34764d044815e8a7111eb892e7d8d796 pmc_34771581.pdf 214b2647096317194a57c63c204982d81a3deebd pmc_34771581.pdf 6e0f3071418bc723b6c277c4228a504de90f8518dd35f563c75056e6d27879c0 pmc_34771581.pdf Title: The Race of CAR Therapies: CAR-NK Cells for Fighting B-Cell Hematological Cancers Subject: Acute lymphoblastic leukemia (ALL) and Chronic lymphocytic leukemia (CLL) are the most common leukemias in children and elderly people, respectively. Standard therapies, such as chemotherapy, are only effective in 40% of ALL adult patients with a five-year survival rate and therefore new alternatives need to be used, such as immunotherapy targeting specific receptors of malignant cells. Among all the options, CAR (Chimeric antigen receptor)-based therapy has arisen as a new opportunity for refractory or relapsed hematological cancer patients. CARs were designed to be used along with T lymphocytes, creating CAR-T cells, but they are presenting such encouraging results that they are already in use as drugs. Nonetheless, their side-effects and the fact that it is not possible to infuse an allogenic CAR-T product without causing graft-versus-host-disease, have meant using a different cell source to solve these problems, such as Natural Killer (NK) cells. Although CAR-based treatment is a high-speed race led by CAR-T cells, CAR-NK cells are slowly (but surely) consolidating their position; their demonstrated efficacy and the lack of undesirable side-effects is opening a new door for CAR-based treatments. CAR-NKs are now in the field to stay. Keywords: CAR-NK; CAR-T; hematological cancer; immunotherapy; blood Author: Lara Herrera, Silvia Santos, Miguel Angel Vesga, Tomas Carrascosa, Juan Carlos Garcia-Ruiz, Antonio Pérez-Martínez, Manel Juan and Cristina Eguizabal Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Nov 3 06:10:03 2021 CET ModDate: Wed Nov 3 06:49:00 2021 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 19 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 13654194 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- EUNBMT+VnURWPalladioL Type 1 Custom yes yes no 10 0 UXCHEH+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 IFECMT+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 EWNXLH+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 YSPQJI+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 37 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 59 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 63 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 67 0 KWKPAT+CMSY10 Type 1 Builtin yes yes no 79 0 AXIHDO+EURM10 Type 1 Builtin yes yes no 100 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-04-01 02:32:18 CEST RepresentationInformation: pmc_34771581.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 12:06:13 CEST Size: 13654194 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 537 FreeObjects: 9 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Background Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Standard Therapies and Treatment Improvements against Hematological Cancers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Standard Therapies for ALL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Standard Therapies for CLL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Immunotherapies against ALL and CLL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: State of the Art of CD19-CAR-T Therapies. From Bench to Current Clinical