REVIEW: MANAGEMENT UPDATES (REVIEWS ON ADVANCES IN TREATMENT)
|Year : 2017 | Volume
| Issue : 4 | Page : 341-347
Efficacy and safety of tacrolimus in myasthenia gravis: A systematic review and meta-analysis
Zuojie Zhang1, Chunsong Yang2, Lingli Zhang2, Qiusha Yi3, Zilong Hao4
1 Department of Pharmacy, Evidence-based Pharmacy Center, West China Second Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University; West China School of Pharmacy, Sichuan University, Sichuan, P.R China
2 Department of Pharmacy, Evidence-based Pharmacy Center, West China Second Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Sichuan, P.R China
3 West China School of Pharmacy, Sichuan University, Sichuan, P.R China
4 Department of Neurology, West China Hospital, Sichuan University, Sichuan, P.R China
|Date of Web Publication||25-Oct-2017|
West China Second University Hospital, Sichuan University, No. 20, Third Section, Renmin Nan Lu, Chengdu, Sichuan - 610041
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aims: This study was designed to determine whether treatments with tacrolimus would provide benefit for patients with myasthenia gravis (MG). Materials and Methods: The databases of Medline, EMBASE, the Cochrane Library, and four Chinese databases were searched for eligible studies. Weighted mean differences and standardized mean differences (SMD) with corresponding 95% confidence intervals (CIs) were used to summarize the primary outcome, namely, steroid-sparing effect of tacrolimus in maintaining minimal manifestations, and the secondary outcome, namely, the effect of tacrolimus in reducing the severity of MG, respectively. Results: After systematic retrieval, 13 researches with two randomized controlled trials (RCTs) and 11 prospective open-label single-arm clinical trials were included in the study. For the primary outcome of two RCTs, one RCT which was followed up for 1 year showed a positive effect and the other RCT which was associated with treatment duration of 28 weeks showed a negative result. For the secondary outcome, meta-analyses of other 11 trials showed a benefit effect, overall. For the quantitative MG (QMG) score, there were significant differences with high heterogeneity (SMD: 2.93; 95% CI: 1.14–4.73; I2 = 86%). In contrast, for MG activities of daily living (MGADL) score, it was reduced by tacrolimus with significant SMD and less heterogeneity (SMD: 0.59; 95% CI: 0.33–0.85; I2 = 7%). Adverse effects were mentioned as mild. Discussion: The opposite results of two RCTs showed that tacrolimus with enough treatment duration might have positive steroid-sparing effect. The most possible cause of heterogeneity in the outcome of QMG score between trials was the baseline severity of MG. Conclusion: The above finding suggests that there might be a potential beneficial role with no serious side effects of tacrolimus, and additional better RCTs including larger sample sizes and long-term study are needed to confirm or refute the results.
Keywords: Efficacy, meta-analysis, myasthenia gravis, safety, tacrolimus
|How to cite this article:|
Zhang Z, Yang C, Zhang L, Yi Q, Hao Z. Efficacy and safety of tacrolimus in myasthenia gravis: A systematic review and meta-analysis. Ann Indian Acad Neurol 2017;20:341-7
|How to cite this URL:|
Zhang Z, Yang C, Zhang L, Yi Q, Hao Z. Efficacy and safety of tacrolimus in myasthenia gravis: A systematic review and meta-analysis. Ann Indian Acad Neurol [serial online] 2017 [cited 2019 Oct 24];20:341-7. Available from: http://www.annalsofian.org/text.asp?2017/20/4/341/217182
Zuojie Zhang and Chunsong Yang contributed equally to this study
| Introduction|| |
Myasthenia gravis (MG) is an autoimmune disorder in which antibodies reduce the available functional nicotinic acetylcholine receptors, thereby impairing neuromuscular transmission, and prevalence rate of which is approximately 1 in 10,000–50,000 every year.
