9cb8ede4e07cc5cdf5faa5394fbcde3d 270621.pdf b7a8df78055dad9e58eaeb1b6f81b9ee5518e950 270621.pdf eb8b2e40e2a55c8835edc59e77e11c575264d1a1581f4b2391c529be4d0580e7 270621.pdf Title: Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas Subject: The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte’s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B-cell non-Hodgkin lymphomas (B-NHLs). In the last decade, the emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton’s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma such as diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients. Keywords: B-cell non-Hodgkin lymphoma (B-NHL); B-cell receptor (BCR); Bruton’s tyrosine kinase (BTK); spleen tyrosine kinase (SYK); phosphoinositide-3-kinase (PI3K); ibrutinib; acalabrutinib; combination therapies Author: Núria Profitós-Pelejà, Juliana Carvalho Santos, Ana Marín-Niebla, Gaël Roué and Marcelo Lima Ribeiro Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Feb 9 11:29:07 2022 CET ModDate: Wed Feb 9 11:33:20 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 22 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1096333 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- YFXVDM+URWPalladioL-Bold Type 1 Custom yes yes no 10 0 WRBWMF+URWPalladioL-Roma Type 1 Custom yes yes no 15 0 UPZVUI+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 SEIQES+VnURWPalladioL-Bold Type 1 Custom yes yes no 23 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 32 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 36 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 40 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 53 0 YQLUTS+EURM10 Type 1 Builtin yes yes no 75 0 FBDBCA+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 92 0 FBDBCB+PalatinoLinotype CID TrueType Identity-H yes yes yes 95 0 FBDBCC+PalatinoLinotype TrueType WinAnsi yes yes no 101 0 FBDBCE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 104 0 OBTFSX+VnURWPalladioL Type 1 Custom yes yes no 139 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-24 02:30:10 CEST RepresentationInformation: 270621.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-05-23 16:45:26 CEST Size: 1096333 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 654 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Main Characteristics of Aggressive B-Cell Lymphoma Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: B-Cell Receptor (BCR) Signaling Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Children: Item: Title: Physiological Roles of BCR Signaling Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Dysregulated BCR Signaling in Aggressive B-Cell Lymphomas Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Pharmacological Targeting of BCR Upstream Kinases and Its Limitations in MCL and DLBCL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Children: Item: Title: Preclinical Drug Development Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Clinical Experience with the Targeting of Apical BCR Kinases in DLBCL and MCL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: BTKi- and PI3Ki-Based Combination Therapies in DLBCL and MCL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Conclusions and Perspectives Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Info: Title: Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas Author: Núria Profitós-Pelejà, Juliana Carvalho Santos, Ana Marín-Niebla, Gaël Roué and Marcelo Lima Ribeiro Subject: The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte’s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B-cell non-Hodgkin lymphomas (B-NHLs). In the last decade, the emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton’s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma such as diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients. Keywords: B-cell non-Hodgkin lymphoma (B-NHL); B-cell receptor (BCR); Bruton’s tyrosine kinase (BTK); spleen tyrosine kinase (SYK); phosphoinositide-3-kinase (PI3K); ibrutinib; acalabrutinib; combination therapies Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Feb 