1. Immunology and Inflammation
  2. Medicine

An open label trial of anakinra to prevent respiratory failure in COVID-19

  1. Evdoxia Kyriazopoulou
  2. Periklis Panagopoulos
  3. Symeon Metallidis
  4. George N Dalekos
  5. Garyphallia Poulakou
  6. Nikolaos Gatselis
  7. Eleni Karakike
  8. Maria Saridaki
  9. Georgia Loli
  10. Aggelos Stefos
  11. Danai Prasianaki
  12. Sarah Georgiadou
  13. Olga Tsachouridou
  14. Vasileios Petrakis
  15. Konstantinos Tsiakos
  16. Maria Kosmidou
  17. Vassiliki Lygoura
  18. Maria Dareioti
  19. Haralampos Milionis
  20. Ilias C Papanikolaou
  21. Karolina Akinosoglou
  22. Dimitra-Melia Myrodia
  23. Areti Gravvani
  24. Aliki Stamou
  25. Theologia Gkavogianni
  26. Konstantina Katrini
  27. Theodoros Marantos
  28. Ioannis P Trontzas
  29. Konstantinos Syrigos
  30. Loukas Chatzis
  31. Stamatios Chatzis
  32. Nikolaos Vechlidis
  33. Christina Avgoustou
  34. Stamatios Chalvatzis
  35. Miltiades Kyprianou
  36. Jos WM van der Meer
  37. Jesper Eugen-Olsen
  38. Mihai G Netea
  39. Evangelos J Giamarellos-Bourboulis  Is a corresponding author
  1. 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Greece
  2. 2nd Department of Internal Medicine, Democritus University of Thrace, Medical School, Greece
  3. 1st Department of Internal Medicine, Aristotle University ofThessaloniki, Greece
  4. Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece
  5. 3rd Department of Internal Medicine, National and Kapodistrian University of Athens, Greece
  6. 1st Department of Internal Medicine,University of Ioannina, School of HealthSciences, Faculty of Medicine, Greece
  7. Department of Pulmonary Medicine, General Hospital of Kerkyra, Greece
  8. Department of Internal Medicine, University of Patras, Medical School, Greece
  9. Department of Internal Medicine and Center for Infectious Diseases, Radboud University, Netherlands
  10. Clinical Research Centre, Copenhagen University Hospital Hvidovre, Denmark
  11. Immunology and Metabolism, Life & Medical Sciences Institute, University of Bonn, Germany
https://doi.org/10.7554/eLife.66125
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Cite this article
  1. Evdoxia Kyriazopoulou
  2. Periklis Panagopoulos
  3. Symeon Metallidis
  4. George N Dalekos
  5. Garyphallia Poulakou
  6. Nikolaos Gatselis
  7. Eleni Karakike
  8. Maria Saridaki
  9. Georgia Loli
  10. Aggelos Stefos
  11. Danai Prasianaki
  12. Sarah Georgiadou
  13. Olga Tsachouridou
  14. Vasileios Petrakis
  15. Konstantinos Tsiakos
  16. Maria Kosmidou
  17. Vassiliki Lygoura
  18. Maria Dareioti
  19. Haralampos Milionis
  20. Ilias C Papanikolaou
  21. Karolina Akinosoglou
  22. Dimitra-Melia Myrodia
  23. Areti Gravvani
  24. Aliki Stamou
  25. Theologia Gkavogianni
  26. Konstantina Katrini
  27. Theodoros Marantos
  28. Ioannis P Trontzas
  29. Konstantinos Syrigos
  30. Loukas Chatzis
  31. Stamatios Chatzis
  32. Nikolaos Vechlidis
  33. Christina Avgoustou
  34. Stamatios Chalvatzis
  35. Miltiades Kyprianou
  36. Jos WM van der Meer
  37. Jesper Eugen-Olsen
  38. Mihai G Netea
  39. Evangelos J Giamarellos-Bourboulis
(2021)
An open label trial of anakinra to prevent respiratory failure in COVID-19
eLife 10:e66125.
https://doi.org/10.7554/eLife.66125
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7 figures, 8 tables and 2 additional files

Figures

Figure 1 with 1 supplement
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Outcome of patients treated with anakinra.

