September  2020, 13(9): 2365-2384. doi: 10.3934/dcdss.2020141

Nonlinear effects in the dynamics of HIV-1 infection predicted by mathematical model with multiple delays

1. 

Sobolev Institute of Mathematics, Siberian Branch of the Russian Academy of Sciences, Omsk Branch, Omsk, 644043, Russian Federation

2. 

Marchuk Institute of Numerical Mathematics, Russian Academy of Sciences, Moscow, 119333, Russian Federation

* Corresponding author: Nikolay Pertsev

Received  January 2019 Revised  April 2019 Published  September 2020 Early access  November 2019

Fund Project: The first and the last authors are supported by Russian Science Foundation grant 18-11-00171

We formulate a novel mathematical model to describe the development of acute HIV-1 infection and the antiviral immune response. The model is formulated using a system of delay differential- and integral equations. The model is applied to study the possibility of eradication of HIV infection during the primary acute phase of the disease. To this end a combination of analytical examination and computational treatment is used. The model belongs to the Wazewski differential equation systems with delay. The conditions of asymptotic stability of a trivial steady state solution are expressed in terms of the algebraic Sevastyanov–Kotelyanskii criterion. The results of the computational experiments with the model calibrated according to the available estimates of parameters suggest that a complete elimination of HIV-1 infection after acute phase of infection is feasible.

Citation: Nikolay Pertsev, Konstantin Loginov, Gennady Bocharov. Nonlinear effects in the dynamics of HIV-1 infection predicted by mathematical model with multiple delays. Discrete and Continuous Dynamical Systems - S, 2020, 13 (9) : 2365-2384. doi: 10.3934/dcdss.2020141
References:
[1]

H. T. Banks and D. M. Bortz, A parameter sensitivity methodology in the context of HIV delay equation models, J. Math. Biol., 50 (2005), 607-625.  doi: 10.1007/s00285-004-0299-x.

[2]

G. BocharovV. ChereshnevI. GainovaS. BazhanB. BachmetyevJ. ArgilaguetJ. Martinez and A. Meyerhans, Human Immunodeficiency Virus Infection: From Biological Observations to Mechanistic Mathematical Modelling, Math. Model. Nat. Phenom., 7 (2012), 78-104.  doi: 10.1051/mmnp/20127507.

[3]

G. A. BocharovYu. M. NechepurenkoM. Yu. Khristichenko and D. S. Grebennikov, Maximum response perturbation-based control of virus infection model with time-delays, Russ. J. Numer. Anal. Math. Modelling, 32 (2017), 275-291.  doi: 10.1515/rnam-2017-0027.

[4]

V. A. Chereshnev, G. A. Bocharov, A. V. Kim, S. I. Bazhan, I. A. Gainova, A. N. Krasovskii, N. G. Shmagel', A. V. Ivanov, M. A. Safronov and R. M. Tret'yakova, Vvedenie V Zadachi Modelirovaniya I Upravleniya Dinamikoi VICH Infektsii, (Russian) [Introduction to the tasks of modeling and managing the dynamics of HIV infection], Ijevsk: Institut komp'yuternykh issledovanii, Moscow, 2016.

[5]

R. D. Driver, Ordinary and Delay Differential Equations, Applied Mathematical Sciences, Vol. 20, Springer-Verlag, New York-Heidelberg, 1977. doi: 10.1007/978-1-4684-9467-9.

[6]

R. EftimieJ. J. Gillard and D. A. Cantrell, Mathematical Models for Immunology: Current State of the Art and Future Research Directions, Bull. Math. Biol., 78 (2016), 2091-2134.  doi: 10.1007/s11538-016-0214-9.

[7]

L. E. El'sgol'ts and S. B. Norkin, Introduction to the Theory and Application of Differential Equations with Deviating Arguments, Translated from the Russian by John L. Casti. Mathematics in Science and Engineering, Vol. 105, Academic Press [A Subsidiary of Harcourt Brace Jovanovich, Publishers], New York-London, 1973.

[8]

F. R. Gantmacher, The Theory of Matrices, AMS Chelsea Publishing, Providence, RI, 1998.

[9]

J. K. Hale, Theory of Functional Differential Equations, Applied Mathematical Sciences, Vol. 3, Springer-Verlag, New York-Heidelberg, 1977. doi: 10.1007/978-1-4612-9892-2.

