Fluctuating synaptic conductances recreate in-vivo-like activity (Destexhe et al 2001)


Destexhe A, Rudolph M, Fellous JM, Sejnowski TJ. (2001). Fluctuating synaptic conductances recreate in vivo-like activity in neocortical neurons. Neuroscience. 107 [PubMed]

See more from authors: Destexhe A · Rudolph M · Fellous JM · Sejnowski TJ

References and models cited by this paper

Barrett JN. (1975). Motoneuron dendrites: role in synaptic integration. Federation proceedings. 34 [PubMed]

Bernander O, Douglas RJ, Martin KA, Koch C. (1991). Synaptic background activity influences spatiotemporal integration in single pyramidal cells. Proceedings of the National Academy of Sciences of the United States of America. 88 [PubMed]

Borg-Graham LJ, Monier C, Frégnac Y. (1998). Visual input evokes transient and strong shunting inhibition in visual cortical neurons. Nature. 393 [PubMed]

Contreras D, Destexhe A, Steriade M. (1997). Intracellular and computational characterization of the intracortical inhibitory control of synchronized thalamic inputs in vivo. Journal of neurophysiology. 78 [PubMed]

Cragg BG. (1967). The density of synapses and neurones in the motor and visual areas of the cerebral cortex. Journal of anatomy. 101 [PubMed]

DeFelipe J, Fariñas I. (1992). The pyramidal neuron of the cerebral cortex: morphological and chemical characteristics of the synaptic inputs. Progress in neurobiology. 39 [PubMed]

Destexhe A, Paré D. (1999). Impact of network activity on the integrative properties of neocortical pyramidal neurons in vivo. Journal of neurophysiology. 81 [PubMed]

Douglas RJ, Martin KA, Whitteridge D. (1991). An intracellular analysis of the visual responses of neurones in cat visual cortex. The Journal of physiology. 440 [PubMed]

Fellous JM et al. (2001). Frequency dependence of spike timing reliability in cortical pyramidal cells and interneurons. Journal of neurophysiology. 85 [PubMed]

Feng J, Brown D. (2000). Impact of correlated inputs on the output of the integrate- and-fire model. Neural computation. 12 [PubMed]

HODGKIN AL, HUXLEY AF. (1952). A quantitative description of membrane current and its application to conduction and excitation in nerve. The Journal of physiology. 117 [PubMed]

Harsch A, Robinson HP. (2000). Postsynaptic variability of firing in rat cortical neurons: the roles of input synchronization and synaptic NMDA receptor conductance. The Journal of neuroscience : the official journal of the Society for Neuroscience. 20 [PubMed]

Hines ML, Carnevale NT. (1997). The NEURON simulation environment. Neural computation. 9 [PubMed]

Holmes WR, Woody CD. (1989). Effects of uniform and non-uniform synaptic 'activation-distributions' on the cable properties of modeled cortical pyramidal neurons. Brain research. 505 [PubMed]

Hô N, Destexhe A. (2000). Synaptic background activity enhances the responsiveness of neocortical pyramidal neurons. Journal of neurophysiology. 84 [PubMed]

Mainen ZF, Sejnowski TJ. (1995). Reliability of spike timing in neocortical neurons. Science (New York, N.Y.). 268 [PubMed]

Matsumura M, Cope T, Fetz EE. (1988). Sustained excitatory synaptic input to motor cortex neurons in awake animals revealed by intracellular recording of membrane potentials. Experimental brain research. 70 [PubMed]

McCormick DA. (1992). Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity. Progress in neurobiology. 39 [PubMed]

McCormick DA, Wang Z, Huguenard J. (1993). Neurotransmitter control of neocortical neuronal activity and excitability. Cerebral cortex (New York, N.Y. : 1991). 3 [PubMed]

Paré D, Lebel E, Lang EJ. (1997). Differential impact of miniature synaptic potentials on the soma and dendrites of pyramidal neurons in vivo. Journal of neurophysiology. 78 [PubMed]

Paré D, Shink E, Gaudreau H, Destexhe A, Lang EJ. (1998). Impact of spontaneous synaptic activity on the resting properties of cat neocortical pyramidal neurons In vivo. Journal of neurophysiology. 79 [PubMed]

Ricciardi LM, Sacerdote L. (1979). The Ornstein-Uhlenbeck process as a model for neuronal activity. I. Mean and variance of the firing time. Biological cybernetics. 35 [PubMed]

Salinas E, Sejnowski TJ. (2000). Impact of correlated synaptic input on output firing rate and variability in simple neuronal models. The Journal of neuroscience : the official journal of the Society for Neuroscience. 20 [PubMed]