09 11:29:07 CET 2022 ModDate: Wed Feb 09 11:33:20 CET 2022 ID: 0xe4858c39f581eea97c4ab29351992710, 0xe4858c39f581eea97c4ab29351992710 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: UPZVUI+URWPalladioL-Ital FontSubset: true FirstChar: 45 LastChar: 122 FontDescriptor: FontName: UPZVUI+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: SEIQES+VnURWPalladioL-Bold FontSubset: true FirstChar: 160 LastChar: 243 FontDescriptor: FontName: SEIQES+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: YFXVDM+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 235 FontDescriptor: FontName: YFXVDM+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: YQLUTS+EURM10 FontSubset: true FirstChar: 11 LastChar: 22 FontDescriptor: FontName: YQLUTS+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: OBTFSX+VnURWPalladioL FontSubset: true FirstChar: 160 LastChar: 254 FontDescriptor: FontName: OBTFSX+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: WRBWMF+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: WRBWMF+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 51, 323, 152, 332 Annotation: Subtype: Link Rect: 34, 313, 87, 320 Annotation: Subtype: Link Rect: 34, 164, 96, 186 Annotation: Subtype: Link Rect: 126, 90, 154, 99 Annotation: Subtype: Link Rect: 34, 78, 147, 87 Annotation: Subtype: Link Rect: 34, 756, 152, 792 Annotation: Subtype: Link Rect: 515, 756, 560, 792 Annotation: Subtype: Link Rect: 143, 661, 154, 674 Annotation: Subtype: Link Rect: 280, 661, 291, 674 Annotation: Subtype: Link Rect: 385, 661, 396, 674 Annotation: Subtype: Link Rect: 460, 661, 471, 674 Annotation: Subtype: Link Rect: 110, 17, 261, 28 Annotation: Subtype: Link Rect: 410, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 408, 86, 427 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 459, 406, 466, 415 ActionDest: 136 Annotation: Subtype: Link Rect: 466, 406, 473, 415 ActionDest: 136 Annotation: Subtype: Link Rect: 214, 355, 221, 365 ActionDest: 136 Annotation: Subtype: Link Rect: 240, 318, 247, 327 ActionDest: 136 Annotation: Subtype: Link Rect: 549, 305, 556, 314 ActionDest: 136 Annotation: Subtype: Link Rect: 212, 280, 219, 289 ActionDest: 136 Annotation: Subtype: Link Rect: 220, 280, 227, 289 ActionDest: 136 Annotation: Subtype: Link Rect: 320, 255, 327, 264 ActionDest: 136 Annotation: Subtype: Link Rect: 504, 205, 511, 214 ActionDest: 136 Annotation: Subtype: Link Rect: 284, 155, 291, 164 ActionDest: 136 Annotation: Subtype: Link Rect: 544, 79, 556, 88 ActionDest: 136 Annotation: Subtype: Link Rect: 473, 67, 485, 76 ActionDest: 136 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 445, 634, 456, 643 ActionDest: 136 Annotation: Subtype: Link Rect: 457, 634, 469, 643 ActionDest: 136 Annotation: Subtype: Link Rect: 229, 521, 241, 530 ActionDest: 136 Annotation: Subtype: Link Rect: 213, 458, 225, 467 ActionDest: 136 Annotation: Subtype: Link Rect: 226, 458, 238, 467 ActionDest: 136 Annotation: Subtype: Link Rect: 280, 421, 292, 429 ActionDest: 136 Annotation: Subtype: Link Rect: 368, 370, 380, 379 ActionDest: 136 Annotation: Subtype: Link Rect: 323, 345, 334, 354 ActionDest: 136 Annotation: Subtype: Link Rect: 337, 345, 349, 354 ActionDest: 136 Annotation: Subtype: Link Rect: 515, 307, 527, 316 ActionDest: 136 Annotation: Subtype: Link Rect: 528, 308, 539, 316 ActionDest: 143 Annotation: Subtype: Link Rect: 505, 282, 517, 291 ActionDest: 143 Annotation: Subtype: Link Rect: 520, 282, 532, 291 ActionDest: 143 Annotation: Subtype: Link Rect: 275, 219, 287, 229 ActionDest: 143 Annotation: Subtype: Link Rect: 288, 219, 300, 229 ActionDest: 143 Annotation: Subtype: Link Rect: 234, 182, 246, 191 ActionDest: 143 Annotation: Subtype: Link Rect: 377, 169, 389, 178 ActionDest: 143 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 367, 723, 374, 732 ActionDest: 136 Annotation: Subtype: Link Rect: 470, 695, 477, 707 ActionDest: 82 Annotation: Subtype: Link Rect: 359, 660, 371, 669 ActionDest: 143 Annotation: Subtype: Link Rect: 249, 622, 261, 631 ActionDest: 143 Annotation: Subtype: Link Rect: 264, 622, 276, 631 ActionDest: 143 Annotation: Subtype: Link Rect: 272, 585, 284, 594 ActionDest: 143 Annotation: Subtype: Link Rect: 285, 585, 297, 594 ActionDest: 143 Annotation: Subtype: Link Rect: 237, 535, 249, 544 ActionDest: 143 Annotation: Subtype: Link Rect: 321, 86, 333, 95 ActionDest: 143 Annotation: Subtype: Link Rect: 372, 83, 379, 95 ActionDest: 82 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 333, 710, 345, 719 ActionDest: 143 Annotation: Subtype: Link Rect: 348, 710, 360, 719 ActionDest: 143 Annotation: Subtype: Link Rect: 463, 685, 475, 694 ActionDest: 143 Annotation: Subtype: Link Rect: 455, 648, 467, 657 ActionDest: 143 Annotation: Subtype: Link Rect: 363, 597, 375, 606 ActionDest: 143 Annotation: Subtype: Link Rect: 341, 560, 353, 569 ActionDest: 143 Annotation: Subtype: Link Rect: 353, 560, 365, 569 ActionDest: 143 Annotation: Subtype: Link Rect: 240, 522, 252, 531 ActionDest: 143 Annotation: Subtype: Link Rect: 279, 509, 291, 519 ActionDest: 143 Annotation: Subtype: Link Rect: 506, 497, 518, 506 ActionDest: 146 Annotation: Subtype: Link Rect: 301, 459, 313, 468 ActionDest: 146 Annotation: Subtype: Link Rect: 545, 422, 556, 431 ActionDest: 143 Annotation: Subtype: Link Rect: 200, 406, 207, 418 ActionDest: 82 Annotation: Subtype: Link Rect: 211, 396, 223, 406 ActionDest: 146 Annotation: Subtype: Link Rect: 310, 371, 322, 380 ActionDest: 146 Annotation: Subtype: Link Rect: 515, 334, 527, 343 ActionDest: 146 Annotation: Subtype: Link Rect: 527, 334, 539, 343 ActionDest: 146 Annotation: Subtype: Link Rect: 329, 309, 341, 318 ActionDest: 146 Annotation: Subtype: Link Rect: 379, 283, 391, 293 ActionDest: 146 Annotation: Subtype: Link Rect: 351, 259, 363, 267 ActionDest: 143 Annotation: Subtype: Link Rect: 455, 233, 467, 242 ActionDest: 146 Annotation: Subtype: Link Rect: 196, 208, 208, 217 ActionDest: 146 Annotation: Subtype: Link Rect: 523, 71, 535, 80 ActionDest: 146 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 373, 698, 385, 707 ActionDest: 143 Annotation: Subtype: Link Rect: 184, 685, 196, 694 ActionDest: 146 Annotation: Subtype: Link Rect: 504, 673, 516, 682 ActionDest: 146 Annotation: Subtype: Link Rect: 545, 660, 557, 669 ActionDest: 146 Annotation: Subtype: Link Rect: 240, 647, 252, 657 ActionDest: 146 Annotation: Subtype: Link Rect: 545, 610, 557, 619 ActionDest: 146 Annotation: Subtype: Link Rect: 418, 585, 430, 594 ActionDest: 146 Annotation: Subtype: Link Rect: 433, 585, 445, 594 ActionDest: 146 Annotation: Subtype: Link Rect: 531, 547, 543, 556 ActionDest: 146 Annotation: Subtype: Link Rect: 544, 547, 556, 556 ActionDest: 146 Annotation: Subtype: Link Rect: 350, 522, 362, 531 ActionDest: 146 Annotation: Subtype: Link Rect: 242, 497, 254, 506 ActionDest: 146 Annotation: Subtype: Link Rect: 263, 484, 275, 493 ActionDest: 146 Annotation: Subtype: Link Rect: 276, 484, 288, 493 ActionDest: 149 Annotation: Subtype: Link Rect: 477, 472, 489, 481 ActionDest: 149 Annotation: Subtype: Link Rect: 539, 459, 551, 468 ActionDest: 149 Annotation: Subtype: Link Rect: 472, 397, 483, 406 ActionDest: 149 Annotation: Subtype: Link Rect: 262, 334, 274, 343 ActionDest: 149 Annotation: Subtype: Link Rect: 274, 334, 286, 343 ActionDest: 149 Annotation: Subtype: Link Rect: 496, 334, 508, 343 ActionDest: 149 Annotation: Subtype: Link Rect: 305, 309, 316, 318 ActionDest: 149 Annotation: Subtype: Link Rect: 232, 296, 244, 305 ActionDest: 149 Annotation: Subtype: Link Rect: 225, 283, 237, 293 ActionDest: 149 Annotation: Subtype: Link Rect: 466, 283, 477, 293 ActionDest: 149 Annotation: Subtype: Link Rect: 456, 271, 468, 280 ActionDest: 149 Annotation: Subtype: Link Rect: 468, 271, 480, 280 ActionDest: 149 Annotation: Subtype: Link Rect: 435, 221, 447, 230 ActionDest: 149 Annotation: Subtype: Link Rect: 529, 208, 541, 217 ActionDest: 149 Annotation: Subtype: Link Rect: 544, 208, 556, 217 ActionDest: 149 Annotation: Subtype: Link Rect: 543, 170, 555, 180 ActionDest: 146 Annotation: Subtype: Link Rect: 339, 158, 351, 167 ActionDest: 149 Annotation: Subtype: Link Rect: 221, 133, 233, 142 ActionDest: 149 Annotation: Subtype: Link Rect: 233, 133, 245, 142 ActionDest: 