[10]

S. I. KabanikhinO. I. KrivorotkoD. V. ErmolenkoV. N. Kashtanova and V. A. Latyshenko, Inverse problems of immunology and epidemiology, Eurasian Journal of Mathematical and Computer Applications, 5 (2017), 14-35. 

[11]

S. I. KabanikhinO. I. KrivorotkoD. A. Voronov and D. V. Ermolenko, Optimization approach for solving the inverse problem of the simplest model of an infectious disease, Siberian Electronic Mathematical Reports, 12 (2015), 154-162. 

[12]

V. B. Kolmanovskii and V. R. Nosov, Ustoichivost' i Periodicheskie Rejimy Sistem Upravleniya s Posledeistviem, (Russian) [Stability and periodic regimes of control systems with aftereffect], [Theoretical Foundations of Engineering Cybernetics] Nauka, Moscow, 1981.

[13]

A. A. Lackner, M. M. Lederman and B. Rodriguez, HIV Pathogenesis: The Host, Cold Spring Harb Perspect Med, 2 (2012), a007005. doi: 10.1101/cshperspect.a007005.

[14]

G. I. Marchuk, Matematicheskie Modeli v Immunologii, (Russian) [Mathematical models in immunology], 2nd edition, With a preface by R. V. Petrov., Nauka, Moscow, 1985.

[15]

G. I. Marchuk, Matematicheskie Modeli V Immunologii. Vychislitel'nye Metody I Eksperimenty, (Russian) [Mathematical models in immunology. Computational methods and experiments], 3rd edition, Nauka, Moscow, 1991.

[16]

S. NakaokaI. Shingo and K. Sato, Dynamics of HIV infection in lymphoid tissue network, J. Math. Biol., 72 (2016), 909-938.  doi: 10.1007/s00285-015-0940-x.

[17]

P. W. Nelson and A. S. Perelson, Mathematical Analysis of delay differential equation models of HIV-1 infection, Math. Biosci., 179 (2002), 73-94.  doi: 10.1016/S0025-5564(02)00099-8.

[18]

A. Yu. Obolenskii, Stability of solutions of autonomous Wazewski systems with delayed action, Ukr. Math. J., 35 (1983), 486-492.  doi: 10.1007/BF01061640.

[19]

S. Pankavich, The effects of latent infection on the dynamics of HIV, Differ. Equ. Dyn. Syst., 24 (2016), 281-303.  doi: 10.1007/s12591-014-0234-6.

[20]

K. A. PawelekS. LiuF. Pahlevani and L. Rong, A model of HIV-1 infection with two time delays: Mathematical analysis and comparison with patient data, Math. Biosci., 235 (2012), 98-109.  doi: 10.1016/j.mbs.2011.11.002.

[21]

A. S. Perelson and R. M. Ribeiro, Modeling The Within-Host Dynamics of HIV Infection, BMC Biology, 2013. doi: 10.1186/1741-7007-11-96.

[22]

N. V. Pertsev, Global Solvability and Estimates of Solutions to the Cauchy Problem for the Retarded Functional Differential Equations That Are Used to Model Living Systems, Sib. Math. J., 59 (2018), 113-125.  doi: 10.1134/S0037446618010135.

[23]

N. V. PertsevB. Yu. Pichugin and K. K. Loginov, Stochastic Analog of the Dynamic Model of HIV-1 Infection Described by Delay Differential Equations, J. Appl. Ind. Math., 13 (2019), 103-117.  doi: 10.1134/S1990478919010125.

[24]

N. V. Pertsev, B. Yu. Pichugin and A. N. Pichugina, Application of M-Matrices in studies of mathematical models of living systems, Mathematical Biology and Bioinformatics, 13 (2018), t104–t131. doi: 10.17537/2018.13.t104.

[25]

M. Pitchaimani and C. Monica, Global stability analysis of HIV-1 infection model with three time delays, J. Appl. Math. Comput., 48 (2015), 293-319.  doi: 10.1007/s12190-014-0803-4.

[26]

D. Sanchez-TaltavullA. Vieiro and T. Alarcon, Stochastic modelling of the eradication of the HIV-1 infection by stimulation of latently infected cells in patients under highly active anti-retroviral therapy, J. Math. Biol., 73 (2016), 919-946.  doi: 10.1007/s00285-016-0977-5.

