Spinal cord injury (SCI) results into an immediate primary injury (physical damages) followed by secondary damages (prolonged posttraumatic inflammatory disorder) resulting into severe motor dysfunction including paralysis. The present chapter discusses and investigates the neuroprotective effects of cyclosporin-A (CsA), minocycline, and tacrolimus (FK506) and their therapeutic effectiveness in recovery from the animal model of SCI. Based on the available recent literature on these three drugs, as well as in perspective of the results obtained on some experimental behavioral, biochemical, and oxidative stress parameters in the present study, the therapeutical potential of these three drugs has been discussed. Furthermore, the animal model of SCI used herein has been reviewed and compared with other reported animal models for understanding the utility, suitability, and reproducibility of the methodology of the present model for screening purposes in quest of searching ideal therapeutic compounds for maximum recovery from SCI.
- tacrolimus (FK506)
- spinal cord injury
- oxidative stress
Spinal cord injury (SCI) is prevalent worldwide [1, 2] and often incapacitates the victims for life resulting in disability. Injury to the spinal cord results in processes that occur in three phases: the first phase is immediate physical phase also known as acute phase comprising affected spinal shock and initial trauma (primary injury) followed by the second phase known as secondary phase which is a prolonged cascade of damaging processes over a time period of minutes to weeks after the injury (secondary injury). Such damages include ischemia, vascular alterations, biochemical alterations, and cellular responses that lead to peripheral posttraumatic inflammatory cell infiltration and cell death (secondary injury) [1, 3, 4, 5]. The third phase that sustains between days and years after SCI trauma is characterized by proapoptotic degeneration and scarring that establishes permanent functional impairment [6, 7]. Secondary injury leads to the key pathophysiological response to SCI causing severe and permanent functional deficits. Most of the clinical trials and experimental studies are conducted for intense research to unfold the underlying pathophysiological processes and for searching ideal and potential therapy for recovery from secondary SCI injuries . Besides motor dysfunction, some of the other important SCI-related biochemical and immunological impairments that get involved are serum tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interleukin-6, nuclear factor (NF)-κB p65, p38 mitogen-activated protein kinase (MAPK), inducible nitric oxide synthase (iNOS), caspase-3, superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) . SCI trauma causes a devastating effect not only to the individual patient, but it also incurs heavy expensive burden to the society in general and to the family members, due to substantial long-term healthcare expenditures .
Despite considerable therapeutic studies, no proven drugs or techniques are available for satisfactory treatment of SCI. Much of these therapeutic studies have been reported from animal models, and it needs to be understood that a successful clinical trial in humans can only be initiated based on previously available preclinical data reported from animal model studies that closely mimic the losses as in human SCI functions . Although rats are the animal model of choice for SCI studies, the major anatomical differences in axonal tracts and sensory motor pathways between quadrupeds and bipeds need to be taken into careful account to improve the targets of human SCI treatments .
Currently, methylprednisolone is the only recognized treatment for human SCI; however, it has significant adverse effects, including respiratory complications, sepsis, and gastrointestinal hemorrhage . Furthermore, other important evidence-based therapies that have potential neuroprotective and neural reparative therapeutic properties and are undergoing clinical trials for human SCI include surgical decompression, blood pressure augmentation, riluzole, granulocyte colony-stimulating factor, minocycline, glibenclamide, cerebrospinal fluid drainage, magnesium, therapeutic hypothermia, Cethrin (VX-210), anti-NOGO antibody, cell-based approaches, and bioengineered biomaterials [5, 14, 15].
Some other experimental drugs that have been studied for therapeutical use in animal SCI are recombinant human erythropoietin , tetrodotoxin , BCL-2 , cyclosporin-A , edaravone , atorvastatin , calpain inhibitors  FK506, and minocycline . Also, some natural products like eugenol oil , curcumin , and melatonin  have shown promising effects in animal SCI functional recovery. It sounds reasonable that instead of using a highly selective treatment that targets a specific molecule or pathway, a compound with multifunctional properties that targets several mediators involved in spinal cord pathology may be more effective for recovery from SCI . In our earlier study , the promising potential of FK506 and minocycline has been reported for their effectiveness in rat SCI model. Thus, in the present study, besides these two multifactorial effective compounds minocycline and FK506, a third compound cyclosporin-A (CsA) was also included, and all the three compounds minocycline, FK506 (tacrolimus), and cyclosporine-A were chosen to evaluate in a comparative manner for their therapeutical potential using some important and reliable parameters that are most commonly used in rat SCI model . Before discussing the outcome of our present results, we review the multifactorial effects of these three compounds that have been reported in literature using rat SCI model.