149 Annotation: Subtype: Link Rect: 208, 108, 219, 117 ActionDest: 149 Annotation: Subtype: Link Rect: 544, 95, 556, 104 ActionDest: 149 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 200, 735, 212, 744 ActionDest: 152 Annotation: Subtype: Link Rect: 470, 723, 482, 732 ActionDest: 152 Annotation: Subtype: Link Rect: 483, 723, 495, 732 ActionDest: 152 Annotation: Subtype: Link Rect: 531, 698, 543, 707 ActionDest: 152 Annotation: Subtype: Link Rect: 389, 647, 401, 657 ActionDest: 152 Annotation: Subtype: Link Rect: 543, 635, 555, 644 ActionDest: 152 Annotation: Subtype: Link Rect: 485, 622, 497, 631 ActionDest: 152 Annotation: Subtype: Link Rect: 497, 622, 514, 631 ActionDest: 152 Annotation: Subtype: Link Rect: 426, 597, 443, 606 ActionDest: 152 Annotation: Subtype: Link Rect: 307, 572, 324, 581 ActionDest: 152 Annotation: Subtype: Link Rect: 354, 547, 371, 556 ActionDest: 152 Annotation: Subtype: Link Rect: 268, 535, 285, 544 ActionDest: 152 Annotation: Subtype: Link Rect: 406, 522, 423, 531 ActionDest: 152 Annotation: Subtype: Link Rect: 279, 497, 296, 506 ActionDest: 152 Annotation: Subtype: Link Rect: 539, 484, 556, 493 ActionDest: 152 Annotation: Subtype: Link Rect: 320, 434, 337, 443 ActionDest: 152 Annotation: Subtype: Link Rect: 266, 409, 283, 418 ActionDest: 152 Annotation: Subtype: Link Rect: 283, 409, 300, 418 ActionDest: 152 Annotation: Subtype: Link Rect: 345, 371, 362, 380 ActionDest: 152 Annotation: Subtype: Link Rect: 363, 372, 380, 380 ActionDest: 152 Annotation: Subtype: Link Rect: 249, 359, 261, 368 ActionDest: 146 Annotation: Subtype: Link Rect: 443, 346, 455, 355 ActionDest: 146 Annotation: Subtype: Link Rect: 538, 334, 555, 343 ActionDest: 152 Annotation: Subtype: Link Rect: 274, 296, 291, 305 ActionDest: 152 Annotation: Subtype: Link Rect: 392, 271, 409, 280 ActionDest: 152 Annotation: Subtype: Link Rect: 415, 258, 432, 267 ActionDest: 155 Annotation: Subtype: Link Rect: 207, 208, 224, 217 ActionDest: 155 Annotation: Subtype: Link Rect: 363, 196, 380, 205 ActionDest: 155 Annotation: Subtype: Link Rect: 242, 170, 259, 180 ActionDest: 155 Annotation: Subtype: Link Rect: 297, 168, 304, 180 ActionDest: 82 Annotation: Subtype: Link Rect: 524, 95, 541, 104 ActionDest: 155 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 519, 685, 536, 694 ActionDest: 155 Annotation: Subtype: Link Rect: 227, 673, 244, 682 ActionDest: 155 Annotation: Subtype: Link Rect: 247, 673, 264, 682 ActionDest: 155 Annotation: Subtype: Link Rect: 418, 673, 435, 682 ActionDest: 155 Annotation: Subtype: Link Rect: 435, 673, 452, 682 ActionDest: 155 Annotation: Subtype: Link Rect: 353, 647, 370, 657 ActionDest: 155 Annotation: Subtype: Link Rect: 384, 522, 401, 531 ActionDest: 155 Annotation: Subtype: Link Rect: 273, 422, 290, 431 ActionDest: 155 Annotation: Subtype: Link Rect: 291, 422, 308, 431 ActionDest: 155 Annotation: Subtype: Link Rect: 295, 356, 302, 368 ActionDest: 117 Annotation: Subtype: Link Rect: 526, 270, 540, 278 ActionDest: 155 Annotation: Subtype: Link Rect: 526, 246, 540, 254 ActionDest: 155 Annotation: Subtype: Link Rect: 526, 218, 540, 225 ActionDest: 155 Annotation: Subtype: Link Rect: 526, 189, 540, 197 ActionDest: 155 Annotation: Subtype: Link Rect: 526, 161, 540, 169 ActionDest: 155 Annotation: Subtype: Link Rect: 526, 123, 540, 131 ActionDest: 158 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 526, 691, 540, 698 ActionDest: 158 Annotation: Subtype: Link Rect: 526, 591, 540, 599 ActionDest: 155 Annotation: Subtype: Link Rect: 526, 553, 540, 561 ActionDest: 158 Annotation: Subtype: Link Rect: 526, 520, 540, 528 ActionDest: 158 Annotation: Subtype: Link Rect: 526, 491, 540, 499 ActionDest: 158 Annotation: Subtype: Link Rect: 526, 463, 540, 471 ActionDest: 158 Annotation: Subtype: Link Rect: 526, 435, 540, 442 ActionDest: 158 Annotation: Subtype: Link Rect: 526, 368, 540, 376 ActionDest: 158 Annotation: Subtype: Link Rect: 526, 316, 540, 324 ActionDest: 158 Annotation: Subtype: Link Rect: 526, 254, 540, 262 ActionDest: 158 Annotation: Subtype: Link Rect: 526, 226, 540, 233 ActionDest: 158 Annotation: Subtype: Link Rect: 519, 183, 533, 191 ActionDest: 158 Annotation: Subtype: Link Rect: 533, 183, 547, 191 ActionDest: 158 Annotation: Subtype: Link Rect: 526, 136, 540, 143 ActionDest: 158 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 197, 673, 214, 682 ActionDest: 158 Annotation: Subtype: Link Rect: 327, 635, 344, 644 ActionDest: 158 Annotation: Subtype: Link Rect: 251, 610, 268, 619 ActionDest: 158 Annotation: Subtype: Link Rect: 196, 597, 213, 606 ActionDest: 158 Annotation: Subtype: Link Rect: 507, 572, 524, 581 ActionDest: 158 Annotation: Subtype: Link Rect: 306, 544, 313, 556 ActionDest: 123 Annotation: Subtype: Link Rect: 521, 510, 538, 519 ActionDest: 155 Annotation: Subtype: Link Rect: 538, 510, 555, 519 ActionDest: 155 Annotation: Subtype: Link Rect: 444, 497, 461, 506 ActionDest: 155 Annotation: Subtype: Link Rect: 461, 497, 478, 506 ActionDest: 155 Annotation: Subtype: Link Rect: 403, 472, 420, 481 ActionDest: 158 Annotation: Subtype: Link Rect: 288, 447, 305, 456 ActionDest: 158 Annotation: Subtype: Link Rect: 510, 431, 517, 444 ActionDest: 117 Annotation: Subtype: Link Rect: 537, 431, 544, 444 ActionDest: 123 Annotation: Subtype: Link Rect: 528, 362, 542, 370 ActionDest: 158 Annotation: Subtype: Link Rect: 528, 314, 542, 322 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 295, 542, 303 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 276, 542, 284 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 196, 542, 204 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 158, 542, 166 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 101, 542, 109 ActionDest: 161 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 528, 686, 542, 694 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 653, 542, 660 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 615, 542, 622 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 553, 542, 561 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 506, 542, 513 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 477, 542, 485 ActionDest: 155 Annotation: Subtype: Link Rect: 528, 449, 542, 456 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 378, 542, 385 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 335, 542, 343 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 306, 542, 314 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 283, 542, 290 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 250, 542, 257 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 179, 542, 186 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 145, 542, 153 ActionDest: 161 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 528, 648, 542, 656 ActionDest: 161 Annotation: Subtype: Link Rect: 528, 572, 542, 580 ActionDest: 165 Annotation: Subtype: Link Rect: 482, 446, 499, 455 ActionDest: 155 Annotation: Subtype: Link Rect: 397, 433, 414, 442 ActionDest: 165 Annotation: Subtype: Link Rect: 256, 393, 264, 405 ActionDest: 117 Annotation: Subtype: Link Rect: 212, 370, 229, 379 ActionDest: 165 Annotation: Subtype: Link Rect: 319, 345, 336, 354 ActionDest: 161 Annotation: Subtype: Link Rect: 477, 245, 494, 254 ActionDest: 161 Annotation: Subtype: Link Rect: 281, 207, 298, 216 ActionDest: 165 Annotation: Subtype: Link Rect: 491, 107, 508, 116 ActionDest: 165 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 463, 723, 480, 732 ActionDest: 165 Annotation: Subtype: Link Rect: 480, 723, 497, 732 ActionDest: 165 Annotation: Subtype: Link Rect: 371, 673, 387, 682 ActionDest: 165 Annotation: Subtype: Link Rect: 419, 156, 560, 167 Annotation: Subtype: Link Rect: 165, 144, 271, 155 Annotation: Subtype: Link Rect: 458, 135, 473, 143 ActionDest: 165 Annotation: Subtype: Link Rect: 476, 135, 491, 143 ActionDest: 165 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 326, 618, 364, 629 Annotation: Subtype: Link Rect: 417, 606, 454, 617 Annotation: Subtype: Link Rect: 461, 606, 497, 617 Annotation: Subtype: Link Rect: 519, 583, 557, 594 Annotation: Subtype: Link Rect: 59, 573, 95, 583 Annotation: Subtype: Link Rect: 399, 549, 437, 560 Annotation: Subtype: Link Rect: 443, 549, 479, 