[27]

A. ShetP. Nagaraja and N. M. Dixit, Viral Decay Dynamics and Mathematical Modeling of Treatment Response: Evidence of Lower in vivo Fitness of HIV-1 Subtype C, J. Acquir. Immune Defic. Syndr., 73 (2016), 245-251.  doi: 10.1097/QAI.0000000000001101.

[28]

R. F. Siliciano and W. C. Greene, HIV Latency, Cold Spring Harb Perspect Med, 1 (2011), a007096. doi: 10.1101/cshperspect.a007096.

[29]

W. I. Sundquist and H.-G. Kraüsslich, HIV-1 Assembly, Budding, and Maturation, Cold Spring Harb Perspect Med, 2 (2012), a006924. doi: 10.1101/cshperspect.a006924.

[30]

J. WangJ. Lang and X. Zou, Analysis of an age structured HIV infection model with virus-to-cell infection and cell-to-cell transmission, Nonlinear Anal. Real World Appl., 34 (2017), 75-96.  doi: 10.1016/j.nonrwa.2016.08.001.

show all references

References:
[1]

H. T. Banks and D. M. Bortz, A parameter sensitivity methodology in the context of HIV delay equation models, J. Math. Biol., 50 (2005), 607-625.  doi: 10.1007/s00285-004-0299-x.

[2]

G. BocharovV. ChereshnevI. GainovaS. BazhanB. BachmetyevJ. ArgilaguetJ. Martinez and A. Meyerhans, Human Immunodeficiency Virus Infection: From Biological Observations to Mechanistic Mathematical Modelling, Math. Model. Nat. Phenom., 7 (2012), 78-104.  doi: 10.1051/mmnp/20127507.

[3]

G. A. BocharovYu. M. NechepurenkoM. Yu. Khristichenko and D. S. Grebennikov, Maximum response perturbation-based control of virus infection model with time-delays, Russ. J. Numer. Anal. Math. Modelling, 32 (2017), 275-291.  doi: 10.1515/rnam-2017-0027.

[4]

V. A. Chereshnev, G. A. Bocharov, A. V. Kim, S. I. Bazhan, I. A. Gainova, A. N. Krasovskii, N. G. Shmagel', A. V. Ivanov, M. A. Safronov and R. M. Tret'yakova, Vvedenie V Zadachi Modelirovaniya I Upravleniya Dinamikoi VICH Infektsii, (Russian) [Introduction to the tasks of modeling and managing the dynamics of HIV infection], Ijevsk: Institut komp'yuternykh issledovanii, Moscow, 2016.

[5]

R. D. Driver, Ordinary and Delay Differential Equations, Applied Mathematical Sciences, Vol. 20, Springer-Verlag, New York-Heidelberg, 1977. doi: 10.1007/978-1-4684-9467-9.

[6]

R. EftimieJ. J. Gillard and D. A. Cantrell, Mathematical Models for Immunology: Current State of the Art and Future Research Directions, Bull. Math. Biol., 78 (2016), 2091-2134.  doi: 10.1007/s11538-016-0214-9.

[7]

L. E. El'sgol'ts and S. B. Norkin, Introduction to the Theory and Application of Differential Equations with Deviating Arguments, Translated from the Russian by John L. Casti. Mathematics in Science and Engineering, Vol. 105, Academic Press [A Subsidiary of Harcourt Brace Jovanovich, Publishers], New York-London, 1973.

[8]

F. R. Gantmacher, The Theory of Matrices, AMS Chelsea Publishing, Providence, RI, 1998.

[9]

J. K. Hale, Theory of Functional Differential Equations, Applied Mathematical Sciences, Vol. 3, Springer-Verlag, New York-Heidelberg, 1977. doi: 10.1007/978-1-4612-9892-2.

[10]

S. I. KabanikhinO. I. KrivorotkoD. V. ErmolenkoV. N. Kashtanova and V. A. Latyshenko, Inverse problems of immunology and epidemiology, Eurasian Journal of Mathematical and Computer Applications, 5 (2017), 14-35. 

[11]

S. I. KabanikhinO. I. KrivorotkoD. A. Voronov and D. V. Ermolenko, Optimization approach for solving the inverse problem of the simplest model of an infectious disease, Siberian Electronic Mathematical Reports, 12 (2015), 154-162. 

