destination: External Annotation: Subtype: Link Rect: 97, 491, 117, 502 Destination: External Annotation: Subtype: Link Rect: 254, 445, 90, 445 Destination: External Annotation: Subtype: Link Rect: 93, 433, 113, 445 Destination: External Annotation: Subtype: Link Rect: 139, 399, 191, 410 Destination: External Annotation: Subtype: Link Rect: 194, 399, 215, 410 Destination: External Annotation: Subtype: Link Rect: 99, 365, 135, 376 Destination: External Annotation: Subtype: Link Rect: 138, 365, 158, 376 Destination: External Annotation: Subtype: Link Rect: 167, 330, 213, 342 Destination: External Annotation: Subtype: Link Rect: 216, 330, 236, 342 Destination: External Annotation: Subtype: Link Rect: 239, 330, 289, 342 Destination: External Annotation: Subtype: Link Rect: 43, 319, 64, 330 Destination: External Annotation: Subtype: Link Rect: 263, 284, 66, 284 Destination: External Annotation: Subtype: Link Rect: 71, 273, 91, 284 Destination: External Annotation: Subtype: Link Rect: 96, 273, 178, 284 Destination: External Annotation: Subtype: Link Rect: 183, 273, 203, 284 Destination: External Annotation: Subtype: Link Rect: 47, 239, 105, 250 Destination: External Annotation: Subtype: Link Rect: 111, 239, 131, 250 Destination: External Annotation: Subtype: Link Rect: 129, 216, 176, 227 Destination: External Annotation: Subtype: Link Rect: 182, 216, 202, 227 Destination: External Annotation: Subtype: Link Rect: 98, 193, 162, 204 Destination: External Annotation: Subtype: Link Rect: 166, 193, 186, 204 Destination: External Annotation: Subtype: Link Rect: 190, 158, 238, 170 Destination: External Annotation: Subtype: Link Rect: 240, 158, 260, 170 Destination: External Annotation: Subtype: Link Rect: 253, 122, 287, 132 Destination: External Annotation: Subtype: Link Rect: 47, 113, 116, 124 Destination: External Annotation: Subtype: Link Rect: 122, 113, 142, 124 Destination: External Annotation: Subtype: Link Rect: 198, 90, 263, 101 Destination: External Annotation: Subtype: Link Rect: 268, 90, 289, 101 Destination: External Annotation: Subtype: Link Rect: 43, 78, 122, 90 Destination: External Annotation: Subtype: Link Rect: 127, 78, 147, 90 Destination: External Annotation: Subtype: Link Rect: 444, 697, 502, 708 Destination: External Annotation: Subtype: Link Rect: 505, 697, 525, 708 Destination: External Annotation: Subtype: Link Rect: 528, 697, 323, 697 Destination: External Annotation: Subtype: Link Rect: 326, 685, 346, 697 Destination: External Annotation: Subtype: Link Rect: 506, 591, 549, 602 Destination: External Annotation: Subtype: Link Rect: 304, 579, 324, 591 Destination: External Annotation: Subtype: Link Rect: 428, 568, 479, 579 Destination: External Annotation: Subtype: Link Rect: 482, 568, 502, 579 Destination: External Annotation: Subtype: Link Rect: 434, 533, 492, 545 Destination: External Annotation: Subtype: Link Rect: 496, 533, 517, 545 Destination: External Annotation: Subtype: Link Rect: 403, 488, 469, 499 Destination: External Annotation: Subtype: Link Rect: 471, 488, 492, 499 Destination: External Annotation: Subtype: Link Rect: 463, 453, 522, 465 Destination: External Annotation: Subtype: Link Rect: 525, 453, 546, 465 Destination: External Annotation: Subtype: Link Rect: 468, 