Minocycline, a semisynthetic second-generation tetracycline, has robust neuroprotective effects in rodent models of neurodegenerative diseases  and provides neuroprotection in experimental models of neurological diseases, including SCI . In a broad range of secondary injury mechanisms via its anti-inflammatory, antioxidant, and antiapoptotic properties, minocycline is effective in reducing secondary injury and promoting locomotor functional recovery [28, 29, 30, 31]. Minocycline prevents N-methyl-d-aspartate (NMDA)-induced excitotoxicity by diminishing NMDA-induced Ca2+ influx and mitochondrial Ca2+ uptake  and protects gray and white matter from SCI . Minocycline also inhibits p38 mitogen-activated protein kinase (p38 MAPK) activation and microglial pro-nerve growth factor (proNGF) expression resulting from inflammatory reactions due to SCI and improves oligodendrocyte survival . Inflammation due to SCI also upregulates and activates a class of enzymes like phospholipase A2s (PLA2s), and minocycline reduces cPLA2s . It also inhibits monocyte and microglial expression of cyclooxygenase 2 (COX2) and production of proinflammatory prostaglandins E2  and suppresses 5-lipoxygenase (5-LOX) action in SCI tissue . Minocycline also eliminates free radicals in the post-SCI microenvironment and protects from oxidative stress . It inhibits malondialdehyde, a by-product of lipid peroxidation [39, 40], and increases glutathione (GSH) , superoxide dismutase, and glutathione peroxidase , suggesting the powerful antioxidative mechanisms of minocycline to recover from secondary injury in SCI. Minocycline is reported to inhibit matrix metalloproteinases (MMPs) that are upregulated following SCI and are involved in injury and recovery processes [41, 42]. Furthermore, minocycline improves functional outcome, reduces lesion size and cell death, and alters cytokine expression after SCI [43, 44, 45]. Minocycline reduces the lesion area, increases the number of descending sympathoexcitatory axons traversing the injury site, and ultimately reduces the severity of autonomic dysreflexia . In a murine model of SCI, minocycline treatment was superior to methylprednisolone in promoting functional improvement  and had neuroprotective effects on the SCI epicenter , motor neuron recovery, and neuropathic pain . Minocycline has recently been reported to be effective in reducing secondary injury and promoting locomotor functional recovery in experimental SCI .
It has also been reported to attenuate reactive astrocytosis in SCI which directly damages cell bodies and triggers endogenous processes including neuroinflammation and reactive astrocytosis [49, 50]. In combination studies also, minocycline has been reported for better recovery from SCI when used in combination with other drugs like FK506  and bone marrow mesenchymal cells (BMSCs)  showing a very significant recovery in behavioral function, oxidative stress, and reduction in lesion size from SCI in rats warranting further research on this drug.
Cyclosporin-A is an immunosuppressive cyclic undecapeptide that inhibits T cells and depresses both cellular and humoral immune responses to prevent graft rejection and reduces the inflammatory responses . CsA significantly decreases the expression levels of interleukin-10, tumor necrosis factor-α, cyclophilin-D (Cyp-D), and apoptosis-inducing factor (AIF) . CsA does not readily cross the blood-spinal cord barrier (BSCB), which restricts the clinical application of CsA for SCI treatment. Thus, polyethylene glycol (PEG)-transactivating-transduction protein (TAT)-modified CsA-loaded cationic multifunctional polymeric liposome-poly (lactic-co-glycolic acid) (PLGA) core/shell nanoparticles (PLGA/CsA NPs) to transport and deliver CsA across the BSCB have a new potential to treat SCI . CsA inhibits primarily the inflammatory reaction and the synthesis of constitutive nitric oxide (NO) and inducible nitric oxide synthases (NOS), well-known neurotoxic agents for SCI diminishing overproduction of free radicals, and secondarily lipid peroxidation (LP) observed after SCI [55, 56]. CsA may also induce other non-immunological effects that could be beneficial for treatment of neurological disorders . CsA has been widely used in the treatment of various diseases including aplastic anemia, nephritic syndrome, rheumatoid arthritis, psoriasis, and cerebral ischemic injuries . CsA promotes neuroprotection by diminishing both demyelination and neuronal cell death, resulting in a better motor outcome after SCI [52, 58, 59]. CsA in combination with FK506 had a neuroprotective treatment against SCI hypoxia-induced damage mediated via their antioxidant actions on mitochondrial ATP, tissue-reduced glutathione, tissue LPO level, and myeloperoxidase (MPO) activity . Administration of CsA in combination with olfactory ensheathing cell (OEC) transplantation results in augmented functional improvements and promotes axon regeneration after SCI .