Trials Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: The Role of NK Cells in the Immune System Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Advantages and Disadvantages of CAR-NK and CAR-T Therapies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Designing NK Cells Specific CAR Constructs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: NK Cells from Several Cell Sources: Adult Peripheral Blood, Umbilical Cord Blood, Hematopoietic Progenitors from Cord Blood and Human-Induced Pluripotent Stem Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: State of the Art of NK Cell Therapies and CD19-CAR-NK Therapies with the Recent Clinical Trial Data in Refractory B Malignancies Patients Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Challenges and Future Perspectives Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Info: Title: The Race of CAR Therapies: CAR-NK Cells for Fighting B-Cell Hematological Cancers Author: Lara Herrera, Silvia Santos, Miguel Angel Vesga, Tomas Carrascosa, Juan Carlos Garcia-Ruiz, Antonio Pérez-Martínez, Manel Juan and Cristina Eguizabal Subject: Acute lymphoblastic leukemia (ALL) and Chronic lymphocytic leukemia (CLL) are the most common leukemias in children and elderly people, respectively. Standard therapies, such as chemotherapy, are only effective in 40% of ALL adult patients with a five-year survival rate and therefore new alternatives need to be used, such as immunotherapy targeting specific receptors of malignant cells. Among all the options, CAR (Chimeric antigen receptor)-based therapy has arisen as a new opportunity for refractory or relapsed hematological cancer patients. CARs were designed to be used along with T lymphocytes, creating CAR-T cells, but they are presenting such encouraging results that they are already in use as drugs. Nonetheless, their side-effects and the fact that it is not possible to infuse an allogenic CAR-T product without causing graft-versus-host-disease, have meant using a different cell source to solve these problems, such as Natural Killer (NK) cells. Although CAR-based treatment is a high-speed race led by CAR-T cells, CAR-NK cells are slowly (but surely) consolidating their position; their demonstrated efficacy and the lack of undesirable side-effects is opening a new door for CAR-based treatments. CAR-NKs are now in the field to stay. Keywords: CAR-NK; CAR-T; hematological cancer; immunotherapy; blood Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Nov 03 06:10:03 CET 2021 ModDate: Wed Nov 03 06:49:00 CET 2021 ID: 0x50ce646c33bcef959742284b6267af29, 0x50ce646c33bcef959742284b6267af29 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: IFECMT+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 122 FontDescriptor: FontName: IFECMT+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: AXIHDO+EURM10 FontSubset: true FirstChar: 11 LastChar: 16 FontDescriptor: FontName: AXIHDO+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: EWNXLH+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: EWNXLH+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: EUNBMT+VnURWPalladioL FontSubset: true FirstChar: 129 LastChar: 226 FontDescriptor: FontName: EUNBMT+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: YSPQJI+VnURWPalladioL-Bold FontSubset: true FirstChar: 178 LastChar: 189 FontDescriptor: FontName: YSPQJI+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: UXCHEH+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 151 