419, 519, 430 Destination: External Annotation: Subtype: Link Rect: 525, 419, 546, 430 Destination: External Annotation: Subtype: Link Rect: 494, 373, 549, 384 Destination: External Annotation: Subtype: Link Rect: 304, 362, 324, 373 Destination: External Annotation: Subtype: Link Rect: 326, 362, 367, 373 Destination: External Annotation: Subtype: Link Rect: 369, 362, 389, 373 Destination: External Annotation: Subtype: Link Rect: 488, 339, 549, 350 Destination: External Annotation: Subtype: Link Rect: 304, 327, 324, 339 Destination: External Annotation: Subtype: Link Rect: 436, 304, 493, 316 Destination: External Annotation: Subtype: Link Rect: 495, 304, 515, 316 Destination: External Annotation: Subtype: Link Rect: 460, 224, 520, 236 Destination: External Annotation: Subtype: Link Rect: 525, 224, 546, 236 Destination: External Annotation: Subtype: Link Rect: 510, 178, 549, 190 Destination: External Annotation: Subtype: Link Rect: 304, 167, 324, 178 Destination: External Annotation: Subtype: Link Rect: 446, 144, 482, 155 Destination: External Annotation: Subtype: Link Rect: 485, 144, 505, 155 Destination: External Annotation: Subtype: Link Rect: 43, 29, 175, 38 Annotation: Subtype: Link Rect: 179, 29, 239, 37 Annotation: Subtype: Link Rect: 425, 29, 551, 38 Page: Label: 10 Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 255, 685, 65, 685 Destination: External Annotation: Subtype: Link Rect: 69, 674, 89, 685 Destination: External Annotation: Subtype: Link Rect: 227, 674, 264, 685 Destination: External Annotation: Subtype: Link Rect: 268, 674, 289, 685 Destination: External Annotation: Subtype: Link Rect: 43, 662, 101, 674 Destination: External Annotation: Subtype: Link Rect: 105, 662, 125, 674 Destination: External Annotation: Subtype: Link Rect: 268, 662, 63, 662 Destination: External Annotation: Subtype: Link Rect: 66, 651, 86, 662 Destination: External Annotation: Subtype: Link Rect: 88, 651, 153, 662 Destination: External Annotation: Subtype: Link Rect: 155, 651, 175, 662 Destination: External Annotation: Subtype: Link Rect: 84, 640, 131, 651 Destination: External Annotation: Subtype: Link Rect: 136, 640, 156, 651 Destination: External Annotation: Subtype: Link Rect: 160, 640, 211, 651 Destination: External Annotation: Subtype: Link Rect: 215, 640, 235, 651 Destination: External Annotation: Subtype: Link Rect: 239, 640, 289, 651 Destination: External Annotation: Subtype: Link Rect: 43, 628, 64, 640 Destination: External Annotation: Subtype: Link Rect: 140, 502, 197, 514 Destination: External Annotation: Subtype: Link Rect: 201, 502, 222, 514 Destination: External Annotation: Subtype: Link Rect: 226, 502, 289, 514 Destination: External Annotation: Subtype: Link Rect: 43, 491, 64, 502 Destination: External Annotation: Subtype: Link Rect: 68, 491, 119, 502 Destination: External Annotation: Subtype: Link Rect: 123, 491, 143, 502 Destination: External Annotation: Subtype: Link Rect: 213, 456, 262, 468 Destination: External Annotation: Subtype: Link Rect: 265, 456, 285, 468 Destination: External Annotation: Subtype: Link Rect: 239, 410, 289, 422 Destination: External Annotation: Subtype: Link Rect: 43, 399, 64, 410 Destination: External Annotation: Subtype: Link Rect: 166, 353, 224, 365 Destination: External Annotation: Subtype: Link Rect: 230, 353, 250, 365 Destination: External Annotation: Subtype: Link Rect: 225, 342, 289, 353 Destination: External Annotation: Subtype: Link Rect: 43, 330, 64, 342 Destination: External Annotation: Subtype: Link Rect: 78, 307, 121, 319 Destination: External Annotation: Subtype: Link Rect: 123, 307, 143, 319 Destination: External Annotation: Subtype: Link Rect: 130, 284, 163, 296 Destination: External Annotation: Subtype: Link Rect: 166, 284, 186, 296 Destination: External Annotation: Subtype: Link Rect: 189, 204, 262, 216 Destination: External Annotation: Subtype: Link Rect: 268, 204, 289, 216 Destination: External Annotation: Subtype: Link Rect: 43, 193, 97, 204 Destination: External Annotation: Subtype: Link Rect: 101, 193, 121, 204 Destination: External Annotation: Subtype: Link Rect: 47, 158, 156, 170 Destination: External Annotation: Subtype: Link Rect: 159, 158, 179, 170 Destination: External Annotation: Subtype: Link Rect: 148, 90, 194, 101 Destination: External Annotation: Subtype: Link Rect: 196, 90, 216, 101 Destination: External Annotation: Subtype: Link Rect: 219, 90, 262, 101 Destination: External Annotation: Subtype: Link Rect: 265, 90, 285, 101 Destination: External Annotation: Subtype: Link Rect: 307, 708, 347, 720 Destination: External Annotation: Subtype: Link Rect: 348, 708, 369, 720 Destination: External Annotation: Subtype: Link Rect: 383, 697, 439, 708 Destination: External Annotation: Subtype: Link Rect: 441, 697, 461, 708 Destination: External Annotation: Subtype: Link Rect: 488, 685, 549, 697 Destination: External Annotation: Subtype: Link Rect: 304, 674, 324, 685 Destination: External Annotation: Subtype: Link Rect: 327, 674, 368, 685 Destination: External Annotation: Subtype: Link Rect: 371, 674, 392, 685 Destination: External Annotation: Subtype: Link Rect: 395, 674, 432, 685 Destination: External Annotation: Subtype: Link Rect: 435, 674, 456, 685 Destination: External Annotation: Subtype: Link Rect: 514, 674, 549, 685 Destination: External Annotation: Subtype: Link Rect: 304, 662, 324, 674 Destination: External Annotation: Subtype: Link Rect: 342, 594, 381, 605 Destination: External Annotation: Subtype: Link Rect: 385, 594, 405, 605 Destination: External Annotation: Subtype: Link Rect: 467, 571, 496, 582 Destination: External Annotation: Subtype: Link Rect: 498, 571, 519, 582 Destination: External Annotation: Subtype: Link Rect: 350, 536, 411, 548 Destination: External Annotation: Subtype: Link Rect: 415, 536, 435, 548 Destination: External Annotation: Subtype: Link Rect: 440, 536, 500, 548 Destination: External Annotation: Subtype: Link Rect: 505, 536, 525, 548 Destination: External Annotation: Subtype: Link Rect: 530, 536, 323, 536 Destination: External Annotation: Subtype: Link Rect: 325, 525, 345, 536 Destination: External Annotation: Subtype: Link Rect: 457, 491, 492, 502 Destination: External Annotation: Subtype: Link Rect: 494, 491, 514, 502 Destination: External Annotation: Subtype: Link Rect: 508, 445, 549, 456 Destination: External Annotation: Subtype: Link Rect: 304, 433, 324, 445 Destination: External Annotation: Subtype: Link Rect: 417, 376, 478, 388 Destination: External Annotation: Subtype: Link Rect: 482, 