Over the past 40 years, changing treatment modalities have obviously reduced mortality and severity of MG. Thymectomy may be useful in selected people. Treatment options include steroids, azathioprine, cyclosporin, cyclophosphamide, methotrexate, and intravenous immunoglobulin. Moreover, corticosteroids might be the relative effective intervention to slow down the development of MG. However, corticosteroids would bring many side effects if patients received them for a long time. Recently, to overcome this condition, tacrolimus (FK506) has been available for MG.
Tacrolimus is a macrolide immunosuppressant, which inhibits the production of interleukin-2 (a T-cell activation factor). Recently, it has been successfully used for preventing organ rejection in organ transplantation. Furthermore, some researchers observed that low-dose tacrolimus could be used as an effective treatment for de novo MG with no significant side effects.,, However, several other studies found that tacrolimus yielded no significant effects., The overall efficacy and safety of tacrolimus in patients suffering from MG is unknown. Although one review has described the role of tacrolimus, no meta-analysis has been performed. Meta-analysis could quantitatively pool all the available evidences and evaluate whether the efficacy of tacrolimus in some trials was stochastic or systematic. Based on these truths, we designed this first meta-analysis to assess whether tacrolimus could successfully control the development of MG with safety.
| Materials and Methods|| |
A systematic literature review was conducted from 1976 to May 2016, with the help of Medline, EMBASE, Cochrane Library, Chinese Biomedical Literature Database, China Knowledge Resource Integrated Database, VIP, and Wangfang using key words: tacrolimus and MG. all relevant references cited in eligible articles were also retrieved.
There were some inclusion standards with regard to choosing eligible studies: the study (1) focused on clinical efficacy and safety of tacrolimus in MG and published in English or Chinese; (2) were prospective studies; (3) reported any of the primary and secondary outcomes. Primary outcome was defined as steroid-sparing effect of tacrolimus in maintaining “Minimal Manifestations (MM)” of Myasthenia Gravis Foundation of America (MGFA) postintervention status, measured as dose of steroid. Secondary outcome was defined as the efficacy of tacrolimus in reducing the severity of MG, which was measured by any of the MG severity scales (a validated quantitative MG [QMG] score for disease severity; MG activities of daily living score [MGADL]; a test to evaluate muscular strength [TEMS]; and clinical absolute evaluation method [CAEM]). The reporting of secondary outcome should include sufficient data for estimating the change means and standard deviations from with tacrolimus to without.
Studies were excluded from the analysis if they used overlapping data published by the same author.
The following informations were extracted from each study independently by two trained investigators using a predefined data extraction form: the first author's name, the year of publication, study design, clinical situation, age of participants, sample size, disease duration, interventions, outcome definition, and adverse events. The methodological quality of included randomized controlled trials (RCTs) was independently assessed by two trained investigators according to Cochrane Handbook for Systematic Reviews of Interventions.
A third investigator coordinated the disagreement between the above two investigators.
Meta-analyses were conducted with the help of Review Manager 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration). For the primary outcome measure, the doses of same kinds of steroid administered at the end point to maintain MM were used to compute the weighted mean differences (WMDs) and corresponding 95% confidence intervals (CIs). The changes in score (QMG score, MGADL, TEMS, and CAEM scores) were used to compute the standardized mean differences (SMDs) and corresponding 95% CIs. Statistical heterogeneity was assessed with the help of the Q statistic and I2 statistic. If I2 < 50%, the WMD and SMD were pooled according to the fixed effects model, otherwise random effects model will be applied. Sensitivity analyses were conducted as well. Besides, if any of the outcomes included over ten studies, funnel plots were used visually to demonstrate publication bias.
| Results|| |
The search yielded 18 studies. Finally, 13 researches ,,,,,,,,,,,, were brought into analyses [Figure 1], of which only two were RCTs and others were prospective open-label single-arm clinical trials. The clinical characteristics of the included studies are registered in [Table 1] and [Table 2]. Five studies were not included because of either inapposite study design or incomplete data to calculate WMD or SMD of outcome measures.,,,,
|Table 1: General characteristics of included randomized controlled trials|
Click here to view
|Table 2: General characteristics of included prospective clinical studies|
Click here to view
A total of 495 patients were included. The median age was 44.58 years and median treatment period was 13.6 months. There was no generally accepted schedule for tacrolimus application, and a fixed daily dose of 3 mg was most frequently used.