Shadlen MN, Newsome WT. (1998). The variable discharge of cortical neurons: implications for connectivity, computation, and information coding. The Journal of neuroscience : the official journal of the Society for Neuroscience. 18 [PubMed]

Sharp AA, O'Neil MB, Abbott LF, Marder E. (1993). The dynamic clamp: artificial conductances in biological neurons. Trends in neurosciences. 16 [PubMed]

Smith CE. (1992). A note on neuronal firing and input variability. Journal of theoretical biology. 154 [PubMed]

Softky WR, Koch C. (1993). The highly irregular firing of cortical cells is inconsistent with temporal integration of random EPSPs. The Journal of neuroscience : the official journal of the Society for Neuroscience. 13 [PubMed]

Stevens CF, Zador AM. (1998). Input synchrony and the irregular firing of cortical neurons. Nature neuroscience. 1 [PubMed]

Svirskis G, Rinzel J. (2000). Influence of temporal correlation of synaptic input on the rate and variability of firing in neurons. Biophysical journal. 79 [PubMed]

Wiesenfeld K, Moss F. (1995). Stochastic resonance and the benefits of noise: from ice ages to crayfish and SQUIDs. Nature. 373 [PubMed]

References and models that cite this paper

Anderson WD, Makadia HK, Vadigepalli R. (2016). Molecular variability elicits a tunable switch with discrete neuromodulatory response phenotypes. Journal of computational neuroscience. 40 [PubMed]

Aradi I, Santhakumar V, Chen K, Soltesz I. (2002). Postsynaptic effects of GABAergic synaptic diversity: regulation of neuronal excitability by changes in IPSC variance. Neuropharmacology. 43 [PubMed]

Arsiero M, Lüscher HR, Lundstrom BN, Giugliano M. (2007). The impact of input fluctuations on the frequency-current relationships of layer 5 pyramidal neurons in the rat medial prefrontal cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience. 27 [PubMed]

Azouz R. (2005). Dynamic spatiotemporal synaptic integration in cortical neurons: neuronal gain, revisited. Journal of neurophysiology. 94 [PubMed]

Badel L et al. (2008). Dynamic I-V curves are reliable predictors of naturalistic pyramidal-neuron voltage traces. Journal of neurophysiology. 99 [PubMed]

Birdno MJ et al. (2012). Stimulus features underlying reduced tremor suppression with temporally patterned deep brain stimulation. Journal of neurophysiology. 107 [PubMed]

Booth V, Poe GR. (2006). Input source and strength influences overall firing phase of model hippocampal CA1 pyramidal cells during theta: relevance to REM sleep reactivation and memory consolidation. Hippocampus. 16 [PubMed]

Breakspear M, Terry JR, Friston KJ. (2003). Modulation of excitatory synaptic coupling facilitates synchronization and complex dynamics in a biophysical model of neuronal dynamics. Network (Bristol, England). 14 [PubMed]

Brette R. (2006). Exact simulation of integrate-and-fire models with synaptic conductances. Neural computation. 18 [PubMed]

Brette R, Gerstner W. (2005). Adaptive exponential integrate-and-fire model as an effective description of neuronal activity. Journal of neurophysiology. 94 [PubMed]

Brette R et al. (2008). High-resolution intracellular recordings using a real-time computational model of the electrode. Neuron. 59 [PubMed]

Béhuret S, Deleuze C, Gomez L, Frégnac Y, Bal T. (2013). Cortically-controlled population stochastic facilitation as a plausible substrate for guiding sensory transfer across the thalamic gateway PLoS computational biology. 9 [PubMed]

Carnevale NT, Hines M. (2003). Personal Communication of NEURON bibliography .

Carnevale NT, Morse TM. (1996). Research reports that have used NEURON Web published citations at the NEURON website.