(A) Curves of the cumulative incidence of severe respiratory failure (SRF); and (B) curves of 30-day mortality; the inset shows the curves in enlarged Y-axis. The analysis includes propensity-scored …

Figure 1—figure supplement 1
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Incidence of SRF among the total of 179 available comparators treated with SOC before matching and the 130 partiicpants in the SAVE trial treated with Anakinra and SOC.
Figure 2
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Effect of anakinra treatment on circulating mediators of patients with lower respiratory tract infection by SARS-CoV-2.

Concentrations of (A) suPAR (soluble urokinase plasminogen activator receptor); (B) the absolute lymphocyte count; (C) interleukin (IL)-6; and (D) sCD163 of patients under parallel standard-of-care (…

Figure 3
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Effect of anakinra treatment on cytokine production capacity from peripheral blood mononuclear cells (PBMCs).

PBMCs were isolated before and 7 days after start of treatment with anakinra. PBMCs were stimulated with lipopolysaccharide (LPS) of Escherichia coli O55:B5 for the production of interleukin (IL)−1β …

Figure 4
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Allocation of patients into the strata of the WHO clinical progression scale by day 28.

The analysis includes propensity-scored fully matched comparators treated with standard-of-care (SOC, n = 130) and the 130 participants in the SAVE trial who were treated with SOC treatment and …

Appendix 1—figure 1
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Trial profile and selection of parallel standard-of-care (SOC) comparators.

SOC comparators were hospitalized at the same time period at seven department of Internal Medicine in tertiary hospitals and they were selected in two steps: at the first step after application of …

Appendix 1—figure 2
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Survival curves until day 90.

Patients participating in the SAVE trial received standard-of-care (SOC) treatment and anakinra and were compared to parallel comparators treated only with SOC. The inset shows the curves in …

Appendix 1—figure 3
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Cost of hospitalization.

The three main categories of cost are shown: total cost, cost of anti-infectives, and cost of stay in the intensive care unit. Statistical comparisons between groups. ns: non-significant; *p<0.05; …

Tables

Table 1
Baseline characteristics of patients.
SOC + anakinra (N = 130)Parallel SOC (N = 179)p-value*Parallel SOC after propensity matching (N = 130)p-value**
Age, years, mean (SD)63 (14)66 (14)0.09464 (14)0.839
Male sex, No. (%)81 (62.3)116 (64.8)0.71984 (64.6)0.797
Days from onset of symptoms to start of treatment, median (range)8 (1–23)6 (4–9)0.0127 (1–12)0.143
Severity indexes, mean (SD)
Charlson’s comorbidity index3 (2)3 (2)0.1233 (2)0.927
ΑPACHE II score7 (3)8 (5)0.0027 (3)0.957
SOFA score2 (1)3 (2)0.0012 (1)0.813
Pneumonia severity index69 (22)80 (28)<0.000170 (20)0.709
WHO classification for COVID-19, No. (%)
Moderatepneumonia, no oxygen61 (46.9)68 (38.0)0.15857 (43.8)0.709
Severe pneumonia69 (53.1)111 (62.0)73 (56.2)
Comorbidities, No. (%)
Type 2 diabetes mellitus41 (31.5)45 (25.1)0.24832 (24.6)0.270
Chronic heart failure11 (8.5)19 (10.6)0.56510 (7.7)1.000
Chronic renal disease1 (0.8)12 (6.7)0.0094 (3.1)0.370
Coronary heart disease10 (7.7)24 (13.4)0.14114 (10.8)0.521
Arterial hypertension68 (52.3)87 (48.6)0.56557 (43.8)0.214
Chronic obstructive pulmonary disease12 (9.2)14 (7.8)0.6826 (4.6)0.221
Solid tumor malignancy8 (6.2)14 (7.8)0.6589 (6.9)1.000
Cerebrovascular disease7 (5.4)13 (7.3)0.6414 (3.1)0.540
Bacterial co-infection, No. (%)1 (0.8)5 (2.8)0.4073 (2.3)0.622
Streptococcus pneumoniae0 (0.0)2 (1.1)0.5112 (1.5)0.498
Escherichia coli0 (0.0)1 (0.6)1.0001 (0.8)1.000
Laboratory values, median (Q1–Q3)
White blood cells, cells/mm35400 (4390–6830)6215 (4805–9013)0.0055879 (4760–7800)0.106
Lymphocytes, cells/mm3950 (722–1252)961 (615–1271)0.307977 (587–1318)0.382
Platelets, cells/mm3184,000
(137,000–246,000)		202,000
(150,000–270,000)		0.121204,400
(150,450–271,625)		0.107
C-reactive protein, mg/l47.4 (14.3–105.5)64.7 (18.3–140.0)0.17968.8 (19.7–141.8)0.117
Procalcitonin, ng/ml0.14 (0.08–0.31)0.23 (0.10–0.71)0.1490.13 (0.08–0.41)0.841
Ferritin, ng/ml536.5 (280.0–898.5)629.5 (375.0–1277.0)<0.001607.5 (367.8–1196.0)0.107
Serum soluble uPAR, ng/ml8.9 (7.0–12.2)9.2 (7.0–13.8)0.3449.0 (7.0–11.7)0.973
PaO2/FiO2, mmHg293.3 (195.7–371.2)262.0 (182.0–350.3)0.090285.7 (208.5–371.7)0.917
Concomitant treatment, No. (%)
Hospitalization at tertiary academic hospitals127 (97.7)156 (87.2)0.191120 (92.3)0.167
β-lactamase inhibitors18 (13.8)16 (8.9)0.19913 (10)0.444
Third generation cephalosporins60 (46.2)66 (36.9)0.12743 (33.1)0.042
Piperacillin/tazobactam37 (28.7)61 (34.1)0.32342 (32.3)0.590
Ceftaroline38 (29.2)50 (27.9)0.80042 (32.3)0.687
Carbapenem11 (8.5)23 (12.8)0.27115 (11.5)0.536
Moxifloxacin/levofloxacin27 (20.9)26 (14.5)0.17017 (13.2)0.136
Glycopeptides2 (1.5)6 (3.4)0.4755 (3.8)0.447
Azithromycin96 (73.8)145 (81.0)0.164104 (80.0)0.303
Remdesivir8 (6.2)12 (6.7)1.00011 (8.5)0.635
Hydroxychloroquine56 (43.1)92 (51.4)0.06668 (52.3)0.172
Dexamethasone52 (40.0)65 (36.3)0.55347 (36.2)0.610
Predicted probability0.488 (0.386–0.571)__0.488 (0.391–0.556)0.629