FK506 (tacrolimus), a macrolide lactane antibiotic, was introduced as an immunosuppressive agent  with virtually no side effects . FK506, a potent calcineurin inhibitor, exhibits neuroprotective actions in several experimental models of central nervous system trauma, including stroke, and improved neurological recovery following peripheral and spinal cord injuries [47, 63, 64, 65, 66, 67]. It is reported that FK506 has beneficial effects in SCI recovery involving various mechanisms such as neuroregeneration and neuroprotection , promotion of axonal outgrowth , and suppression of oxidative stress . FK506 improves the functional outcome of SCI [67, 68, 69] and has an in vivo neurotrophic action, whereby it enhances the rate of axon regeneration, leading to more rapid neurological recovery [70, 71, 72, 73]. Significant functional recovery from SCI due to FK506 treatment has been reported in rat models [22, 67, 74]. Activation of NF-κB and proinflammatory cytokines (TNF-a, IL-1b, and IL-6) expression levels in SCI animals is reversed by FK506 treatment involving microglial activation after SCI . FK506 upregulates epidermal growth factor (EGF)-level expression of astrocytes that have an important role as mediators for SCI functional recovery promoting axonal regeneration . FK506 in combination as a cocktail with other drugs like minocycline , CSA , RhoA inhibitors , nerve growth factor (NFG) , and methylprednisolone (MP)  has shown significant therapeutic recovery from SCI in rats.
Considering the above-discussed multifactorial effects of CsA, minocycline, and FK506, the present study was undertaken to investigate the neuroprotective effects of these three compounds in a comparative manner on recovery from experimental SCI, as these three drugs target multiple processes involved in mediating cell death and the development of secondary injury in SCI. Furthermore, our earlier findings on FK506 and minocycline  prompted us to include CsA (another promising drug for SCI recovery) and compare their effectiveness in rat model of SCI, using the behavioral and biochemical parameters as in earlier .
2. Utility of experimental animal models for SCI studies
For SCI studies, animal models are used because of their easy accessibility, convenience, and capability of the researchers to explore them at several levels (simulated to human clinical SCI levels) for motor functional, biochemical, and oxidative stress and genetic, therapeutic, and pathophysiological evaluations . Over the last decade, a variety of animal models have been used for experimental SCI studies, including rats, mice, gerbils, guinea pigs, hamsters, rabbits, dogs, goats, pigs, and nonhuman primates . Among these animals, rodents in general and rats in particular are the most widely and commonly studied SCI models . In the present study also, we have used young adult male Sprague-Dawley rats with all similar specifications of breeding, housing facilities, and experimental handlings, as described in our earlier study .
To establish an ideal SCI animal model for research purposes, various models have been tried and reported till to date in quest of searching methodology to obtain maximum recovery from SCI. These experimental animal models include spinal cord traumatic injury model , photochemical-induced SCI model , spinal cord transection model , bidirectional distraction SCI model , and the spinal cord ischemia-reperfusion injury model . For traumatic injury model, the contusive SCI model is used by inducing contusion on the dorsal spinal cord by dropping a desired weight either from a computer-controlled impact device  or from a customized impact device . Another traumatic injury model known as compressive SCI model is also very commonly used where instead of dropping the weight, it is placed on the exposed spinal cord segment in the dorsoventral direction to induce a compressive SCI [88, 89]. However, since SCI caused by impact and compression is more common in clinical patients , in the present study also, we have used the compressed SCI model induced in the rats as described in our earlier study . Briefly, the SCI was induced in the rats following the modified method of Nystrom and Berglund . Laminectomy was performed at the T 7–8 level, and spinal cord compression injury was produced by placing a load with a total weight of 35 g, for 5 min over the exposed extradural area.