FontDescriptor: FontName: UXCHEH+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: KWKPAT+CMSY10 FontSubset: true FirstChar: 0 LastChar: 21 FontDescriptor: FontName: KWKPAT+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 35, 759, 153, 795 Annotation: Subtype: Link Rect: 515, 759, 560, 795 Annotation: Subtype: Link Rect: 528, 659, 539, 673 Annotation: Subtype: Link Rect: 164, 647, 175, 661 Annotation: Subtype: Link Rect: 273, 647, 284, 661 Annotation: Subtype: Link Rect: 409, 647, 420, 661 Annotation: Subtype: Link Rect: 135, 371, 154, 379 Annotation: Subtype: Link Rect: 35, 358, 154, 367 Annotation: Subtype: Link Rect: 35, 348, 87, 355 Annotation: Subtype: Link Rect: 35, 162, 97, 184 Annotation: Subtype: Link Rect: 153, 89, 154, 98 Annotation: Subtype: Link Rect: 35, 77, 147, 86 Annotation: Subtype: Link Rect: 114, 17, 265, 28 Annotation: Subtype: Link Rect: 408, 17, 558, 28 Annotation: Subtype: Link Rect: 35, 458, 87, 477 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 549, 709, 556, 718 ActionDest: 153 Annotation: Subtype: Link Rect: 255, 633, 262, 642 ActionDest: 153 Annotation: Subtype: Link Rect: 252, 608, 259, 617 ActionDest: 153 Annotation: Subtype: Link Rect: 190, 558, 197, 567 ActionDest: 153 Annotation: Subtype: Link Rect: 548, 558, 555, 567 ActionDest: 153 Annotation: Subtype: Link Rect: 535, 545, 542, 554 ActionDest: 153 Annotation: Subtype: Link Rect: 478, 508, 485, 517 ActionDest: 153 Annotation: Subtype: Link Rect: 191, 457, 198, 466 ActionDest: 153 Annotation: Subtype: Link Rect: 504, 407, 511, 416 ActionDest: 153 Annotation: Subtype: Link Rect: 544, 395, 556, 404 ActionDest: 153 Annotation: Subtype: Link Rect: 534, 332, 546, 341 ActionDest: 153 Annotation: Subtype: Link Rect: 510, 268, 522, 277 ActionDest: 153 Annotation: Subtype: Link Rect: 522, 268, 534, 277 ActionDest: 153 Annotation: Subtype: Link Rect: 371, 67, 383, 76 ActionDest: 156 Annotation: Subtype: Link Rect: 386, 67, 398, 76 ActionDest: 156 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 214, 735, 226, 744 ActionDest: 156 Annotation: Subtype: Link Rect: 207, 722, 219, 731 ActionDest: 156 Annotation: Subtype: Link Rect: 543, 710, 555, 719 ActionDest: 156 Annotation: Subtype: Link Rect: 501, 647, 513, 656 ActionDest: 156 Annotation: Subtype: Link Rect: 514, 647, 526, 656 ActionDest: 156 Annotation: Subtype: Link Rect: 222, 508, 234, 518 ActionDest: 156 Annotation: Subtype: Link Rect: 321, 471, 333, 480 ActionDest: 156 Annotation: Subtype: Link Rect: 401, 370, 413, 380 ActionDest: 156 Annotation: Subtype: Link Rect: 266, 292, 273, 304 ActionDest: 86 Annotation: Subtype: Link Rect: 531, 245, 543, 254 ActionDest: 156 Annotation: Subtype: Link Rect: 544, 245, 556, 254 ActionDest: 156 Annotation: Subtype: Link Rect: 343, 157, 355, 166 ActionDest: 156 Annotation: Subtype: Link Rect: 221, 132, 233, 141 ActionDest: 156 Annotation: Subtype: Link Rect: 470, 94, 481, 103 ActionDest: 156 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 354, 448, 366, 458 ActionDest: 156 Annotation: Subtype: Link Rect: 366, 448, 378, 458 ActionDest: 156 Annotation: Subtype: Link Rect: 216, 423, 228, 432 ActionDest: 156 Annotation: Subtype: Link Rect: 215, 398, 227, 407 ActionDest: 156 Annotation: Subtype: Link Rect: 294, 386, 306, 395 ActionDest: 156 Annotation: Subtype: Link Rect: 458, 361, 470, 370 ActionDest: 156 Annotation: Subtype: Link Rect: 252, 335, 264, 345 ActionDest: 156 Annotation: Subtype: Link Rect: 427, 335, 439, 345 