[12]

V. B. Kolmanovskii and V. R. Nosov, Ustoichivost' i Periodicheskie Rejimy Sistem Upravleniya s Posledeistviem, (Russian) [Stability and periodic regimes of control systems with aftereffect], [Theoretical Foundations of Engineering Cybernetics] Nauka, Moscow, 1981.

[13]

A. A. Lackner, M. M. Lederman and B. Rodriguez, HIV Pathogenesis: The Host, Cold Spring Harb Perspect Med, 2 (2012), a007005. doi: 10.1101/cshperspect.a007005.

[14]

G. I. Marchuk, Matematicheskie Modeli v Immunologii, (Russian) [Mathematical models in immunology], 2nd edition, With a preface by R. V. Petrov., Nauka, Moscow, 1985.

[15]

G. I. Marchuk, Matematicheskie Modeli V Immunologii. Vychislitel'nye Metody I Eksperimenty, (Russian) [Mathematical models in immunology. Computational methods and experiments], 3rd edition, Nauka, Moscow, 1991.

[16]

S. NakaokaI. Shingo and K. Sato, Dynamics of HIV infection in lymphoid tissue network, J. Math. Biol., 72 (2016), 909-938.  doi: 10.1007/s00285-015-0940-x.

[17]

P. W. Nelson and A. S. Perelson, Mathematical Analysis of delay differential equation models of HIV-1 infection, Math. Biosci., 179 (2002), 73-94.  doi: 10.1016/S0025-5564(02)00099-8.

[18]

A. Yu. Obolenskii, Stability of solutions of autonomous Wazewski systems with delayed action, Ukr. Math. J., 35 (1983), 486-492.  doi: 10.1007/BF01061640.

[19]

S. Pankavich, The effects of latent infection on the dynamics of HIV, Differ. Equ. Dyn. Syst., 24 (2016), 281-303.  doi: 10.1007/s12591-014-0234-6.

[20]

K. A. PawelekS. LiuF. Pahlevani and L. Rong, A model of HIV-1 infection with two time delays: Mathematical analysis and comparison with patient data, Math. Biosci., 235 (2012), 98-109.  doi: 10.1016/j.mbs.2011.11.002.

[21]

A. S. Perelson and R. M. Ribeiro, Modeling The Within-Host Dynamics of HIV Infection, BMC Biology, 2013. doi: 10.1186/1741-7007-11-96.

[22]

N. V. Pertsev, Global Solvability and Estimates of Solutions to the Cauchy Problem for the Retarded Functional Differential Equations That Are Used to Model Living Systems, Sib. Math. J., 59 (2018), 113-125.  doi: 10.1134/S0037446618010135.

[23]

N. V. PertsevB. Yu. Pichugin and K. K. Loginov, Stochastic Analog of the Dynamic Model of HIV-1 Infection Described by Delay Differential Equations, J. Appl. Ind. Math., 13 (2019), 103-117.  doi: 10.1134/S1990478919010125.

[24]

N. V. Pertsev, B. Yu. Pichugin and A. N. Pichugina, Application of M-Matrices in studies of mathematical models of living systems, Mathematical Biology and Bioinformatics, 13 (2018), t104–t131. doi: 10.17537/2018.13.t104.

[25]

M. Pitchaimani and C. Monica, Global stability analysis of HIV-1 infection model with three time delays, J. Appl. Math. Comput., 48 (2015), 293-319.  doi: 10.1007/s12190-014-0803-4.

[26]

D. Sanchez-TaltavullA. Vieiro and T. Alarcon, Stochastic modelling of the eradication of the HIV-1 infection by stimulation of latently infected cells in patients under highly active anti-retroviral therapy, J. Math. Biol., 73 (2016), 919-946.  doi: 10.1007/s00285-016-0977-5.

[27]

A. ShetP. Nagaraja and N. M. Dixit, Viral Decay Dynamics and Mathematical Modeling of Treatment Response: Evidence of Lower in vivo Fitness of HIV-1 Subtype C, J. Acquir. Immune Defic. Syndr., 73 (2016), 245-251.  doi: 10.1097/QAI.0000000000001101.

[28]

R. F. Siliciano and W. C. Greene, HIV Latency, Cold Spring Harb Perspect Med, 1 (2011), a007096. doi: 10.1101/cshperspect.a007096.