376, 503, 388 Destination: External Annotation: Subtype: Link Rect: 507, 376, 549, 388 Destination: External Annotation: Subtype: Link Rect: 304, 365, 324, 376 Destination: External Annotation: Subtype: Link Rect: 414, 330, 471, 342 Destination: External Annotation: Subtype: Link Rect: 473, 330, 493, 342 Destination: External Annotation: Subtype: Link Rect: 495, 330, 549, 342 Destination: External Annotation: Subtype: Link Rect: 304, 319, 324, 330 Destination: External Annotation: Subtype: Link Rect: 488, 273, 549, 284 Destination: External Annotation: Subtype: Link Rect: 304, 261, 324, 273 Destination: External Annotation: Subtype: Link Rect: 451, 227, 520, 239 Destination: External Annotation: Subtype: Link Rect: 525, 227, 546, 239 Destination: External Annotation: Subtype: Link Rect: 307, 181, 354, 193 Destination: External Annotation: Subtype: Link Rect: 357, 181, 377, 193 Destination: External Annotation: Subtype: Link Rect: 364, 78, 442, 90 Destination: External Annotation: Subtype: Link Rect: 444, 78, 464, 90 Destination: External Annotation: Subtype: Link Rect: 43, 29, 175, 38 Annotation: Subtype: Link Rect: 179, 29, 239, 37 Annotation: Subtype: Link Rect: 425, 29, 551, 38 Page: Label: 11 Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 47, 674, 99, 685 Destination: External Annotation: Subtype: Link Rect: 101, 674, 121, 685 Destination: External Annotation: Subtype: Link Rect: 229, 536, 289, 548 Destination: External Annotation: Subtype: Link Rect: 43, 525, 64, 536 Destination: External Annotation: Subtype: Link Rect: 66, 525, 111, 536 Destination: External Annotation: Subtype: Link Rect: 114, 525, 134, 536 Destination: External Annotation: Subtype: Link Rect: 231, 502, 289, 514 Destination: External Annotation: Subtype: Link Rect: 43, 491, 64, 502 Destination: External Annotation: Subtype: Link Rect: 66, 491, 123, 502 Destination: External Annotation: Subtype: Link Rect: 125, 491, 145, 502 Destination: External Annotation: Subtype: Link Rect: 231, 468, 289, 479 Destination: External Annotation: Subtype: Link Rect: 43, 456, 64, 468 Destination: External Annotation: Subtype: Link Rect: 67, 456, 126, 468 Destination: External Annotation: Subtype: Link Rect: 129, 456, 150, 468 Destination: External Annotation: Subtype: Link Rect: 140, 399, 174, 410 Destination: External Annotation: Subtype: Link Rect: 176, 399, 196, 410 Destination: External Annotation: Subtype: Link Rect: 103, 342, 151, 353 Destination: External Annotation: Subtype: Link Rect: 157, 342, 177, 353 Destination: External Annotation: Subtype: Link Rect: 171, 307, 222, 319 Destination: External Annotation: Subtype: Link Rect: 227, 307, 247, 319 Destination: External Annotation: Subtype: Link Rect: 83, 273, 137, 284 Destination: External Annotation: Subtype: Link Rect: 139, 273, 160, 284 Destination: External Annotation: Subtype: Link Rect: 106, 227, 151, 239 Destination: External Annotation: Subtype: Link Rect: 154, 227, 174, 239 Destination: External Annotation: Subtype: Link Rect: 167, 147, 213, 158 Destination: External Annotation: Subtype: Link Rect: 216, 147, 236, 158 Destination: External Annotation: Subtype: Link Rect: 180, 124, 231, 135 Destination: External Annotation: Subtype: Link Rect: 233, 124, 253, 135 