Cavallari S, Panzeri S, Mazzoni A. (2014). Comparison of the dynamics of neural interactions between current-based and conductance-based integrate-and-fire recurrent networks. Frontiers in neural circuits. 8 [PubMed]

Cavarretta F, Marasco A, Hines ML, Shepherd GM, Migliore M. (2016). Glomerular and Mitral-Granule Cell Microcircuits Coordinate Temporal and Spatial Information Processing in the Olfactory Bulb. Frontiers in computational neuroscience. 10 [PubMed]

Chambers JD et al. (2012). Parametric computation predicts a multiplicative interaction between synaptic strength parameters that control gamma oscillations. Frontiers in computational neuroscience. 6 [PubMed]

Chance FS. (2007). Receiver operating characteristic (ROC) analysis for characterizing synaptic efficacy. Journal of neurophysiology. 97 [PubMed]

Chance FS, Abbott LF, Reyes AD. (2002). Gain modulation from background synaptic input. Neuron. 35 [PubMed]

Debay D, Wolfart J, Le Franc Y, Le Masson G, Bal T. (2004). Exploring spike transfer through the thalamus using hybrid artificial-biological neuronal networks. Journal of physiology, Paris. 98 [PubMed]

Delgado JY, Gómez-González JF, Desai NS. (2010). Pyramidal neuron conductance state gates spike-timing-dependent plasticity. The Journal of neuroscience : the official journal of the Society for Neuroscience. 30 [PubMed]

Desai NS, Walcott EC. (2006). Synaptic bombardment modulates muscarinic effects in forelimb motor cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience. 26 [PubMed]

Destexhe A, Rudolph M. (2002). Point-conductance models of cortical neurons with high discharge variability Neurocomputing. 44-46

Destexhe A, Rudolph M. (2004). Extracting information from the power spectrum of synaptic noise. Journal of computational neuroscience. 17 [PubMed]

Destexhe A, Rudolph M, Bal T, Badoual M, Piwkowska Z. (2004). A novel method for characterizing synaptic noise in cortical neurons Neurocomputing. 58

Destexhe A, Rudolph M, Paré D. (2003). The high-conductance state of neocortical neurons in vivo. Nature reviews. Neuroscience. 4 [PubMed]

Fellous JM, Rudolph M, Destexhe A, Sejnowski TJ. (2003). Synaptic background noise controls the input/output characteristics of single cells in an in vitro model of in vivo activity. Neuroscience. 122 [PubMed]

Földy C, Aradi I, Howard A, Soltesz I. (2004). Diversity beyond variance: modulation of firing rates and network coherence by GABAergic subpopulations. The European journal of neuroscience. 19 [PubMed]

Gabbiani F, Cox SJ. (2010). Mathematics for Neuroscientists.

Gasparini S, Migliore M, Magee JC. (2004). On the initiation and propagation of dendritic spikes in CA1 pyramidal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience. 24 [PubMed]

Gutkin B, Ermentrout GB, Rudolph M. (2003). Spike generating dynamics and the conditions for spike-time precision in cortical neurons. Journal of computational neuroscience. 15 [PubMed]

Haeusler S, Maass W. (2007). A statistical analysis of information-processing properties of lamina-specific cortical microcircuit models. Cerebral cortex (New York, N.Y. : 1991). 17 [PubMed]

Higley MJ, Contreras D. (2006). Balanced excitation and inhibition determine spike timing during frequency adaptation. The Journal of neuroscience : the official journal of the Society for Neuroscience. 26 [PubMed]

Hoch T, Wenning G, Obermayer K. (2003). Optimal noise-aided signal transmission through populations of neurons. Physical review. E, Statistical, nonlinear, and soft matter physics. 68 [PubMed]

Hong S, Ratté S, Prescott SA, De Schutter E. (2012). Single neuron firing properties impact correlation-based population coding. The Journal of neuroscience : the official journal of the Society for Neuroscience. 32 [PubMed]

Jolivet R, Lewis TJ, Gerstner W. (2004). Generalized integrate-and-fire models of neuronal activity approximate spike trains of a detailed model to a high degree of accuracy. Journal of neurophysiology. 92 [PubMed]

Kim H, Kim M. (2018). PyMUS: Python-Based Simulation Software for Virtual Experiments on Motor Unit System. Frontiers in neuroinformatics. 12 [PubMed]

Kitano K. (2023). The network configuration in Parkinsonian state compensates network activity change caused by loss of dopamine Physiological reports. 11 [PubMed]

Kitano K, Fukai T. (2007). Variability v.s. synchronicity of neuronal activity in local cortical network models with different wiring topologies. Journal of computational neuroscience. 23 [PubMed]

Kobayashi R et al. (2019). Reconstructing neuronal circuitry from parallel spike trains. Nature communications. 10 [PubMed]

Köndgen H et al. (2008). The dynamical response properties of neocortical neurons to temporally modulated noisy inputs in vitro. Cerebral cortex (New York, N.Y. : 1991). 18 [PubMed]

La Camera G, Rauch A, Lüscher HR, Senn W, Fusi S. (2004). Minimal models of adapted neuronal response to in vivo-like input currents. Neural computation. 16 [PubMed]