ActionDest: 156 Annotation: Subtype: Link Rect: 448, 285, 460, 294 ActionDest: 159 Annotation: Subtype: Link Rect: 298, 210, 310, 219 ActionDest: 159 Annotation: Subtype: Link Rect: 255, 147, 267, 156 ActionDest: 156 Annotation: Subtype: Link Rect: 259, 110, 271, 119 ActionDest: 159 Annotation: Subtype: Link Rect: 474, 107, 481, 119 ActionDest: 97 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 246, 699, 257, 707 ActionDest: 159 Annotation: Subtype: Link Rect: 249, 688, 260, 696 ActionDest: 159 Annotation: Subtype: Link Rect: 271, 677, 282, 685 ActionDest: 159 Annotation: Subtype: Link Rect: 237, 666, 248, 674 ActionDest: 156 Annotation: Subtype: Link Rect: 243, 655, 254, 663 ActionDest: 156 Annotation: Subtype: Link Rect: 247, 644, 258, 653 ActionDest: 156 Annotation: Subtype: Link Rect: 244, 633, 255, 642 ActionDest: 156 Annotation: Subtype: Link Rect: 277, 622, 288, 631 ActionDest: 156 Annotation: Subtype: Link Rect: 245, 611, 256, 620 ActionDest: 159 Annotation: Subtype: Link Rect: 280, 529, 292, 538 ActionDest: 159 Annotation: Subtype: Link Rect: 309, 454, 321, 463 ActionDest: 159 Annotation: Subtype: Link Rect: 434, 454, 446, 463 ActionDest: 159 Annotation: Subtype: Link Rect: 428, 428, 440, 438 ActionDest: 159 Annotation: Subtype: Link Rect: 443, 403, 455, 412 ActionDest: 159 Annotation: Subtype: Link Rect: 320, 328, 332, 337 ActionDest: 159 Annotation: Subtype: Link Rect: 333, 328, 345, 337 ActionDest: 159 Annotation: Subtype: Link Rect: 267, 303, 279, 312 ActionDest: 159 Annotation: Subtype: Link Rect: 544, 278, 556, 287 ActionDest: 159 Annotation: Subtype: Link Rect: 204, 240, 216, 249 ActionDest: 159 Annotation: Subtype: Link Rect: 459, 228, 471, 237 ActionDest: 159 Annotation: Subtype: Link Rect: 407, 203, 419, 212 ActionDest: 159 Annotation: Subtype: Link Rect: 263, 115, 275, 124 ActionDest: 159 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 523, 631, 535, 640 ActionDest: 159 Annotation: Subtype: Link Rect: 329, 569, 341, 578 ActionDest: 159 Annotation: Subtype: Link Rect: 341, 569, 353, 578 ActionDest: 159 Annotation: Subtype: Link Rect: 502, 543, 514, 553 ActionDest: 159 Annotation: Subtype: Link Rect: 531, 518, 543, 527 ActionDest: 159 Annotation: Subtype: Link Rect: 544, 518, 556, 527 ActionDest: 159 Annotation: Subtype: Link Rect: 442, 493, 454, 502 ActionDest: 159 Annotation: Subtype: Link Rect: 440, 418, 452, 427 ActionDest: 159 Annotation: Subtype: Link Rect: 263, 280, 275, 289 ActionDest: 159 Annotation: Subtype: Link Rect: 204, 230, 216, 239 ActionDest: 159 Annotation: Subtype: Link Rect: 217, 230, 229, 239 ActionDest: 159 Annotation: Subtype: Link Rect: 521, 217, 533, 226 ActionDest: 159 Annotation: Subtype: Link Rect: 372, 205, 384, 214 ActionDest: 159 Annotation: Subtype: Link Rect: 544, 167, 556, 176 ActionDest: 159 Annotation: Subtype: Link Rect: 433, 142, 445, 151 ActionDest: 159 Annotation: Subtype: Link Rect: 308, 117, 320, 126 ActionDest: 159 Annotation: Subtype: Link Rect: 543, 104, 555, 113 ActionDest: 162 Annotation: Subtype: Link Rect: 544, 92, 556, 101 ActionDest: 162 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 544, 657, 556, 666 ActionDest: 162 Annotation: Subtype: Link Rect: 384, 569, 396, 578 ActionDest: 162 Annotation: Subtype: Link Rect: 420, 544, 432, 553 ActionDest: 162 Annotation: Subtype: Link Rect: 524, 531, 536, 540 ActionDest: 162 Annotation: Subtype: Link Rect: 453, 506, 464, 515 ActionDest: 162 Annotation: Subtype: Link Rect: 465, 