Destination: External Annotation: Subtype: Link Rect: 255, 124, 64, 124 Destination: External Annotation: Subtype: Link Rect: 67, 113, 87, 124 Destination: External Annotation: Subtype: Link Rect: 90, 113, 132, 124 Destination: External Annotation: Subtype: Link Rect: 135, 113, 155, 124 Destination: External Annotation: Subtype: Link Rect: 138, 90, 182, 101 Destination: External Annotation: Subtype: Link Rect: 185, 90, 205, 101 Destination: External Annotation: Subtype: Link Rect: 442, 662, 482, 674 Destination: External Annotation: Subtype: Link Rect: 486, 662, 506, 674 Destination: External Annotation: Subtype: Link Rect: 492, 640, 549, 651 Destination: External Annotation: Subtype: Link Rect: 304, 628, 324, 640 Destination: External Annotation: Subtype: Link Rect: 481, 559, 549, 571 Destination: External Annotation: Subtype: Link Rect: 304, 548, 324, 559 Destination: External Annotation: Subtype: Link Rect: 307, 525, 369, 536 Destination: External Annotation: Subtype: Link Rect: 374, 525, 394, 536 Destination: External Annotation: Subtype: Link Rect: 472, 468, 525, 479 Destination: External Annotation: Subtype: Link Rect: 529, 468, 549, 479 Destination: External Annotation: Subtype: Link Rect: 304, 456, 344, 468 Destination: External Annotation: Subtype: Link Rect: 346, 456, 367, 468 Destination: External Annotation: Subtype: Link Rect: 369, 456, 430, 468 Destination: External Annotation: Subtype: Link Rect: 432, 456, 452, 468 Destination: External Annotation: Subtype: Link Rect: 377, 307, 446, 319 Destination: External Annotation: Subtype: Link Rect: 451, 307, 471, 319 Destination: External Annotation: Subtype: Link Rect: 475, 307, 549, 319 Destination: External Annotation: Subtype: Link Rect: 304, 296, 324, 307 Destination: External Annotation: Subtype: Link Rect: 328, 296, 388, 307 Destination: External Annotation: Subtype: Link Rect: 392, 296, 413, 307 Destination: External Annotation: Subtype: Link Rect: 477, 261, 549, 273 Destination: External Annotation: Subtype: Link Rect: 304, 250, 324, 261 Destination: External Annotation: Subtype: Link Rect: 307, 135, 348, 147 Destination: External Annotation: Subtype: Link Rect: 349, 135, 370, 147 Destination: External Annotation: Subtype: Link Rect: 333, 101, 366, 113 Destination: External Annotation: Subtype: Link Rect: 368, 101, 388, 113 Destination: External Annotation: Subtype: Link Rect: 390, 101, 439, 113 Destination: External Annotation: Subtype: Link Rect: 441, 101, 461, 113 Destination: External Annotation: Subtype: Link Rect: 43, 29, 175, 38 Annotation: Subtype: Link Rect: 179, 29, 239, 37 Annotation: Subtype: Link Rect: 425, 29, 551, 38 Page: Label: 12 Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 246, 674, 289, 685 Destination: External Annotation: Subtype: Link Rect: 43, 662, 64, 674 Destination: External Annotation: Subtype: Link Rect: 222, 594, 289, 605 Destination: External Annotation: Subtype: Link Rect: 43, 582, 64, 594 Destination: External Annotation: Subtype: Link Rect: 67, 582, 115, 594 Destination: External Annotation: Subtype: Link Rect: 118, 582, 138, 594 Destination: External Annotation: Subtype: Link Rect: 118, 491, 185, 502 Destination: External Annotation: Subtype: Link Rect: 189, 491, 209, 502 Destination: External