560 Annotation: Subtype: Link Rect: 104, 515, 142, 525 Annotation: Subtype: Link Rect: 148, 515, 184, 525 Annotation: Subtype: Link Rect: 144, 481, 182, 491 Annotation: Subtype: Link Rect: 188, 481, 224, 491 Annotation: Subtype: Link Rect: 228, 445, 266, 456 Annotation: Subtype: Link Rect: 164, 412, 202, 422 Annotation: Subtype: Link Rect: 430, 399, 468, 410 Annotation: Subtype: Link Rect: 185, 377, 222, 387 Annotation: Subtype: Link Rect: 59, 343, 96, 353 Annotation: Subtype: Link Rect: 156, 319, 193, 330 Annotation: Subtype: Link Rect: 200, 319, 236, 330 Annotation: Subtype: Link Rect: 262, 296, 299, 307 Annotation: Subtype: Link Rect: 305, 296, 341, 307 Annotation: Subtype: Link Rect: 433, 284, 470, 295 Annotation: Subtype: Link Rect: 476, 284, 512, 295 Annotation: Subtype: Link Rect: 262, 261, 300, 272 Annotation: Subtype: Link Rect: 390, 238, 427, 249 Annotation: Subtype: Link Rect: 153, 181, 191, 192 Annotation: Subtype: Link Rect: 214, 159, 251, 169 Annotation: Subtype: Link Rect: 234, 135, 271, 146 Annotation: Subtype: Link Rect: 252, 112, 289, 123 Annotation: Subtype: Link Rect: 206, 89, 244, 100 Annotation: Subtype: Link Rect: 238, 66, 276, 77 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 59, 722, 96, 733 Annotation: Subtype: Link Rect: 102, 722, 138, 733 Annotation: Subtype: Link Rect: 127, 688, 164, 698 Annotation: Subtype: Link Rect: 108, 665, 146, 675 Annotation: Subtype: Link Rect: 464, 652, 501, 664 Annotation: Subtype: Link Rect: 507, 652, 543, 664 Annotation: Subtype: Link Rect: 135, 630, 173, 640 Annotation: Subtype: Link Rect: 209, 607, 247, 617 Annotation: Subtype: Link Rect: 108, 584, 146, 594 Annotation: Subtype: Link Rect: 167, 561, 205, 571 Annotation: Subtype: Link Rect: 211, 561, 247, 571 Annotation: Subtype: Link Rect: 131, 538, 168, 548 Annotation: Subtype: Link Rect: 175, 538, 211, 548 Annotation: Subtype: Link Rect: 208, 503, 246, 514 Annotation: Subtype: Link Rect: 252, 503, 288, 514 Annotation: Subtype: Link Rect: 476, 480, 513, 491 Annotation: Subtype: Link Rect: 519, 480, 555, 491 Annotation: Subtype: Link Rect: 399, 457, 436, 468 Annotation: Subtype: Link Rect: 442, 457, 478, 468 Annotation: Subtype: Link Rect: 371, 422, 409, 433 Annotation: Subtype: Link Rect: 260, 400, 298, 410 Annotation: Subtype: Link Rect: 59, 366, 96, 376 Annotation: Subtype: Link Rect: 59, 343, 96, 353 Annotation: Subtype: Link Rect: 450, 319, 487, 330 Annotation: Subtype: Link Rect: 417, 296, 455, 307 Annotation: Subtype: Link Rect: 461, 296, 497, 307 Annotation: Subtype: Link Rect: 59, 262, 96, 272 Annotation: Subtype: Link Rect: 102, 262, 138, 272 Annotation: Subtype: Link Rect: 412, 238, 450, 249 Annotation: Subtype: Link Rect: 456, 238, 492, 249 Annotation: Subtype: Link Rect: 59, 205, 96, 215 Annotation: Subtype: Link Rect: 59, 170, 96, 180 Annotation: Subtype: Link Rect: 99, 136, 137, 146 Annotation: Subtype: Link Rect: 104, 101, 141, 111 Annotation: Subtype: Link Rect: 260, 66, 298, 77 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 187, 710, 225, 721 Annotation: Subtype: Link Rect: 458, 687, 495, 698 Annotation: Subtype: Link Rect: 395, 664, 432, 675 Annotation: Subtype: Link Rect: 439, 664, 475, 675 Annotation: Subtype: Link Rect: 519, 652, 557, 664 Annotation: Subtype: Link Rect: 59, 642, 95, 652 Annotation: Subtype: Link Rect: 520, 618, 557, 629 Annotation: Subtype: Link Rect: 59, 607, 95, 617 Annotation: Subtype: Link Rect: 312, 572, 349, 583 Annotation: Subtype: Link Rect: 356, 572, 392, 583 Annotation: Subtype: Link Rect: 117, 550, 155, 560 Annotation: Subtype: Link Rect: 235, 514, 272, 525 Annotation: Subtype: Link Rect: 518, 491, 555, 502 Annotation: Subtype: Link Rect: 386, 468, 424, 479 Annotation: Subtype: Link Rect: 307, 434, 345, 445 Annotation: Subtype: Link Rect: 379, 400, 416, 410 Annotation: Subtype: Link Rect: 59, 366, 96, 376 Annotation: Subtype: Link Rect: 102, 366, 138, 376 Annotation: Subtype: Link Rect: 520, 342, 557, 353 Annotation: Subtype: Link Rect: 59, 331, 95, 341 Annotation: Subtype: Link Rect: 227, 296, 265, 307 Annotation: Subtype: Link Rect: 271, 296, 307, 307 Annotation: Subtype: Link Rect: 178, 262, 216, 272 Annotation: Subtype: Link Rect: 222, 262, 258, 272 Annotation: Subtype: Link Rect: 292, 227, 330, 238 Annotation: Subtype: Link Rect: 336, 227, 372, 238 Annotation: Subtype: Link Rect: 199, 192, 237, 203 Annotation: Subtype: Link Rect: 407, 169, 445, 180 Annotation: Subtype: Link Rect: 492, 146, 530, 157 Annotation: Subtype: Link Rect: 312, 112, 349, 123 Annotation: Subtype: Link Rect: 163, 78, 201, 88 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 229, 710, 267, 721 Annotation: Subtype: Link Rect: 410, 676, 447, 687 Annotation: Subtype: Link Rect: 454, 676, 490, 687 Annotation: Subtype: Link Rect: 379, 652, 417, 664 Annotation: Subtype: Link Rect: 423, 652, 459, 664 Annotation: Subtype: Link Rect: 59, 619, 96, 629 Annotation: Subtype: Link Rect: 59, 584, 96, 594 Annotation: Subtype: Link Rect: 137, 537, 174, 548 Annotation: Subtype: Link Rect: 131, 504, 168, 514 Annotation: Subtype: Link Rect: 347, 480, 385, 491 Annotation: Subtype: Link Rect: 269, 457, 306, 468 Annotation: Subtype: Link Rect: 199, 423, 236, 433 Annotation: Subtype: Link Rect: 379, 399, 417, 410 Annotation: Subtype: Link Rect: 149, 366, 186, 376 Annotation: Subtype: Link Rect: 59, 331, 96, 341 Annotation: Subtype: Link Rect: 446, 307, 484, 318 Annotation: Subtype: Link Rect: 490, 307, 526, 318 Annotation: Subtype: Link Rect: 256, 284, 294, 295 Annotation: Subtype: Link Rect: 59, 251, 96, 261 Annotation: Subtype: Link Rect: 104, 216, 142, 226 Annotation: Subtype: Link Rect: 511, 192, 548, 203 Annotation: Subtype: Link Rect: 440, 169, 478, 180 Annotation: Subtype: Link Rect: 209, 135, 246, 146 Annotation: Subtype: Link Rect: 396, 112, 433, 123 Annotation: Subtype: Link Rect: 440, 112, 476, 123 Annotation: Subtype: Link Rect: 144, 78, 182, 88 Annotation: Subtype: Link Rect: 188, 78, 224, 88 Page: Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 266, 710, 303, 721 Annotation: Subtype: Link Rect: 496, 687, 534, 698 Annotation: Subtype: Link Rect: 140, 653, 177, 664 Annotation: Subtype: Link Rect: 433, 618, 470, 629 Annotation: Subtype: Link Rect: 59, 596, 96, 606 Annotation: Subtype: Link Rect: 108, 561, 146, 571 Annotation: Subtype: Link Rect: 520, 549, 557, 560 Annotation: Subtype: Link Rect: 99, 504, 137, 514 Annotation: Subtype: Link Rect: 454, 480, 492, 491 Annotation: Subtype: Link Rect: 376, 445, 414, 456 Annotation: Subtype: Link Rect: 420, 445, 456, 456 Annotation: Subtype: Link Rect: 140, 412, 178, 422 Annotation: Subtype: Link Rect: 184, 412, 220, 422 Annotation: Subtype: Link Rect: 155, 377, 193, 387 Annotation: Subtype: Link Rect: 199, 377, 235, 387 Annotation: Subtype: Link Rect: 282, 353, 320, 364 Annotation: Subtype: Link Rect: 501, 330, 538, 341 Annotation: Subtype: Link Rect: 337, 296, 374, 307 Annotation: Subtype: Link Rect: 157, 262, 194, 272 Annotation: Subtype: Link Rect: 335, 238, 372, 249 Annotation: Subtype: Link Rect: 217, 204, 255, 215 Annotation: Subtype: Link Rect: 59, 159, 96, 169 Annotation: Subtype: Link Rect: 108, 124, 146, 134 Annotation: Subtype: Link Rect: 519, 112, 557, 123 Annotation: Subtype: Link Rect: 59, 101, 95, 111 Annotation: Subtype: Link Rect: 167, 67, 204, 77 Page: Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 452, 722, 489, 733 Annotation: Subtype: Link Rect: 496, 722, 532, 733 Annotation: Subtype: Link Rect: 59, 688, 96, 698 Annotation: Subtype: Link Rect: 102, 688, 138, 698 Annotation: Subtype: Link Rect: 178, 653, 216, 664 Annotation: Subtype: Link Rect: 285, 618, 322, 629 Annotation: Subtype: Link Rect: 519, 595, 556, 606 Annotation: Subtype: Link Rect: 167, 561, 204, 571 Annotation: Subtype: Link Rect: 59, 527, 96, 537 Annotation: Subtype: Link Rect: 102, 527, 138, 537 Annotation: Subtype: Link Rect: 267, 491, 304, 502 Annotation: Subtype: Link Rect: 310, 491, 346, 502 Annotation: Subtype: Link Rect: 331, 457, 368, 468 Annotation: Subtype: Link Rect: 374, 457, 410, 468 Annotation: Subtype: Link Rect: 307, 422, 345, 433 Annotation: Subtype: Link Rect: 306, 389, 343, 399 Annotation: Subtype: Link Rect: 267, 353, 304, 364 Annotation: Subtype: Link Rect: 113, 320, 