506, 477, 515 ActionDest: 162 Annotation: Subtype: Link Rect: 495, 481, 507, 490 ActionDest: 162 Annotation: Subtype: Link Rect: 544, 468, 556, 477 ActionDest: 162 Annotation: Subtype: Link Rect: 292, 443, 304, 452 ActionDest: 162 Annotation: Subtype: Link Rect: 347, 430, 359, 440 ActionDest: 162 Annotation: Subtype: Link Rect: 373, 405, 384, 414 ActionDest: 162 Annotation: Subtype: Link Rect: 480, 380, 492, 389 ActionDest: 162 Annotation: Subtype: Link Rect: 492, 380, 504, 389 ActionDest: 162 Annotation: Subtype: Link Rect: 321, 368, 333, 377 ActionDest: 162 Annotation: Subtype: Link Rect: 325, 317, 337, 327 ActionDest: 162 Annotation: Subtype: Link Rect: 533, 292, 545, 301 ActionDest: 162 Annotation: Subtype: Link Rect: 544, 280, 556, 289 ActionDest: 162 Annotation: Subtype: Link Rect: 200, 265, 207, 277 ActionDest: 110 Annotation: Subtype: Link Rect: 335, 217, 347, 226 ActionDest: 162 Annotation: Subtype: Link Rect: 361, 167, 373, 176 ActionDest: 162 Annotation: Subtype: Link Rect: 373, 167, 385, 176 ActionDest: 162 Annotation: Subtype: Link Rect: 330, 152, 337, 164 ActionDest: 110 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 200, 340, 211, 348 ActionDest: 159 Annotation: Subtype: Link Rect: 198, 329, 209, 337 ActionDest: 162 Annotation: Subtype: Link Rect: 456, 329, 467, 337 ActionDest: 162 Annotation: Subtype: Link Rect: 263, 318, 274, 326 ActionDest: 162 Annotation: Subtype: Link Rect: 444, 318, 455, 326 ActionDest: 162 Annotation: Subtype: Link Rect: 212, 296, 222, 304 ActionDest: 162 Annotation: Subtype: Link Rect: 462, 296, 473, 304 ActionDest: 162 Annotation: Subtype: Link Rect: 473, 296, 484, 304 ActionDest: 162 Annotation: Subtype: Link Rect: 237, 285, 248, 293 ActionDest: 162 Annotation: Subtype: Link Rect: 527, 285, 538, 293 ActionDest: 162 Annotation: Subtype: Link Rect: 538, 285, 549, 293 ActionDest: 162 Annotation: Subtype: Link Rect: 357, 213, 369, 222 ActionDest: 162 Annotation: Subtype: Link Rect: 419, 188, 431, 197 ActionDest: 162 Annotation: Subtype: Link Rect: 297, 173, 304, 185 ActionDest: 121 Annotation: Subtype: Link Rect: 529, 150, 541, 159 ActionDest: 162 Annotation: Subtype: Link Rect: 544, 150, 556, 159 ActionDest: 165 Annotation: Subtype: Link Rect: 544, 125, 556, 134 ActionDest: 165 Annotation: Subtype: Link Rect: 328, 88, 340, 97 ActionDest: 165 Annotation: Subtype: Link Rect: 309, 62, 321, 72 ActionDest: 165 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 485, 697, 497, 706 ActionDest: 165 Annotation: Subtype: Link Rect: 496, 264, 503, 276 ActionDest: 132 Annotation: Subtype: Link Rect: 539, 229, 556, 238 ActionDest: 165 Annotation: Subtype: Link Rect: 292, 167, 309, 176 ActionDest: 165 Annotation: Subtype: Link Rect: 311, 167, 328, 176 ActionDest: 165 Annotation: Subtype: Link Rect: 360, 129, 377, 138 ActionDest: 165 Page: Sequence: 10 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 450, 722, 467, 731 ActionDest: 165 Annotation: Subtype: Link Rect: 519, 722, 536, 731 ActionDest: 165 Annotation: Subtype: Link Rect: 219, 710, 236, 719 ActionDest: 165 Annotation: Subtype: Link Rect: 267, 685, 284, 694 ActionDest: 165 Annotation: Subtype: Link Rect: 284, 685, 301, 694 ActionDest: 165 Annotation: Subtype: Link Rect: 237, 609, 254, 618 ActionDest: 165 Annotation: Subtype: Link Rect: 255, 609, 272, 618 ActionDest: 165 Annotation: Subtype: Link Rect: 281, 597, 298, 606 ActionDest: 165 Annotation: Subtype: Link Rect: 298, 597, 315, 606 ActionDest: 165 Annotation: Subtype: Link Rect: 457, 597, 474, 606 ActionDest: 165 Annotation: Subtype: Link Rect: 487, 335, 504, 344 ActionDest: 165 Annotation: Subtype: Link Rect: 525, 260, 542, 269 ActionDest: 165 Annotation: Subtype: Link Rect: 240, 244, 247, 256 ActionDest: 132 Annotation: Subtype: Link Rect: 544, 209, 556, 218 ActionDest: 162 Annotation: Subtype: Link Rect: 544, 184, 556, 193 ActionDest: 162 Annotation: Subtype: Link Rect: 443, 109, 460, 118 ActionDest: 165 Annotation: Subtype: Link Rect: 221, 59, 238, 68 ActionDest: 165 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 220, 722, 236, 731 ActionDest: 165 Annotation: Subtype: Link Rect: 261, 710, 278, 719 ActionDest: 165 Annotation: Subtype: Link Rect: 359, 660, 376, 669 ActionDest: 168 Annotation: Subtype: Link Rect: 379, 659, 396, 669 ActionDest: 168 Annotation: Subtype: Link Rect: 544, 597, 556, 606 ActionDest: 162 Annotation: Subtype: Link Rect: 357, 572, 369, 581 ActionDest: 162 Annotation: Subtype: Link Rect: 370, 572, 387, 581 ActionDest: 168 Annotation: Subtype: Link Rect: 282, 546, 299, 556 ActionDest: 168 Annotation: Subtype: Link Rect: 349, 521, 361, 530 ActionDest: 162 Annotation: Subtype: Link Rect: 409, 396, 426, 405 ActionDest: 168 Annotation: Subtype: Link Rect: 455, 358, 467, 367 ActionDest: 162 Annotation: Subtype: Link Rect: 425, 333, 442, 342 ActionDest: 168 Annotation: Subtype: Link Rect: 211, 245, 227, 254 ActionDest: 168 Annotation: Subtype: Link Rect: 249, 132, 266, 141 ActionDest: 168 Page: Sequence: 13 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 125, 399, 323, 410 Annotation: Subtype: Link Rect: 194, 376, 497, 387 Annotation: Subtype: Link Rect: 108, 343, 146, 353 Annotation: Subtype: Link Rect: 152, 343, 188, 353 Annotation: Subtype: Link Rect: 393, 307, 431, 318 Annotation: Subtype: Link Rect: 59, 239, 97, 249 Annotation: Subtype: Link Rect: 103, 239, 139, 249 Annotation: Subtype: Link Rect: 283, 192, 320, 203 Annotation: Subtype: Link Rect: 90, 124, 128, 134 Annotation: Subtype: Link Rect: 340, 112, 560, 123 Annotation: Subtype: Link Rect: 56, 100, 255, 111 Annotation: Subtype: Link Rect: 59, 78, 97, 88 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 451, 721, 488, 732 Annotation: Subtype: Link Rect: 82, 699, 119, 709 Annotation: Subtype: Link Rect: 125, 699, 162, 709 Annotation: Subtype: Link Rect: 460, 663, 498, 674 Annotation: Subtype: Link Rect: 520, 640, 557, 651 Annotation: Subtype: Link Rect: 59, 630, 95, 640 Annotation: Subtype: Link Rect: 202, 606, 239, 617 Annotation: Subtype: Link Rect: 171, 584, 208, 594 Annotation: Subtype: Link Rect: 215, 584, 251, 594 Annotation: Subtype: Link Rect: 82, 549, 119, 559 Annotation: Subtype: Link Rect: 126, 549, 162, 559 Annotation: Subtype: Link Rect: 158, 515, 196, 525 Annotation: Subtype: Link Rect: 202, 515, 238, 525 Annotation: Subtype: Link Rect: 441, 502, 478, 513 Annotation: Subtype: Link Rect: 485, 502, 521, 513 Annotation: Subtype: Link Rect: 199, 469, 237, 479 Annotation: Subtype: Link Rect: 243, 433, 281, 444 Annotation: Subtype: Link Rect: 256, 422, 521, 433 Annotation: Subtype: Link Rect: 264, 399, 508, 410 Annotation: Subtype: Link Rect: 59, 365, 97, 375 Annotation: Subtype: Link Rect: 333, 330, 370, 341 Annotation: Subtype: Link Rect: 176, 308, 213, 318 Annotation: Subtype: Link Rect: 220, 308, 256, 318 Annotation: Subtype: Link Rect: 245, 285, 282, 295 Annotation: Subtype: Link Rect: 519, 272, 557, 283 Annotation: Subtype: Link Rect: 59, 262, 95, 272 