Study quality of randomized controlled trials
Overall, for the only two RCTs, the quality of trial conducted by Yoshikawa et al. was better than that of Nagane et al. The trial conducted by Yoshikawa et al. had been registered in the network of ClinicalTrial.gov (Clinical trial registration number: NCT00309088), and it was a double-blind, placebo-CT. The section of random sequence generation, allocation concealment and binding was rated as low. However, the trial by Nagane et al. was an unblinded and nonplacebo CT without registration in advance and the participants were randomly and reciprocally selected to receive treatment with or without FK506. Hence, it was judged to be prone to a high risk of bias in the section of random sequence generation and blinding. Other risk biases of included RCTs were displayed in [Table 3].
The only two RCTs (Numbers of patient = 114) investigated the steroid-sparing effect of tacrolimus; however, we could not pool the primary outcome since the duration of these two studies was very different from each other. The study by Yoshikawa et al. was a 28-week double-blind trial, while the study by Nagane et al. investigating the steroid-sparing effects of tacrolimus to maintain MM was followed up for 1 year. In the former study, a total of eighty patients who received prednisolone (PSL) and were maintained in the state of MM were randomized to 3 mg tacrolimus (n = 40) or placebo (n = 40) nightly. The authors failed to find a significant difference between tacrolimus and placebo in the full analysis set (WDM: –1.6; 95% CI: –3.57, 0.37). Nagane et al. investigated the efficacy of tacrolimus for de novo MG patients. In the early-phase therapy, these individuals were randomized to interventions with (n = 18) tacrolimus or without (n = 16), and they discharged from early-phase therapy in hospital until they reached MM. After that, authors investigated the steroid-sparing effects of tacrolimus to maintain MM for 1 year. In this therapy phase, immunoabsorption (IA) plus high-dose intravenous methylprednisolone (HMP) (IA + HMP), HMP alone, oral PSL, or pyridostigmine bromide were administered as needed to maintain MM. The 1-year follow-up indicated that tacrolimus significantly decreased the number of treatments with steroids (WDM: –3.5; 95% CI: –5.73, –1.27).
Quantitative myasthenia gravis score
For seven prospective clinical trials with 227 patients, there were significant differences with high heterogeneity, so we used the random effects model to pool the estimate (SMD: 2.93; 95% CI: 1.14, 4.73; I2 = 86%) [Table 4].
|Table 4: Summary of different secondary outcome results of included prospective clinical trial|
Click here to view
Myasthenia gravis activities of daily living
Six prospective clinical trials yielding 63 patients involved the outcomes of MGADL. The difference was statistically significant with SMD 0.59 (95% CI: 0.33, 0.85; I2 = 7%) [Table 4].
Test to evaluate muscular strength
Three prospective clinical trials yielding 140 patients involved the outcomes of TEMS, which was reduced by tacrolimus with SMD - 4.12 (95% CI: 5.46, –2.79; I2 = 0%) [Table 4].
Clinical absolute evaluation method score
Four prospective clinical trials yielding 122 patients involved the outcomes of CAEM score, which was reduced by tacrolimus with SMD 1.35 (95% CI: 0.14, 2.56; I2 = 0%) [Table 4].
Heterogeneity and bias
No significant heterogeneity was apparent for all these outcomes except QMG score. As for the sensitivity analysis, the results of pooled SMD did not change greatly through removing any one research. In addition, because none of our outcomes included ten or more studies, we did not evaluate publication bias in our meta-analysis based on the recommendations of Cochrane Handbook.