[29]

W. I. Sundquist and H.-G. Kraüsslich, HIV-1 Assembly, Budding, and Maturation, Cold Spring Harb Perspect Med, 2 (2012), a006924. doi: 10.1101/cshperspect.a006924.

[30]

J. WangJ. Lang and X. Zou, Analysis of an age structured HIV infection model with virus-to-cell infection and cell-to-cell transmission, Nonlinear Anal. Real World Appl., 34 (2017), 75-96.  doi: 10.1016/j.nonrwa.2016.08.001.

Figure 1.  Schematic representation of the model of acute HIV-1 infection
Figure 2.  Computational Experiment 1. Dynamics of $ y_1(t) $, $ y_2(t) $, $ y_3(t) $ for $ R_0 = 0.9224 $, $ V^0 = 10^4 $
Figure 3.  Computational Experiment 2. Dynamics of $ y_1(t) $, $ y_2(t) $, $ y_3(t) $ for $ R_0 = 0.9073 $, $ V^0 = 10^4 $
Figure 4.  Computational Experiment 3. Dynamics of $ y_1(t) $, $ y_2(t) $, $ y_3(t) $ for $ R_0 = 2.2875 $. (a) $ V^0 = 10^4 $, (b) $ V^0 = 10^6 $
Figure 5.  Computational Experiment 4. Dynamics of $ y_1(t) $, $ y_2(t) $, $ y_3(t) $ for $ R_0 = 2.2875 $. (a) $ V^0 = 10^4 $, (b) $ V^0 = 10^6 $
Figure 6.  Computational Experiment 5. Dynamics of $ y_1(t) $, $ y_2(t) $, $ y_3(t) $ for $ R_0 = 13.2135 $. (a) $ V^0 = 10^2 $, (b) $ V^0 = 10^6 $
Figure 7.  Computational Experiment 6. Dynamics of $ y_1(t) $, $ y_2(t) $, $ y_3(t) $ for $ R_0 = 3.3789 $. (a) $ V^0 = 10^4 $, (b) $ V^0 = 10^6 $
Table 1.  Time post infection needed for a complete elimination of HIV-1 infection
$ V_0 $ Computational experiment number, the value $ \tau_0 $ (day)
1 2 3 4 5 6
$ 10 $ 1 1 $ - $ $ - $ $ - $ 46
$ 10^2 $ 51 46 $ - $ 51 $ - $ 44
$ 10^4 $ 60 115 $ - $ 37 $ - $ 42
$ 10^6 $ 67 132 76 78 102 53
$ 10^7 $ 72 140 96 94 $ - $ 57
$ V_0 $ Computational experiment number, the value $ \tau_0 $ (day)
1 2 3 4 5 6
$ 10 $ 1 1 $ - $ $ - $ $ - $ 46
$ 10^2 $ 51 46 $ - $ 51 $ - $ 44
$ 10^4 $ 60 115 $ - $ 37 $ - $ 42
$ 10^6 $ 67 132 76 78 102 53
$ 10^7 $ 72 140 96 94 $ - $ 57
[1]

Olivier Bonnefon, Jérôme Coville, Jimmy Garnier, Lionel Roques. Inside dynamics of solutions of integro-differential equations. Discrete and Continuous Dynamical Systems - B, 2014, 19 (10) : 3057-3085. doi: 10.3934/dcdsb.2014.19.3057

[2]

Narcisa Apreutesei, Arnaud Ducrot, Vitaly Volpert. Travelling waves for integro-differential equations in population dynamics. Discrete and Continuous Dynamical Systems - B, 2009, 11 (3) : 541-561. doi: 10.3934/dcdsb.2009.11.541

[3]

Songbai Guo, Wanbiao Ma. Global behavior of delay differential equations model of HIV infection with apoptosis. Discrete and Continuous Dynamical Systems - B, 2016, 21 (1) : 103-119. doi: 10.3934/dcdsb.2016.21.103

[4]

Mohammed Al Horani, Angelo Favini, Hiroki Tanabe. Singular integro-differential equations with applications. Evolution Equations and Control Theory, 2021  doi: 10.3934/eect.2021051

[5]

Mohammed Al Horani, Angelo Favini, Hiroki Tanabe. Inverse problems on degenerate integro-differential equations. Discrete and Continuous Dynamical Systems - S, 2022  doi: 10.3934/dcdss.2022025