Annotation: Subtype: Link Rect: 59, 215, 97, 226 Annotation: Subtype: Link Rect: 103, 215, 139, 226 Annotation: Subtype: Link Rect: 447, 192, 485, 203 Annotation: Subtype: Link Rect: 491, 192, 527, 203 Annotation: Subtype: Link Rect: 397, 157, 435, 168 Annotation: Subtype: Link Rect: 441, 157, 477, 168 Annotation: Subtype: Link Rect: 415, 134, 453, 145 Annotation: Subtype: Link Rect: 487, 100, 525, 111 Annotation: Subtype: Link Rect: 243, 65, 281, 76 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 59, 722, 97, 732 Annotation: Subtype: Link Rect: 483, 709, 520, 720 Annotation: Subtype: Link Rect: 56, 686, 291, 697 Annotation: Subtype: Link Rect: 355, 663, 392, 674 Annotation: Subtype: Link Rect: 140, 641, 178, 651 Annotation: Subtype: Link Rect: 184, 641, 220, 651 Annotation: Subtype: Link Rect: 313, 606, 350, 617 Annotation: Subtype: Link Rect: 306, 583, 343, 594 Annotation: Subtype: Link Rect: 339, 560, 376, 571 Annotation: Subtype: Link Rect: 422, 548, 460, 559 Annotation: Subtype: Link Rect: 466, 548, 502, 559 Annotation: Subtype: Link Rect: 259, 526, 297, 536 Annotation: Subtype: Link Rect: 303, 526, 339, 536 Annotation: Subtype: Link Rect: 118, 503, 155, 513 Annotation: Subtype: Link Rect: 162, 503, 198, 513 Annotation: Subtype: Link Rect: 508, 479, 545, 490 Annotation: Subtype: Link Rect: 183, 456, 220, 467 Annotation: Subtype: Link Rect: 226, 456, 262, 467 Annotation: Subtype: Link Rect: 380, 433, 417, 444 Annotation: Subtype: Link Rect: 334, 400, 371, 410 Annotation: Subtype: Link Rect: 514, 387, 551, 398 Annotation: Subtype: Link Rect: 341, 364, 379, 375 Annotation: Subtype: Link Rect: 385, 341, 423, 352 Annotation: Subtype: Link Rect: 429, 341, 465, 352 Annotation: Subtype: Link Rect: 417, 318, 454, 329 Annotation: Subtype: Link Rect: 460, 318, 496, 329 Annotation: Subtype: Link Rect: 520, 307, 557, 318 Annotation: Subtype: Link Rect: 183, 285, 219, 295 Annotation: Subtype: Link Rect: 234, 261, 272, 272 Annotation: Subtype: Link Rect: 278, 261, 314, 272 Annotation: Subtype: Link Rect: 95, 238, 133, 249 Annotation: Subtype: Link Rect: 464, 226, 502, 237 Annotation: Subtype: Link Rect: 508, 226, 544, 237 Annotation: Subtype: Link Rect: 478, 203, 516, 214 Annotation: Subtype: Link Rect: 519, 192, 557, 203 Annotation: Subtype: Link Rect: 59, 181, 95, 191 Annotation: Subtype: Link Rect: 223, 157, 260, 168 Annotation: Subtype: Link Rect: 519, 146, 557, 157 Annotation: Subtype: Link Rect: 289, 123, 326, 134 Annotation: Subtype: Link Rect: 332, 123, 368, 134 Annotation: Subtype: Link Rect: 173, 100, 210, 111 Annotation: Subtype: Link Rect: 217, 100, 253, 111 Annotation: Subtype: Link Rect: 158, 66, 195, 76 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 167, 722, 204, 732 Annotation: Subtype: Link Rect: 417, 698, 454, 709 Annotation: Subtype: Link Rect: 491, 675, 528, 686 Annotation: Subtype: Link Rect: 274, 652, 311, 663 Annotation: Subtype: Link Rect: 318, 652, 354, 663 Annotation: Subtype: Link Rect: 104, 630, 142, 640 Annotation: Subtype: Link Rect: 148, 630, 184, 640 Annotation: Subtype: Link Rect: 59, 595, 97, 605 Annotation: Subtype: Link Rect: 397, 571, 434, 582 Annotation: Subtype: Link Rect: 156, 549, 194, 559 Annotation: Subtype: Link Rect: 200, 549, 236, 559 Annotation: Subtype: Link Rect: 77, 526, 115, 536 Annotation: Subtype: Link Rect: 438, 514, 475, 525 Annotation: Subtype: Link Rect: 150, 492, 188, 502 Annotation: Subtype: Link Rect: 278, 456, 315, 467 Annotation: Subtype: Link