All experimental rats were randomly divided into the following six groups with eight animals in each as described earlier :
Group I: The normal control group without laminectomy or compression injury
Group II: Sham group with laminectomy alone but no spinal compression injury
Group III: SCI control group with laminectomy and spinal compression injury
SCI-treated groups were the same as the SCI control group (Group III) and consisted of three groups in which the effect on the recovery from SCI using the same parameters is mentioned in our earlier study . Doses of the three drugs CSA, minocycline, and FK506 were selected on the basis of our pilot screening of these drugs at low, medium, and high doses, and the best effective dose in each was used in the present study as follows:
Group IV: Cyclosporin-A 5 mg/kg
Group V: Minocycline 50 mg/kg
Group VI: FK506 (tacrolimus) 1 mg/kg
All protocols for the drug administration, follow-ups, care, and experimental handlings of the animals for various evaluation parameters were the same as described earlier .
3. Behavioral evaluations in SCI animals
To analyze the therapeutic recovery from induced SCI in animal models, several behavioral outcome measures have been developed and widely used, such as the catwalk , the Basso-Beattie-Bresnahan (BBB) locomotor scale , the horizontal ladder test, and the cylinder rearing test . From the literature review of the recent years, it is found that BBB locomotor scale has been most widely used in SCI rat models to evaluate motor functional recovery from SCI [9, 12, 22, 23, 24, 53, 58, 74, 77, 93]. However, in the present study, besides BBB locomotor scale , a battery of some more behavioral motor functions was included like Tarlov scoring , inclined plane test , and some functional deficit scorings like toe spread, platform hang, wire mesh descent, and hind foot bar grab [97, 98]. Our pilot study showed that a naive control group of animals treated with CsA, minocycline, and FK506 without SCI showed no different behaviors than the naïve control untreated groups (data not shown in behavioral results) for all the observed behavioral parameters. Thus, the results of the drug treatments alone were not included in all behavioral results (Figures 1, 2, 3, 4). The present results of behavioral observations indicated that treatment with all the three drugs in this study induced significant recovery from SCI with respect to time in all behavioral activities compared to the SCI control group, and the drugs were effective in the order of FK506 > minocycline > CsA (F = 13.49, F = 5.82, and F = 3.14; df = 3; p < 0.001, p < 0.01, and p < 0.05, respectively) throughout (Figures 1–4).
4. Biochemical evaluations in SCI animal models
Biochemical evaluations have a vast list of parameters that exist as biomarkers for assessing recovery from SCI in animal models. Some of the most important biochemical parameters include oxidative stress indices like lipid peroxidation and total glutathione, nitric oxide synthase, myeloperoxidase, mitochondrial permeability, inflammatory responses, autonomic dysreflexia, cerebrospinal fluid biomarkers, immune responses, astrocyte modulations, etc., and all of these have been reviewed in detail earlier in this chapter, especially for the three drugs, CsA, minocycline, and FK506, that have been evaluated in the present study.
The biochemical parameters evaluated in this study included determination of monoamines 5-hydroxy-indoleacetic acid (5-HIAA) and serotonin or 5-hydroxy tryptamine (5-HT) , lipid peroxides determined as thiobarbituric acid-reactive substances (TBARS) [100, 101], total glutathione [102, 103], and myeloperoxidase  and have been described for their methods in our earlier study .
The present biochemical results showed significant ameliorating effect of all three drugs on the levels of 5-HT (Figure 5A, 5-HIAA; Figure 5B, on the ratio of 5-HIAA; and Figure 5C, 5-HT). TBARS was significantly stimulated (Figure 6A), whereas GSH was significantly inhibited (Figure 6B), and MPO level was significantly diminished toward the normal level (Figure 6C). Overall, the entire biochemical parameters evaluated in the present study were significantly affected by the three drugs effectively in the order FK506 > minocycline > CsA throughout.
SCI leads to persistent pain and motor dysfunction, both of which lack effective therapeutics . Therapeutic approaches that promote both neuroprotection and neuroregeneration are valuable for SCI therapies . From the present discussed literature, the potential agents that have generated interest in SCI studies in the recent past include the multifactorial drugs minocycline, FK506, and CsA [18, 22, 52, 106].