Annotation: Subtype: Link Rect: 47, 456, 66, 468 Destination: External Annotation: Subtype: Link Rect: 72, 456, 92, 468 Destination: External Annotation: Subtype: Link Rect: 258, 445, 68, 445 Destination: External Annotation: Subtype: Link Rect: 76, 433, 96, 445 Destination: External Annotation: Subtype: Link Rect: 251, 259, 285, 269 Destination: External Annotation: Subtype: Link Rect: 181, 144, 215, 154 Destination: External Annotation: Subtype: Link Rect: 353, 662, 410, 674 Destination: External Annotation: Subtype: Link Rect: 414, 662, 435, 674 Destination: External Annotation: Subtype: Link Rect: 464, 617, 516, 628 Destination: External Annotation: Subtype: Link Rect: 518, 617, 539, 628 Destination: External Annotation: Subtype: Link Rect: 362, 569, 396, 579 Destination: External Annotation: Subtype: Link Rect: 376, 465, 411, 476 Destination: External Annotation: Subtype: Link Rect: 328, 388, 402, 399 Destination: External Annotation: Subtype: Link Rect: 407, 388, 427, 399 Destination: External Annotation: Subtype: Link Rect: 516, 365, 326, 365 Destination: External Annotation: Subtype: Link Rect: 331, 353, 351, 365 Destination: External Annotation: Subtype: Link Rect: 379, 319, 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Annotation: Subtype: Link Rect: 327, 219, 381, 228 Annotation: Subtype: Link Rect: 327, 162, 430, 171 Annotation: Subtype: Link Rect: 327, 124, 405, 133 Annotation: Subtype: Link Rect: 491, 96, 542, 105 Annotation: Subtype: Link Rect: 43, 28, 175, 37 Annotation: Subtype: Link Rect: 179, 28, 239, 36 Annotation: Subtype: Link Rect: 425, 28, 551, 37 Page: Label: 14 Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 148, 699, 201, 706 Annotation: Subtype: Link Rect: 102, 659, 189, 668 Annotation: Subtype: Link Rect: 66, 623, 153, 630 Annotation: Subtype: Link Rect: 95, 584, 153, 593 Annotation: Subtype: Link Rect: 210, 555, 288, 564 Annotation: Subtype: Link Rect: 89, 519, 178, 526 Annotation: Subtype: Link Rect: 198, 490, 266, 498 Annotation: Subtype: Link Rect: 66, 452, 168, 460 Annotation: Subtype: Link Rect: 140, 415, 225, 422 Annotation: Subtype: Link Rect: 95, 375, 182, 384 Annotation: Subtype: Link Rect: 194, 339, 273, 346 Annotation: Subtype: Link Rect: 66, 300, 122, 308 Annotation: Subtype: Link Rect: 66, 233, 148, 243 Annotation: Subtype: Link Rect: 165, 206, 267, 214 Annotation: Subtype: Link Rect: 88, 167, 166, 176 Annotation: Subtype: Link Rect: 196, 131, 249, 138 Annotation: Subtype: Link Rect: 66, 91, 155, 101 Annotation: Subtype: Link Rect: 327, 699, 412, 706 Annotation: Subtype: Link Rect: 327, 670, 386, 678 Annotation: Subtype: Link Rect: 327, 642, 389, 649 Annotation: Subtype: Link Rect: 453, 613, 551, 621 Annotation: Subtype: Link Rect: 327, 576, 412, 583 Annotation: Subtype: Link Rect: 327, 538, 394, 545 Annotation: Subtype: Link Rect: 413, 508, 492, 517 Annotation: Subtype: Link Rect: 425, 462, 527, 469 Annotation: Subtype: Link Rect: 327, 424, 410, 432 Annotation: Subtype: Link Rect: 420, 385, 477, 394 Annotation: Subtype: Link Rect: 420, 348, 519, 356 Annotation: Subtype: Link Rect: 461, 309, 540, 318 Annotation: Subtype: Link Rect: 408, 273, 496, 280 Annotation: Subtype: Link Rect: 438, 235, 535, 242 Annotation: Subtype: Link Rect: 