[6]

Frederic Abergel, Remi Tachet. A nonlinear partial integro-differential equation from mathematical finance. Discrete and Continuous Dynamical Systems, 2010, 27 (3) : 907-917. doi: 10.3934/dcds.2010.27.907

[7]

Kun-Peng Jin, Jin Liang, Ti-Jun Xiao. Uniform polynomial stability of second order integro-differential equations in Hilbert spaces with positive definite kernels. Discrete and Continuous Dynamical Systems - S, 2021, 14 (9) : 3141-3166. doi: 10.3934/dcdss.2021077

[8]

A. M. Elaiw, N. H. AlShamrani, A. Abdel-Aty, H. Dutta. Stability analysis of a general HIV dynamics model with multi-stages of infected cells and two routes of infection. Discrete and Continuous Dynamical Systems - S, 2021, 14 (10) : 3541-3556. doi: 10.3934/dcdss.2020441

[9]

Jean-Michel Roquejoffre, Juan-Luis Vázquez. Ignition and propagation in an integro-differential model for spherical flames. Discrete and Continuous Dynamical Systems - B, 2002, 2 (3) : 379-387. doi: 10.3934/dcdsb.2002.2.379

[10]

Liang Zhang, Bingtuan Li. Traveling wave solutions in an integro-differential competition model. Discrete and Continuous Dynamical Systems - B, 2012, 17 (1) : 417-428. doi: 10.3934/dcdsb.2012.17.417

[11]

Tomás Caraballo, P.E. Kloeden. Non-autonomous attractors for integro-differential evolution equations. Discrete and Continuous Dynamical Systems - S, 2009, 2 (1) : 17-36. doi: 10.3934/dcdss.2009.2.17

[12]

Yi Cao, Jianhua Wu, Lihe Wang. Fundamental solutions of a class of homogeneous integro-differential elliptic equations. Discrete and Continuous Dynamical Systems, 2019, 39 (3) : 1237-1256. doi: 10.3934/dcds.2019053

[13]

Yubo Chen, Wan Zhuang. The extreme solutions of PBVP for integro-differential equations with caratheodory functions. Conference Publications, 1998, 1998 (Special) : 160-166. doi: 10.3934/proc.1998.1998.160

[14]

Ramasamy Subashini, Chokkalingam Ravichandran, Kasthurisamy Jothimani, Haci Mehmet Baskonus. Existence results of Hilfer integro-differential equations with fractional order. Discrete and Continuous Dynamical Systems - S, 2020, 13 (3) : 911-923. doi: 10.3934/dcdss.2020053

[15]

Tonny Paul, A. Anguraj. Existence and uniqueness of nonlinear impulsive integro-differential equations. Discrete and Continuous Dynamical Systems - B, 2006, 6 (5) : 1191-1198. doi: 10.3934/dcdsb.2006.6.1191

[16]

Tianling Jin, Jingang Xiong. Schauder estimates for solutions of linear parabolic integro-differential equations. Discrete and Continuous Dynamical Systems, 2015, 35 (12) : 5977-5998. doi: 10.3934/dcds.2015.35.5977

[17]

Sertan Alkan. A new solution method for nonlinear fractional integro-differential equations. Discrete and Continuous Dynamical Systems - S, 2015, 8 (6) : 1065-1077. doi: 10.3934/dcdss.2015.8.1065

[18]

Eitan Tadmor, Prashant Athavale. Multiscale image representation using novel integro-differential equations. Inverse Problems and Imaging, 2009, 3 (4) : 693-710. doi: 10.3934/ipi.2009.3.693

[19]

Patricio Felmer, Ying Wang. Qualitative properties of positive solutions for mixed integro-differential equations. Discrete and Continuous Dynamical Systems, 2019, 39 (1) : 369-393. doi: 10.3934/dcds.2019015

[20]

Sebti Kerbal, Yang Jiang. General integro-differential equations and optimal controls on Banach spaces. Journal of Industrial and Management Optimization, 2007, 3 (1) : 119-128. doi: 10.3934/jimo.2007.3.119

2020 Impact Factor: 2.425

Metrics

  • PDF downloads (289)
  • HTML views (333)
  • Cited by (0)

[Back to Top]