In the present chapter also, the treated rats showed recovery in their hind limb reflexes rapidly regaining responses comparable with those of uninjured control rats (Figure 1). Although all drug-treated groups showed improved recovery in BBB and all behavioral activities, the best and the most significant recovery was observed with FK506 treatment. The drugs were effective in the order FK506 > minocycline > CsA throughout. Earlier studies have also used BBB scoring along with other behavioral parameters and have shown significant behavioral functional outcome in the SCI animals treated with FK506 [7, 22, 60, 67, 69, 70, 74, 76], minocycline [22, 28, 43, 44, 45], and CsA [18, 52, 53, 58, 61]. In addition to the therapeutic effects of the three drugs, it has been also suggested that the daily routine behavioral assessment procedures may also assist the animals as equivalent to their exercises that help them to recover from SCI . However, more studies are required to confirm this presumption. Additionally, no notable side effects were noted at the dosing regimen of the drugs (selected from the pilot studies) used in the present chapter. However, it has been suggested particularly for FK506  that the therapeutic dosing regimen is a key factor that can affect efficacy as a neuroprotectant for CNS injuries.
FK506 has been reported by others also for being a potential therapy for SCI recovery through various mechanisms [7, 60, 63, 68, 108]. It is evidently proven that FK506 prevents the activation of NF-κB in microglia which reduces production of proinflammatory cytokines like TNF-a, IL-1b, and IL-6 in the SCI responses for effective recovery [7, 109]. Furthermore, it is suggested that inhibition of inflammatory reaction in SCI by FK506 could be due to its inhibitory action on decreasing the free radical formation and lipid peroxidation preventing calcineurin-mediated dephosphorylation of NOS activity in a Ca2+-dependent manner . FK506 also enhances neurite outgrowth and improves functional recovery from SCI by stimulating astrocytes to secrete epidermal growth factor (EGF) for neural repair .
CsA has also been reviewed and reported as a potent neuroprotectant for functional recovery from SCI [5, 55]. The significant protective role of CsA has been reported for recovery from SCI through inhibiting the apoptosis of spinal cord cells , improving locomotor function , increasing mean arterial pressure , inhibiting NOS , diminishing demyelination and neuronal cell death , attenuating reactive astrocytosis due to injury improved neurologic outcome , and reducing pain .
Minocycline has also been reviewed recently for its effectiveness through multiple mechanisms for functional recovery from SCI . The multiple targets that minocycline works for SCI functional recovery include upregulation of the protein VEGF and BDNF expressions; downregulation of protein p-38MAPK, proNGF, p75NTR, and RhoA expressions and suppressed caspase-3 activity ; and improved antioxidant activity through amelioration in oxidative stress in the SCI tissue .
Monoamines such as norepinephrine (NE), dopamine (DA), and serotonin (5-HT) can activate the spinal neurons involved in walking [112, 113, 114]. Thus, the decrease in the level of 5-HT and 5-HIAA in the SCI animals in the present chapter clearly indicates that SCI inevitably affects the normal functioning of these spinal neurotransmitters involved in locomotor function. SCI-injured animals treated with the drugs herein improved levels of 5-HT and 5-HIAA (Figure 5A–C, respectively). Our present behavioral findings also showed an overall correlation and significant improvement in the functional deficits of the hind limbs after treatment with these drugs, indicating the presence of potential mechanisms of serotonergic agents in these drugs, as present in indorenate (5-methoxytryptamine, beta-methyl carboxylate hydrochloride), a 5-HT1A agonist that improved motor function in rats with chronic SCI .
The oxidant/antioxidant balance was clearly reflected by the increased level of TBARS (Figure 6A) and decreased level of GSH (Figure 6B) in the contused tissue of SCI control animals. However, treatment of SCI animals with the drugs interfered with the formation of free radicals following traumatic SCI. The comparative behavioral restorative effects of these drugs in the formation of free radicals in injured SC were in the order of FK506 > minocycline > CsA.