Rect: 321, 456, 357, 467 Annotation: Subtype: Link Rect: 423, 422, 461, 433 Annotation: Subtype: Link Rect: 365, 387, 403, 398 Annotation: Subtype: Link Rect: 409, 387, 445, 398 Annotation: Subtype: Link Rect: 131, 354, 169, 364 Annotation: Subtype: Link Rect: 175, 354, 211, 364 Annotation: Subtype: Link Rect: 118, 319, 155, 329 Annotation: Subtype: Link Rect: 344, 307, 381, 318 Annotation: Subtype: Link Rect: 387, 307, 423, 318 Annotation: Subtype: Link Rect: 396, 284, 433, 295 Annotation: Subtype: Link Rect: 477, 272, 514, 283 Annotation: Subtype: Link Rect: 521, 272, 557, 283 Annotation: Subtype: Link Rect: 109, 250, 146, 260 Annotation: Subtype: Link Rect: 77, 227, 115, 237 Annotation: Subtype: Link Rect: 113, 204, 151, 214 Annotation: Subtype: Link Rect: 210, 169, 248, 180 Annotation: Subtype: Link Rect: 354, 134, 391, 145 Annotation: Subtype: Link Rect: 447, 111, 485, 122 Annotation: Subtype: Link Rect: 491, 111, 527, 122 Annotation: Subtype: Link Rect: 59, 77, 97, 88 Page: Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 308, 710, 346, 720 Annotation: Subtype: Link Rect: 352, 710, 388, 720 Annotation: Subtype: Link Rect: 440, 686, 478, 697 Annotation: Subtype: Link Rect: 373, 663, 411, 674 Annotation: Subtype: Link Rect: 294, 640, 332, 651 Annotation: Subtype: Link Rect: 338, 640, 374, 651 Annotation: Subtype: Link Rect: 149, 618, 187, 628 Annotation: Subtype: Link Rect: 59, 584, 97, 594 Annotation: Subtype: Link Rect: 86, 549, 124, 559 Annotation: Subtype: Link Rect: 130, 549, 166, 559 Annotation: Subtype: Link Rect: 145, 515, 182, 525 Annotation: Subtype: Link Rect: 188, 515, 224, 525 Annotation: Subtype: Link Rect: 235, 491, 272, 502 Annotation: Subtype: Link Rect: 241, 411, 278, 421 Annotation: Subtype: Link Rect: 59, 354, 97, 364 Annotation: Subtype: Link Rect: 246, 330, 284, 341 Annotation: Subtype: Link Rect: 290, 330, 326, 341 Annotation: Subtype: Link Rect: 59, 296, 97, 306 Annotation: Subtype: Link Rect: 367, 272, 404, 284 Annotation: Subtype: Link Rect: 376, 249, 414, 260 Annotation: Subtype: Link Rect: 420, 249, 456, 260 Annotation: Subtype: Link Rect: 302, 215, 339, 226 Annotation: Subtype: Link Rect: 345, 215, 382, 226 Annotation: Subtype: Link Rect: 211, 192, 248, 203 Annotation: Subtype: Link Rect: 254, 192, 290, 203 Annotation: Subtype: Link Rect: 269, 169, 306, 180 Annotation: Subtype: Link Rect: 312, 169, 348, 180 Annotation: Subtype: Link Rect: 291, 123, 329, 134 Annotation: Subtype: Link Rect: 515, 100, 552, 111 Annotation: Subtype: Link Rect: 479, 77, 516, 88 Page: Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 520, 721, 557, 732 Annotation: Subtype: Link Rect: 409, 698, 447, 709 Annotation: Subtype: Link Rect: 453, 698, 489, 709 Annotation: Subtype: Link Rect: 250, 641, 287, 651 Annotation: Subtype: Link Rect: 293, 641, 330, 651 Annotation: Subtype: Link Rect: 95, 618, 132, 628 Annotation: Subtype: Link Rect: 139, 618, 175, 628 Annotation: Subtype: Link Rect: 59, 584, 97, 594 Annotation: Subtype: Link Rect: 103, 584, 139, 594 Annotation: Subtype: Link Rect: 349, 560, 386, 571 Annotation: Subtype: Link Rect: 393, 560, 429, 571 Annotation: Subtype: Link Rect: 206, 548, 560, 559 Annotation: Subtype: Link Rect: 56, 537, 233, 548 Annotation: Subtype: Link Rect: 286, 514, 323, 525 Annotation: Subtype: Link Rect: 329, 514, 365, 525 Checksum: a3fe5208 Type: CRC32 Checksum: 34764d044815e8a7111eb892e7d8d796 Type: MD5 Checksum: 214b2647096317194a57c63c204982d81a3deebd Type: SHA-1