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254, 117, 261 Annotation: Subtype: Link Rect: 142, 214, 200, 223 Annotation: Subtype: Link Rect: 93, 178, 182, 185 Annotation: Subtype: Link Rect: 178, 150, 244, 157 Annotation: Subtype: Link Rect: 66, 112, 166, 119 Annotation: Subtype: Link Rect: 327, 697, 423, 706 Annotation: Subtype: Link Rect: 327, 661, 403, 668 Annotation: Subtype: Link Rect: 356, 623, 441, 630 Annotation: Subtype: Link Rect: 373, 585, 458, 592 Annotation: Subtype: Link Rect: 373, 555, 466, 564 Annotation: Subtype: Link Rect: 327, 528, 412, 536 Annotation: Subtype: Link Rect: 386, 490, 441, 498 Annotation: Subtype: Link Rect: 422, 460, 491, 469 Annotation: Subtype: Link Rect: 327, 424, 430, 431 Annotation: Subtype: Link Rect: 366, 385, 448, 394 Annotation: Subtype: Link Rect: 327, 348, 415, 356 Annotation: Subtype: Link Rect: 327, 311, 429, 318 Annotation: Subtype: Link Rect: 442, 263, 528, 271 Annotation: Subtype: Link Rect: 407, 225, 493, 233 Annotation: Subtype: Link Rect: 435, 197, 538, 204 Annotation: Subtype: Link Rect: 327, 159, 430, 166 Annotation: Subtype: Link Rect: 456, 111, 547, 119 Annotation: Subtype: Link Rect: 454, 83, 519, 91 Annotation: Subtype: Link Rect: 43, 29, 175, 38 Annotation: Subtype: Link Rect: 179, 29, 239, 37 Annotation: Subtype: Link Rect: 425, 29, 551, 38 Page: Label: 16 Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 129, 699, 191, 706 Annotation: Subtype: Link Rect: 66, 659, 153, 668 Annotation: Subtype: Link Rect: 132, 631, 217, 640 Annotation: Subtype: Link Rect: 208, 593, 287, 602 Annotation: Subtype: Link Rect: 156, 566, 245, 573 Annotation: Subtype: Link Rect: 66, 528, 143, 536 Annotation: Subtype: Link Rect: 66, 490, 145, 498 Annotation: Subtype: Link Rect: 202, 451, 275, 460 Annotation: Subtype: Link Rect: 204, 424, 290, 431 Annotation: Subtype: Link Rect: 66, 386, 159, 394 Annotation: Subtype: Link Rect: 143, 348, 208, 356 Annotation: Subtype: Link Rect: 171, 320, 258, 328 Annotation: Subtype: Link Rect: 202, 292, 287, 299 Annotation: Subtype: Link Rect: 66, 252, 150, 261 Annotation: Subtype: Link Rect: 102, 214, 206, 223 Annotation: Subtype: Link Rect: 66, 178, 132, 186 Annotation: Subtype: Link Rect: 217, 112, 286, 119 Annotation: Subtype: Link Rect: 66, 74, 145, 81 Annotation: Subtype: Link Rect: 343, 689, 418, 697 Annotation: Subtype: Link Rect: 443, 650, 502, 659 Annotation: Subtype: Link Rect: 327, 612, 392, 621 Annotation: Subtype: Link Rect: 486, 576, 546, 583 Annotation: Subtype: Link Rect: 327, 536, 414, 545 Annotation: Subtype: Link Rect: 458, 509, 523, 517 Annotation: Subtype: Link Rect: 460, 481, 525, 488 Annotation: Subtype: Link Rect: 327, 451, 398, 460 Annotation: Subtype: Link Rect: 327, 413, 381, 422 Annotation: Subtype: Link Rect: 363, 377, 447, 384 Annotation: Subtype: Link Rect: 327, 348, 402, 356 Annotation: Subtype: Link Rect: 552, 300, 313, 319 Annotation: Subtype: Link Rect: 363, 263, 448, 271 Annotation: Subtype: Link Rect: 327, 235, 426, 242 Annotation: Subtype: Link Rect: 327, 195, 384, 205 Annotation: Subtype: Link Rect: 386, 159, 466, 167 Annotation: Subtype: Link Rect: 377, 110, 451, 119 Annotation: Subtype: Link Rect: 552, 73, 313, 92 Annotation: Subtype: Link Rect: 43, 29, 175, 38 Annotation: Subtype: Link Rect: 179, 29, 239, 37 Annotation: Subtype: Link Rect: 425, 29, 551, 38 Page: Label: 17 Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 66, 669, 147, 678 Annotation: Subtype: Link Rect: 157, 642, 242, 649 Annotation: Subtype: Link Rect: 66, 602, 154, 611 Annotation: Subtype: Link Rect: 66, 564, 136, 573 Annotation: Subtype: Link Rect: 187, 489, 266, 498 Annotation: Subtype: Link Rect: 195, 451, 273, 460 Annotation: Subtype: Link Rect: 106, 424, 191, 431 Annotation: Subtype: Link Rect: 95, 394, 173, 403 Annotation: Subtype: Link Rect: 201, 375, 289, 384 Annotation: Subtype: Link Rect: 66, 347, 167, 356 Annotation: Subtype: Link Rect: 121, 311, 211, 318 Annotation: Subtype: Link Rect: 145, 281, 215, 289 Annotation: Subtype: Link Rect: 66, 243, 162, 252 Annotation: Subtype: Link Rect: 165, 206, 250, 214 Annotation: Subtype: Link Rect: 156, 167, 253, 176 Annotation: Subtype: Link Rect: 106, 129, 184, 138 Annotation: Subtype: Link Rect: 148, 93, 233, 100 Annotation: Subtype: Link Rect: 429, 688, 487, 696 Annotation: Subtype: Link Rect: 327, 650, 375, 659 Annotation: Subtype: Link Rect: 458, 621, 541, 631 Annotation: Subtype: Link Rect: 327, 574, 404, 583 Annotation: Subtype: Link Rect: 327, 527, 426, 536 Annotation: Subtype: Link Rect: 327, 498, 406, 508 Annotation: Subtype: Link Rect: 327, 460, 405, 469 Annotation: Subtype: Link Rect: 356, 422, 445, 432 Annotation: Subtype: Link Rect: 327, 394, 396, 403 Annotation: Subtype: Link Rect: 327, 356, 414, 366 Annotation: Subtype: Link Rect: 552, 310, 313, 328 Annotation: Subtype: Link Rect: 404, 281, 476, 289 Annotation: Subtype: Link Rect: 327, 244, 412, 252 Annotation: Subtype: Link Rect: 453, 214, 508, 223 Annotation: Subtype: Link Rect: 327, 167, 404, 176 Annotation: Subtype: Link Rect: 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Rect: 156, 148, 212, 157 Annotation: Subtype: Link Rect: 66, 121, 143, 129 Annotation: Subtype: Link Rect: 327, 699, 430, 706 Annotation: Subtype: Link Rect: 409, 661, 513, 668 Annotation: Subtype: Link Rect: 327, 623, 412, 630 Annotation: Subtype: Link Rect: 327, 585, 412, 592 Annotation: Subtype: Link Rect: 416, 546, 501, 554 Annotation: Subtype: Link Rect: 370, 517, 435, 526 Annotation: Subtype: Link Rect: 327, 481, 412, 488 Annotation: Subtype: Link Rect: 361, 441, 452, 450 Annotation: Subtype: Link Rect: 460, 413, 542, 422 Annotation: Subtype: Link Rect: 370, 377, 469, 384 Annotation: Subtype: Link Rect: 386, 339, 471, 346 Annotation: Subtype: Link Rect: 327, 299, 413, 309 Annotation: Subtype: Link Rect: 327, 262, 385, 271 Annotation: Subtype: Link Rect: 552, 213, 313, 234 Annotation: Subtype: Link Rect: 458, 149, 484, 156 Annotation: Subtype: Link Rect: 484, 149, 516, 156 Annotation: Subtype: Link Rect: 515, 149, 551, 157 Annotation: Subtype: Link Rect: 304, 140, 327, 147 Annotation: Subtype: Link Rect: 327, 139, 354, 147 Annotation: Subtype: Link Rect: 43, 29, 175, 38 Annotation: Subtype: Link Rect: 179, 29, 239, 37 Annotation: Subtype: Link Rect: 425, 29, 551, 38 Checksum: c6e99a05 Type: CRC32 Checksum: 3b4e3b18623871a605161b6e03930e18 Type: MD5 Checksum: aa47d44ad457e9cd826a7351aeff1206818fa068 Type: SHA-1 Checksum: 01113a1718a14673d9ae6b6770ee1a24561df82cda069fe0734051fdb643743e Type: SHA-256