  1. Abbreviations: APACHE: acute physiology and chronic health evaluation; n: number; Q: quartile; SD: standard deviation; SOC: standard-of-care; SOFA: sequential organ failure assessment; uPAR: urokinase-type plasminogen activator receptor; WHO: World Health Organization.

    *p-value of comparison between SOC + anakinra treated patients and parallel standard-care comparators.

  2. **p-value of comparison between SOC + anakinra treated patients and parallel standard-care comparators after propensity matching.

Table 2
Primary, secondary, and exploratory study outcomes.
Parallel SOC (N = 130)SOC + Anakinra after propensity matching (N = 130)OR (95% CI)p-value
Severe respiratory failure by day 14, No. (%)77 (59.2)29 (22.3)0.19 (0.12–0.34)<0.0001
Mechanical ventilation (MV) by day 14, No. (%)65 (50.0)25 (19.2)0.24 (0.14–0.42)<0.0001
Non-invasive MV by day 14, No. (%)9 (6.9)6 (4.6)0.65 (0.23–1.88)0.596
14-day mortality, No. (%)16 (12.3)6 (4.6)0.35 (0.13–0.91)0.043
SOFA score on day 7, median (Q1–Q3)2 (0 to 3)1 (0 to 3)NA0.540
SOFA score on day 14, median (Q1–Q3)2 (0–9)1 (0–3)NA0.191
Absolute change of SOFA score by day 7 compared to baseline, median (Q1–Q3)0 (−1 to 1)0 (−1 to 0)NA0.356
Absolute change of SOFA score by day 14 compared to baseline, median (Q1–Q3)0 (−1 to 6)−2 (−1 to 0)NA0.004
Absolute change of respiratory symptoms score by day 7 compared to baseline, median (Q1–Q3)0 (0 to 0.75)−1 (−3 to 0)NA0.019
Absolute change of respiratory symptoms score by day 14 compared to baseline, median (Q1–Q3)0 (−0.75 to 0)−2 (−4 to −1)NA0.016
Ventilator-free days, mean (SD)18 (11)25 (8)NA<0.0001
30-day mortality, No. (%)29 (22.3)15 (11.5)0.45 (0.23–0.90)0.031
90-day mortality, No. (%)40 (30.8)22 (16.9)0.46 (0.25–0.83)0.013

  1. Abbreviations: CI: confidence interval; n: number; NA: non-applicable; OR: odds ratio; Q: quartile; SD: standard deviation; SOC; standard-of-care; SOFA: sequential organ failure assessment.