Adverse effects were mentioned as mild in many trials. The most common event was increase in hemoglobin A1C level and neutrophil count [Table 5]. This symptom often settled if researchers stop the drug or reduce the dose. Some reported problems such as abnormality in liver and renal function were transient. Of note, the data revealed here are not comprehensive, because the trials included in this meta-analysis were mostly small and often short lasting.
| Discussion|| |
MG is a chronic autoimmune disease which might need long-term immunization therapy; therefore, therapies must not only be efficacious but should also cause less side effect. Clinical guideline indicated that corticosteroids might be an effective medicine for the management of MG, but even the dose of <7.5 mg/day might increase the risk of side effect, which made researchers to add other immunosuppressive regimens to decrease the dose of it. Immunosuppression is effective in controlling the progression of MG,, which can be sorted into three categories: inhibition of the cell cycle (such as azathioprine, cyclophosphamide, and mycophenolate mofetil), immunosuppression of T-cells (such as tacrolimus), and B-cell depletion (such as rituximab). Tacrolimus is a macrolide and binds to FK506-binding protein 12 (FKBP12) to form a complex of tacrolimus–FKBP12 which can inhibit T-lymphocyte, and then inhibit the phosphatase activity of calcineurin.
Until now, one review, several RCTs, prospective clinical trials, and case reports have addressed the efficacy and safety of tacrolimus in MG. However, none of these studies pooled all the relevant data into meta-analysis to provide comprehensive information for clinic workers. Therefore, we conducted this first meta-analysis investigating the efficacy and safety of tacrolimus for the management of MG.
Our research only found 2 RCTs (Numbers of patient = 114) and 11 prospective clinical trials (N = 381). Various clinical situations have been included, such as de novo diagnosis, cyclosporine- and prednisone-dependent MG, steroid-dependent MG, and postoperative thymectomy. However, we could not find any other kind of properly designed studies relevant to this topic.
Overall, our meta-analysis suggested that tacrolimus might benefit the development of MG.
In the primary outcome, since steroids might bring many side effects if patients received them for a long time, we investigated the steroid-sparing effects of tacrolimus to maintain MM. The only two RCTs showed contradictory results, a possible explanation for which might be that the duration of these two trials was different. Participants of the study by Nagane et al. were followed up and were treated to maintain MM for 1 year, investigators of which found that tacrolimus significantly reduced the use of steroids; however, the study by Yoshikawa et al. which only lasted for 28 weeks yielded the opposite result. The above two RCTs showed that tacrolimus with enough treatment duration might have positive steroid-sparing effects.
In the secondary outcome, namely the efficacy of tacrolimus in reducing the severity of MG, the meta-analyses of prospective clinical trials showed a benefit effect. To be specific, QMG score was reduced by tacrolimus with high heterogeneity, in which we found that the most possible cause of heterogeneity between trials was the baseline severity of MG. Three studies conducted by Ponseti et al. were associated with high baseline severity of MG. Since we failed to find value stratification of MG baseline severity, we did not conduct subgroup analysis. In contrast, other outcomes including MGADL, TEMS, and CAEM scores all suggested that tacrolimus could significantly improve the development of MG.
To date, there is only one review conducted to assess the efficacy of tacrolimus by Cruz et al., which only described prospective clinical trials focusing on clinical outcomes in patients with generalized MG without quantitative analysis. We used meta-analytic method to provide more comprehensive information and our conclusions aligned with their review. Differing from this review, we included four more trials ,,, and excluded two trials from their eligible studies due to insufficient data for outcome calculation.,
Limitations of this meta-analysis
The most important limitation which largely discounted the reliability of our findings might be the poor quality of included evidences and limited study sample sizes with low statistical power. What is more, it is possible that corticosteroids or other combined interventions might influence our outcomes. However, we could not access the efficacy of tacrolimus as a monotherapy because tacrolimus in all included studies was combined with other immunotherapies.
What is more, the estimates of overall side effects might be imprecise, which could be attributed to the fact that researches have reported details of side effects but not all. It might be also because that the duration of follow-up in some trials might be insufficient enough to detect comprehensive adverse events.
