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However, when the adaptive capacity is overcome, hemolytic erythrocyte-derived products act as signaling molecules, namely DAMPs, which promote inflammation via triggering TLR4-dependent activation of endothelial cells associated with NF-B-mediated synthesis of proinflammatory cytokines, TLR4-independent, ROS-, NADPH oxidase- and heme iron-mediated promotion of neutrophil extracellular traps (NETs) formation, TLR4-dependent activation of macrophages accompanied by secretion of tumor necrosis factor (TNF-), and MyD88/TRIF pathway-mediated TLR4-dependent microglia activation that triggers neuroinflammation [224]

We also are proposing to include the estimated supplemental payments for eligible IHS/Tribal hospitals and Puerto Rico hospitals on both sides of our comparison of aggregate payments when determining all budget neutrality factors described in section II.A.4