Table 3
Anakinra as an independent protective factor from development of severe respiratory failure (SRF) by day 14.

Univariate and multivariate (Cox forward conditional) models, for patients receiving anakinra with standard-of-care (SOC) treatment and for parallel comparators receiving only SOC treatment are …

Univariate analysisMultivariate analysis
Variable, no. (%)SRF (−) (N = 154)SRF (+) (N = 106)HR (95% CI)p-valueHR (95% CI)p-value
Anakinra treatment, n (%)101 (65.6)29 (27.4)0.30 (0.20–0.47)<0.00010.28 (0.18–0.44)<0.0001
APACHE II, mean (SD)6 (3)8 (3)1.12 (1.07–1.19)<0.0001
SOFA score, mean (SD)2 (1)3 (1)1.58 (1.38–1.82)<0.00011.41 (1.21–1.65)<0.0001
Pneumonia severity index, mean (SD)66 (22)73 (19)1.01 (1.00–1.02)0.017
Severe COVID-19 by WHO classification, n (%)65 (42.2)77 (72.6)2.78 (1.81–4.27)<0.00011.74 (1.09–2.79)0.020
Soluble uPAR, ng/ml, median (Q1–Q3)8.3 (6.7–11.0)10.0 (8.0–13.9)1.10 (1.04–1.17)0.0011.07 (1.01–1.14)0.022
Lymphocytes/mm3, median (Q1–Q3)1000 (733–1315)930 (579–1197)0.99 (0.99–1.00)0.026
C-reactive protein, mg/l, median (Q1–Q3)41.1 (12.7–95.2)73.4 (30.6–153.1)1.00 (1.00–1.00)<0.0001
Ferritin, ng/ml, median (Q1–Q3)525.0 (280.0–804.5)641.5 (451.3–1556.8)1.00 (1.00–1.00)<0.0001
PaO2/FiO2, mmHg, median (Q1–Q3)330.8 (231.9–386.7)244.4 (161.7–305.8)0.99 (0.99–0.99)<0.0001
Treatment with third generation cephalosporin, n (%)73 (47.4)30 (28.3)0.53 (0.35–0.82)0.004
Treatment with piperacillin/tazobactam, n (%)37 (24.0)42 (39.6)1.60 (1.08–2.38)0.019
Treatment with carbapenem, n (%)7 (4.5)19 (17.9)2.79 (1.69–4.60)<0.00012.19 (1.26–3.83)0.006
Treatment with glycopeptide, n (%)1 (0.6)6 (5.7)2.60 (1.14–5.95)0.023
Treatment with dexamethasone, n (%)46 (29.9)53 (50.0)1.73 (1.19–2.54)0.005

  1. Abbreviations: APACHE: acute physiology and chronic health evaluation; CI: confidence interval; HR: hazard ratio; n: number; PaO2/FiO2: ratio of partial oxygen pressure to the fraction of inspired oxygen; Q: quartile; SD: standard deviation; SOFA: sequential organ failure assessment; SRF: severe respiratory failure; uPAR: urokinase-type plasminogen activator receptor.

Table 4
Adverse events and serious adverse events.

The incidence of the same events was depicted among parallel SOC treated, propensity-matched comparators.