Suggestion for future research
Since our meta-analysis was based only on two RCTs and several prospective clinical trials, more RCTs with larger sample size and long-term duration will be necessary in investigating the efficacy and safety of tacrolimus for the therapy of MG, as well as to help reduce random error and identify publication bias. Especially, in the field of steroid-sparing effect of tacrolimus to maintain MM, the enough treatment duration might be particularly crucial.
| Conclusion|| |
Despite the above limitations, this meta-analysis suggests that there might be a potential beneficial role with safety for tacrolimus in the management of MG; additional high-quality researches are needed to confirm or refute these results. However, in applying these evidences to MG patients, the choice of tacrolimus for an individual patient is neither automatic nor straightforward, as risks of drawbacks and benefits of this drug must be balanced.
The authors would like to thank the group of people with highest risk of drug exposure of International Network for the Rational Use of Drugs, China, for providing support to coordinate circulation of the manuscript to all co-authors and to collect comments from all co-authors.
Financial support and sponsorship
This work was supported by the Natural Science Foundation of China: Evidence-based establishment of evaluation index system for pediatric rational drug use in China (grant number 81373381).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Drachman DB. Myasthenia gravis. N Engl J Med 1994;330:1797-810.
Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis. Lancet 2001;357:2122-8.
Hohlfeld R, Melms A, Schneider C. Therapy of Myasthenia Gravis and Myasthenic Syndromes. Ch. 94. Neurological Disorders, 2003:1341-62.
Skeie GO, Apostolski S, Evoli A, Gilhus NE, Hart IK, Harms L, et al.
Guidelines for the treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 2006;13:691-9.
van Staa TP, Geusens P, Pols HA, de Laet C, Leufkens HG, Cooper C. A simple score for estimating the long-term risk of fracture in patients using oral glucocorticoids. QJM 2005;98:191-8.
Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, et al.
FK-506, a novel immunosuppressant isolated from a Streptomyces
. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 1987;40:1249-55.
Flanagan WM, Corthésy B, Bram RJ, Crabtree GR. Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature 1991;352:803-7.
Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group. Lancet 1994;344:423-8.
Utsugisawa K, Nagane Y, Yonezawa H, Obara D, Kondoh R, Tohgi H. Effects of FK506 on myasthenia gravis patients with high interleukin-2 productivity in peripheral blood mononuclear cells. Muscle Nerve 2003;27:245-8.
Nagane Y, Utsugisawa K, Obara D, Kondoh R, Terayama Y. Effi cacy of low-dose FK506 in the treatment of myasthenia gravis – A randomized pilot study. Eur Neurol 2005;53:146-50.
Chung S, Park CW, Song J, Kim JA, Shin SJ, Chang YS. Simultaneous and sustained remission of intractable myasthenia gravis and focal segmental glomerulosclerosis with tacrolimus treatment. Clin Nephrol 2008;70:59-61.
Yoshikawa H, Kiuchi T, Saida T, Takamori M. Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis. J Neurol Neurosurg Psychiatry 2011;82:970-7.
Furukawa Y, Yoshikawa H, Iwasa K, Yamada M. Clinical efficacy and cytokine network-modulating effects of tacrolimus in myasthenia gravis. J Neuroimmunol 2008;195:108-15.
Cruz JL, Wolff ML, Vanderman AJ, Brown JN. The emerging role of tacrolimus in myasthenia gravis. Ther Adv Neurol Disord 2015;8:92-103.
Jaretzki A 3rd
, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, et al.
Myasthenia gravis: Recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology 2000;55:16-23.
Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn RJ. Myasthenia gravis activities of daily living profile. Neurology 1999;52:1487-9.
Ponseti JM. Miastenia Gravis. Manual Terapéutico. Berlin: Springer Verlag Ibérica; 1994.
Wang HY, Xu XH. Myasthenia gravis patients clinical absolute evaluation method and relative evaluation method. Chin Neurosci J 1997;2:87-90.
Higgins JP, Green S(editor). Cochrane Handbook for Systematic Reviews of Interventions. Ver. 5.1.0. Chichester: The Cochrane Collaboration; 2011. Available from: http://www.cochrane-handbook.org
. [Last updated on 2011 Mar 11].
Ponseti JM, Azem J, Fort JM, López-Cano M, Vilallonga R, Gamez J, et al.