Spinal cord injury in mice results in severe trauma characterized by edema and neutrophil infiltration (measured as an increase in myeloperoxidase activity), and these neutrophils are thought to be involved in tissue injury through the release of various inflammatory mediators [116, 117]. The MPO levels in the present SCI animals were also significantly increased in the injured spinal cord tissue (Figure 6C). However, administration of minocycline, FK506, and CsA interfered significantly with the formation of MPO following traumatic SCI. The comparative restorative effects of these drugs in the formation of MPO in injured SC were in the order of FK506 > minocycline > CsA.
The pathophysiological events resulting from SCI are reported to involve free radical production; lipid peroxidation; excitotoxic molecules such as glutamate, eicosanoid, and prostaglandin production; protease activity; and intracellular increases in Ca2+ . Furthermore, the primary auto-destructive event is initiated by the hydrolysis of fatty acids from membrane phospholipids, leading to cellular damage , and microglia becomes activated , which in turn may release neurotoxic molecules that further damage nearby neurons .
The hind limb functional deficits in the model of SCI (like the one as in the present chapter) are largely due to the loss of white matter axonal tracts [16, 122]. The white matter degeneration is caused by the primary injury (i.e., mechanical lesion), and there is also evidence that post-SCI demyelination caused by oligodendrocyte death/malfunction contributes significantly to chronic SCI functional deficits [123, 124].
The secondary injury is reported to result from several proposed auto-destructive events, including reactive oxygen species-induced lipid peroxidation , activation of non-NMDA ionotropic glutamate receptors , and caspase-3 activation [127, 128]. Secondary injury events include Na+ influx-mediated intra-axonal Ca+ accumulation leading to proteinase activation, which destroys the cytoskeleton [16, 129], as well as the induction of oligodendroglial apoptosis with subsequent demyelination of the surviving axons [79, 130]. Lipid peroxidation is one of the main pathological mechanisms involved in secondary damage after SCI . Another key factor in the secondary injury mechanism is Ca2+ ions. Following trauma or ischemia, Ca2+ influx plays an important role in the pathogenesis of neural injury [130, 131]. Many drugs, including steroids, gangliosides, ion channel blockers, antioxidants, and free radical scavengers, have mild therapeutic effectiveness in experimental spinal cord injury [74, 119]. Another mechanism to promote functional recovery after spinal cord injury is enhancing axonal regeneration. Several strategies, including blocking myelin or glial scar inhibitors, delivery of neurotrophic factors, and cell transplantation, induce axonal outgrowth after experimental spinal cord injury. Among them, olfactory ensheathing cell grafts promote neuroprotection, axonal regeneration, and functional recovery after incomplete spinal cord injury [132, 133]. Furthermore, a regular enforced movement activity may additionally help provide faster functional restoration and recovery after SCI .
Studies on combinatorial effects of CsA, minocycline, and FK506 in various combinations with each other or with other compounds may prove to be more effective in recovery from SCI. Earlier combined treatments like FK506 and NGF , FK506 and minocycline , FK506 and methylprednisolone , FK506 and RhoA inhibitor [76, 77], minocycline and bone marrow mesenchymal stem cells , and CsA with PEG-TAT  have all shown significant functional recovery from SCI as compared to these compounds individually.
From the overall literature review on the multifactorial effects of CsA, minocycline, and FK506 and from the discussion of the present findings, it can be concluded that the drugs CsA, minocycline, and FK506 induce good recovery from experimentally induced SCI in rats. However, these drugs significantly improve functional restoration, replenish 5-HT and 5-HIAA levels, and restore the oxidant/antioxidant balance in the contused tissue after moderate SCI in rats in the order FK506 < minocycline < CsA. Furthermore, it is suggested that the present compressive SCI model of rats could still serve as the most convenient model for therapeutic screenings of various drugs in search of ideal therapy for SCI. CsA, minocycline, and FK506 appear to have gained support in a multifactorial effective manner through ample research work and should be considered as ideal therapeutical agents for the treatment of acute SCI. These drugs should be supported for clinical trials with further studies and tests. Although FK506 appears to be the most promising among the three drugs, more work is needed to screen all three compounds as cocktails in various combinations with better expected outcomes in SCI recovery possibly due to their cumulative multifactorial beneficial effects.
The authors are thankful to the Deanship of Scientific Research, College of Nursing Research Centre at King Saud University, for funding this research.
Conflict of interest
The authors have no conflict of interests.
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