Parallel SOC (N = 130)SOC + anakinra (N = 130)OR (95% CI)p-value
At least one SAE by day 14, No. (%)63 (48.5)32 (24.6)0.34 (0.21–0.59)<0.0001
Extended hospitalization63 (48.5)32 (24.6)0.34 (0.21–0.59)<0.0001
Death16 (12.3)6 (4.6)0.35 (0.13–0.91)0.043
Shock56 (43.1)27 (20.8)0.34 (0.20–0.59)<0.0001
Acute kidney injury37 (28.5)15 (11.5)0.32 (0.17–0.63)0.001
Any bacterial infection30 (23.1)9 (6.9)0.22 (0.10–0.49)<0.0001
Thromboembolic event5 (3.8)2 (1.5)0.32 (0.06–1.72)0.188
Pulmonary edema0 (0)1 (0)NA1.00
At least one AE by day 14, No. (%)89 (68.5)85 (65.4)0.87 (0.51–1.45)0.693
Gastrointestinal disturbances9 (6.9)15 (11.5)1.74 (0.74–4.17)0.284
Electrolyte abnormalities41 (31.5)35 (26.9)0.80 (0.47–1.37)0.496
Elevated liver function tests51 (39.2)40 (30.8)0.69 (0.41–1.15)0.193
Anemia26 (20.0)22 (16.9)0.82 (0.44–1.53)0.632
Leukopenia3 (2.3)11 (8.5)3.91 (1.07–14.37)0.051
Thrombopenia7 (5.4)9 (6.9)1.31 (0.47–3.62)0.797
Headache2 (1.5)4 (3.1)2.03 (0.37–11.29)0.684
Allergic reaction7 (5.4)4 (3.1)0.56 (0.16–1.95)0.540
Any heart arrhythmia22 (16.9)9 (6.9)0.37 (0.16–0.83)0.020

  1. Abbreviations: AE: non-serious adverse event; CI: confidence interval; n: number; NA: non-available; OR: odds ratio; SAE: serious adverse event; SOC: standard-of-care.

Key resources table
Reagent type
(species) or
resource		DesignationSource or
reference		IdentifiersAdditional
information
Commercial assay or kitHuman IL-1b uncoated ELISAInvitrogen88–7261
Commercial assay or kitHuman IL-6 uncoated ELISAInvitrogen88–7066
Commercial assay or kitHuman IL-10 uncoated ELISAInvitrogen88–7066
Commercial assay or kitHuman IL-2R uncoated ELISAInvitrogen88-7025-22
Commercial assay or kitHuman sCD163 uncoated ELISAAffymetrix IncRAB0082
Commercial assay or kitHuman Ferritin ELISAORGENTEC Diagnostika GmbHORG 5FE
Chemical compound, drugLymphosep, Lymphocyte Separation MediaBiowestL0560
Chemical compound, drugPBS Dulbecco’s Phosphate Buffered Saline w/o Magnesium, w/o CalciumBiowestL0615
Chemical compound, drugFBS Superior; standardized Fetal Bovine Serum, EU-approvedBiochromS0615
Chemical compound, drugGentamycin Sulfate BioChemicaPanReac AppliChemA1492
Chemical compound, drugPenicillin G Potassium Salt BioChemicaPanReac AppliChemA1837
Chemical compound, drugLipopolysaccharides from Escherichia coli O55:B5Sigma-AldrichL2880
Appendix 1—table 1
List of participating study sites where patients were hospitalized.
Name of study siteCityLevel of careSOC (n)SOC + anakinra (n)
4th Department of Internal Medicine, ATTIKON University HospitalAthensTertiary Academic17
3rd Department of Internal Medicine, Sotiria General HospitalAthensTertiary Academic26
1st Department of Pulmonary Medicine, Sotiria General HospitalAthensTertiary Academic25
AHEPA General Hospital
COVID-19 unit I		ThessalonikiTertiary Academic43
AHEPA General Hospital
COVID-19 unit II		ThessalonikiTertiary Academic32
University General Hospital of LarissaLarissaTertiary Academic36
University General Hospital of Alexandroupolis, COVID-19 unit IAlexandroupolisTertiary Academic18
University General Hospital of Alexandroupolis, COVID-19 unit IIAlexandroupolisTertiary Academic18
University General Hospital of Ioannina, COVID-19 unit IIoanninaTertiary Academic3
University General Hospital of Ioannina, COVID-19 unit IIIoanninaTertiary Academic11
University General Hospital of PatrasPatrasTertiary Academic15
1st Department of Internal Medicine, Thriasio General HospitalAthensTertiary NHS12
Department of Pulmonary Medicine, Kerkyra General HospitalKerkyraTertiary NHS4

  1. Abbreviations N: number; NHS: national health system; SOC: standard-of-care.

Appendix 1—table 2
Anakinra as an independent protective factor from development of severe respiratory failure (SRF) by day 14 among patients treated with dexamethasone.