Experience with starting tacrolimus postoperatively after transsternal extended thymectomy in patients with myasthenia gravis. Curr Med Res Opin 2006;22:885-95.
Ponseti JM, Azem J, Fort JM, López-Cano M, Vilallonga R, Buera M, et al.
Long-term results of tacrolimus in cyclosporine- and prednisone-dependent myasthenia gravis. Neurology 2005;64:1641-3.
Ponseti JM, Azem J, Fort JM, Codina A, Montoro JB, Armengol M. Benefits of FK506 (tacrolimus) for residual, cyclosporin- and prednisone-resistant myasthenia gravis: One-year follow-up of an open-label study. Clin Neurol Neurosurg 2005;107:187-90.
Konishi T, Yoshiyama Y, Takamori M, Yagi K, Mukai E, Saida T et al
. Clinical study of FK506 in patients with myasthenia gravis. Muscle Nerve 2003;28:570-4.
Kawaguchi N, Yoshiyama Y, Nemoto Y, Munakata S, Fukutake T, Hattori T. Low-dose tacrolimus treatment in thymectomised and steroid-dependent myasthenia gravis. Curr Med Res Opin 2004;20:1269-73.
Konishi T, Yoshiyama Y, Takamori M, Saida T. Long-term treatment of generalised myasthenia gravis with FK506 (tacrolimus). J Neurol Neurosurg Psychiatry 2005;76:448-50.
Zhao CB, Zhu WH, Hong LJ. Small dose of tacrolimus for the treatment of refractory systemic type myasthenia gravis preliminary study. J Clin Neurosci China 2005;13:406-9.
Tada M, Shimohata T, Tada M, Oyake M, Igarashi S, Onodera O, et al.
Long-term therapeutic efficacy and safety of low-dose tacrolimus (FK506) for myasthenia gravis. J Neurol Sci 2006;247:17-20.
Zhao CB, Zhang X, Zhang H, Hu XQ, Lu JH, Lu CZ, et al.
Clinical efficacy and immunological impact of tacrolimus in Chinese patients with generalized myasthenia gravis. Int Immunopharmacol 2011;11:519-24.
Wang ZQ. Tacrolimus refractory myasthenia gravis treatment efficacy and safety study. J Pract Med China 2014;9:160-1.
Chen Z, Li X. 82 cases of tacrolimus in the treatment of refractory myasthenia gravis feasibility analysis. China Disabled Med 2015;13:100-1.
Wakata N, Saito T, Tanaka S, Hirano T, Oka K. Tacrolimus hydrate (FK506): Therapeutic effects and selection of responders in the treatment of myasthenia gravis. Clin Neurol Neurosurg 2003;106:5-8.
Mitsui T, Kunishige M, Ichimiya M, Shichijo K, Endo I, Matsumoto T. Beneficial effect of tacrolimus on myasthenia gravis with thymoma. Neurologist 2007;13:83-6.
Shimojima Y, Matsuda M, Gono T, Ishii W, Tokuda T, Ikeda S. Tacrolimus in refractory patients with myasthenia gravis: Coadministration and tapering of oral prednisolone. J Clin Neurosci 2006;13:39-44.
Huei CP, Song JW. Small dose of tacrolimus in the treatment of refractory myasthenia gravis patients clinical analysis. China Med Guide 2015;24:154-5.
Pei YH, Wang L, Shi YF. Tacrolimus treatment the curative effect of slow metabolism type myasthenia gravis. Guangdong Med 2012;7:1004-5.
Curtis JR, Westfall AO, Allison J, Bijlsma JW, Freeman A, George V, et al
. Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Care Res 2006;55:420-6.
Yoshikawa H, Iwasa K, Satoh K, Takamori M. FK506 prevents induction of rat experimental autoimmune myasthenia gravis. J Autoimmun 1997;10:11-6.
Sathasivam S. Steroids and immunosuppressant drugs in myasthenia gravis. Nat Clin Pract Neurol 2008;4:317-27.
Harding MW, Galat A, Uehling DE, Schreiber SL. A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature 1989;341:758-60.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]