150, 330 Annotation: Subtype: Link Rect: 113, 285, 151, 295 Annotation: Subtype: Link Rect: 117, 251, 155, 261 Annotation: Subtype: Link Rect: 144, 216, 182, 226 Annotation: Subtype: Link Rect: 285, 181, 323, 192 Annotation: Subtype: Link Rect: 332, 146, 369, 157 Annotation: Subtype: Link Rect: 375, 146, 411, 157 Annotation: Subtype: Link Rect: 104, 113, 141, 123 Annotation: Subtype: Link Rect: 147, 113, 183, 123 Annotation: Subtype: Link Rect: 108, 78, 146, 88 Annotation: Subtype: Link Rect: 152, 78, 188, 88 Page: Sequence: 20 Annotations: Annotation: Subtype: Link Rect: 282, 710, 320, 721 Annotation: Subtype: Link Rect: 398, 676, 436, 687 Annotation: Subtype: Link Rect: 258, 641, 296, 652 Annotation: Subtype: Link Rect: 240, 606, 277, 617 Annotation: Subtype: Link Rect: 341, 572, 379, 583 Annotation: Subtype: Link Rect: 286, 537, 323, 548 Annotation: Subtype: Link Rect: 200, 503, 237, 514 Annotation: Subtype: Link Rect: 243, 503, 280, 514 Annotation: Subtype: Link Rect: 251, 468, 289, 479 Annotation: Subtype: Link Rect: 514, 434, 551, 445 Annotation: Subtype: Link Rect: 472, 399, 509, 410 Annotation: Subtype: Link Rect: 515, 399, 551, 410 Annotation: Subtype: Link Rect: 416, 365, 454, 376 Annotation: Subtype: Link Rect: 259, 330, 297, 341 Annotation: Subtype: Link Rect: 118, 285, 155, 295 Annotation: Subtype: Link Rect: 292, 250, 329, 261 Annotation: Subtype: Link Rect: 167, 216, 204, 226 Annotation: Subtype: Link Rect: 520, 181, 557, 192 Annotation: Subtype: Link Rect: 490, 146, 528, 157 Annotation: Subtype: Link Rect: 140, 113, 177, 123 Annotation: Subtype: Link Rect: 184, 113, 220, 123 Annotation: Subtype: Link Rect: 173, 78, 210, 88 Page: Sequence: 21 Annotations: Annotation: Subtype: Link Rect: 370, 710, 408, 721 Annotation: Subtype: Link Rect: 201, 676, 239, 687 Annotation: Subtype: Link Rect: 245, 676, 281, 687 Annotation: Subtype: Link Rect: 122, 642, 159, 652 Annotation: Subtype: Link Rect: 327, 606, 364, 617 Annotation: Subtype: Link Rect: 109, 573, 146, 583 Annotation: Subtype: Link Rect: 59, 538, 96, 548 Annotation: Subtype: Link Rect: 207, 503, 244, 514 Annotation: Subtype: Link Rect: 510, 468, 547, 479 Annotation: Subtype: Link Rect: 77, 423, 115, 433 Annotation: Subtype: Link Rect: 293, 388, 331, 399 Annotation: Subtype: Link Rect: 337, 388, 373, 399 Annotation: Subtype: Link Rect: 358, 353, 395, 364 Annotation: Subtype: Link Rect: 401, 353, 437, 364 Annotation: Subtype: Link Rect: 470, 319, 507, 330 Annotation: Subtype: Link Rect: 229, 284, 267, 295 Annotation: Subtype: Link Rect: 106, 239, 144, 249 Annotation: Subtype: Link Rect: 117, 205, 155, 215 Annotation: Subtype: Link Rect: 109, 170, 146, 180 Annotation: Subtype: Link Rect: 235, 135, 273, 146 Annotation: Subtype: Link Rect: 279, 135, 315, 146 Annotation: Subtype: Link Rect: 95, 101, 133, 111 Annotation: Subtype: Link Rect: 139, 101, 175, 111 Annotation: Subtype: Link Rect: 304, 66, 342, 77 Annotation: Subtype: Link Rect: 348, 66, 384, 77 Page: Sequence: 22 Annotations: Annotation: Subtype: Link Rect: 270, 710, 308, 721 Annotation: Subtype: Link Rect: 135, 676, 173, 687 Annotation: Subtype: Link Rect: 488, 652, 525, 664 Annotation: Subtype: Link Rect: 59, 607, 96, 617 Annotation: Subtype: Link Rect: 315, 572, 352, 583 Annotation: Subtype: Link Rect: 450, 537, 487, 548 Annotation: Subtype: Link Rect: 255, 503, 292, 514 Annotation: Subtype: Link Rect: 466, 480, 504, 491 Annotation: Subtype: Link Rect: 198, 445, 236, 456 Annotation: Subtype: Link Rect: 388, 422, 425, 433 Annotation: Subtype: Link Rect: 431, 422, 467, 433 Annotation: Subtype: Link Rect: 458, 388, 496, 399 Annotation: Subtype: Link Rect: 104, 343, 141, 353 Annotation: Subtype: Link Rect: 135, 308, 173, 318 Annotation: Subtype: Link Rect: 265, 273, 303, 284 Annotation: Subtype: Link Rect: 188, 227, 226, 238 Annotation: Subtype: Link Rect: 488, 192, 526, 203 Annotation: Subtype: Link Rect: 118, 159, 155, 169 Annotation: Subtype: Link Rect: 59, 113, 96, 123 Checksum: 92563785 Type: CRC32 Checksum: 9cb8ede4e07cc5cdf5faa5394fbcde3d Type: MD5 Checksum: b7a8df78055dad9e58eaeb1b6f81b9ee5518e950 Type: SHA-1