Univariate and multivariate (Cox forward conditional) models, for the anakinra with standard-of-care group (SOC) and parallel SOC comparators are presented. Only admission variables that differ …

Univariate analysisMultivariate analysis
Variable no. (%)SRF (−) (N = 46)SRF (+) (N = 53)HR (95% CI)p-valueHR (95% CI)p-value
Anakinra treatment, n (%)31 (67.4)21 (39.6)0.55 (0.32–0.97)0.0380.56 (0.32–0.97)0.038
Soluble uPAR, ng/ml, median (Q1–Q3)9.60 (7.2–12.6)11.6 (7.3–12.6)1.10 (1.00–1.20)0.0301.97 (1.14–3.41)0.018
Ferritin, ng/ml, median (Q1–Q3)593.0
(411.3–968.5)		633.0
(412.0–968.0)		1.00 (1.00–1.00)0.025

  1. Abbreviations: CI: confidence interval; HR: hazard ratio; n: number; Q: quartile; SRF: severe respiratory failure; uPAR: urokinase-type plasminogen activator receptor.

Appendix 1—table 3
Anakinra as an independent protective factor from 30-day mortality.

Univariate and multivariate (Cox forward conditional) models, for the anakinra with standard-of-care (SOC) group and parallel SOC comparators are presented. Only admission variables that differ …

Univariate analysisMultivariate analysis
Parameters, no. (%)Survival (N = 216)Death (N = 44)HR (95% CI)p-valueHR (95% CI)p-value
Anakinra treatment, n(%)115 (53.2)15 (34.1)0.49 (0.26–0.91)0.0240.49 (0.25–0.97)0.041
Charlson’s comorbidity index, mean (SD)3 (2)4 (2)1.29 (1.13–1.48)<0.00011.26 (1.09–1.48)0.002
APACHE II score, mean (SD)6 (3)9 (3)1.24 (1.14–1.35)<0.0001
SOFA score, mean (SD)2 (1)3 (1)2.13 (1.73–2.63)<0.00012.03 (1.61–2.55)<0.0001
Pneumonia severity index, mean (SD)67 (21)81 (18)3.66 (1.85–7.24)<0.0001
Severe COVID-19 by WHO classification,
n (%)		105 (48.6)37 (84.1)4.86 (2.17–10.92)0.0001
Soluble uPAR, ng/ml, median (Q1–Q3)8.8 (6.8–11.4)10.4 (8.0–14.7)1.15 (1.05–1.26)0.003
Lymphocytes/mm3, median (Q1–Q3)984 (699–1275)839 (545–1167)0.999 (0.99–1.00)0.024
C-reactive protein, mg/l, median (Q1–Q3)50.7 (17.5–118.4)80.1 (18.7–156.7)1.003 (1.00–1.01)0.033
PaO2/FiO2 mmHg, median (Q1–Q3)301 (224.6–374.4)195.8 (88.2–290.4)0.99 (0.98–0.99)<0.0001
History of type 2 diabetes mellitus, n (%)53 (24.5)20 (45.5)2.38 (1.31–4.31)0.004
Treatment with third generation cephalosporin, n (%)93 (43.1)10 (22.7)0.43 (0.21–0.88)0.020
Treatment with piperacillin/tazobactam,
n (%)		59 (27.3)20 (45.5)2.03 (1.11–3.69)0.021
Treatment with remdesivir, n (%)11 (5.1)8 (18.6)3.22 (1.50–6.95)0.0031.27 (1.09–1.47)0.002

  1. Abbreviations: APACHE: acute physiology and chronic health evaluation; CI: confidence interval; HR: hazard ratio; n: number; PaO2/FiO2: ratio of partial oxygen pressure to the fraction of inspired oxygen; q: quartile; SD: standard deviation; SOFA: sequential organ failure assessment; uPAR: urokinase-type plasminogen activator receptor.

Additional files

Supplementary file 1

Protocol and statistical analysis plan.

https://cdn.elifesciences.org/articles/66125/elife-66125-supp1-v2.docx
Transparent reporting form
https://cdn.elifesciences.org/articles/66125/elife-66125-transrepform-v2.docx

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