Legenstein R, Pecevski D, Maass W. (2008). A learning theory for reward-modulated spike-timing-dependent plasticity with application to biofeedback. PLoS computational biology. 4 [PubMed]

Linaro D, Couto J, Giugliano M. (2014). Command-line cellular electrophysiology for conventional and real-time closed-loop experiments. Journal of neuroscience methods. 230 [PubMed]

Linaro D, Ocker GK, Doiron B, Giugliano M. (2019). Correlation Transfer by Layer 5 Cortical Neurons Under Recreated Synaptic Inputs In Vitro. The Journal of neuroscience : the official journal of the Society for Neuroscience. 39 [PubMed]

Maass W, Joshi P, Sontag ED. (2007). Computational aspects of feedback in neural circuits. PLoS computational biology. 3 [PubMed]

Martínez L, Pérez T, Mirasso CR, Manjarrez E. (2007). Stochastic resonance in the motor system: effects of noise on the monosynaptic reflex pathway of the cat spinal cord. Journal of neurophysiology. 97 [PubMed]

Meffin H, Burkitt AN, Grayden DB. (2004). An analytical model for the "large, fluctuating synaptic conductance state" typical of neocortical neurons in vivo. Journal of computational neuroscience. 16 [PubMed]

Michalikova M, Remme MW, Kempter R. (2017). Spikelets in Pyramidal Neurons: Action Potentials Initiated in the Axon Initial Segment That Do Not Activate the Soma. PLoS computational biology. 13 [PubMed]

Migliore M, De Blasi I, Tegolo D, Migliore R. (2011). A modeling study suggesting how a reduction in the context-dependent input on CA1 pyramidal neurons could generate schizophrenic behavior. Neural networks : the official journal of the International Neural Network Society. 24 [PubMed]

Migliore M, Novara G, Tegolo D. (2008). Single neuron binding properties and the magical number 7. Hippocampus. 18 [PubMed]

Migliore M, Tegolo D, Spera E, Unsworth N. (2016). On the cellular mechanisms underlying working memory capacity in humans Neural Network World. 4

Migliore R, De Simone G, Leinekugel X, Migliore M. (2017). The possible consequences for cognitive functions of external electric fields at power line frequency on hippocampal CA1 pyramidal neurons. The European journal of neuroscience. 45 [PubMed]

Morgan RJ, Santhakumar V, Soltesz I. (2007). Modeling the dentate gyrus. Progress in brain research. 163 [PubMed]

Morse TM. (2008). ModelDB in computational neuroscience education - a research tool as interactive educational media. Brains, minds & media : journal of new media in neural and cognitive science and education. 3 [PubMed]

Muller E, Buesing L, Schemmel J, Meier K. (2007). Spike-frequency adapting neural ensembles: beyond mean adaptation and renewal theories. Neural computation. 19 [PubMed]

Murphy BK, Miller KD. (2003). Multiplicative gain changes are induced by excitation or inhibition alone. The Journal of neuroscience : the official journal of the Society for Neuroscience. 23 [PubMed]

Ozer M, Graham LJ, Erkaymaz O, Uzuntarla M. (2007). Impact of synaptic noise and conductance state on spontaneous cortical firing. Neuroreport. 18 [PubMed]

Palmer SE, Miller KD. (2007). Effects of inhibitory gain and conductance fluctuations in a simple model for contrast-invariant orientation tuning in cat V1. Journal of neurophysiology. 98 [PubMed]

Pena RFO, Zaks MA, Roque AC. (2018). Dynamics of spontaneous activity in random networks with multiple neuron subtypes and synaptic noise : Spontaneous activity in networks with synaptic noise. Journal of computational neuroscience. 45 [PubMed]

Platkiewicz J, Brette R. (2010). A threshold equation for action potential initiation. PLoS computational biology. 6 [PubMed]

Platkiewicz J, Brette R. (2011). Impact of fast sodium channel inactivation on spike threshold dynamics and synaptic integration. PLoS computational biology. 7 [PubMed]

Pospischil M, Piwkowska Z, Bal T, Destexhe A. (2009). Extracting synaptic conductances from single membrane potential traces. Neuroscience. 158 [PubMed]

Pospischil M, Piwkowska Z, Rudolph M, Bal T, Destexhe A. (2007). Calculating event-triggered average synaptic conductances from the membrane potential. Journal of neurophysiology. 97 [PubMed]

Powers RK, Elbasiouny SM, Rymer WZ, Heckman CJ. (2012). Contribution of intrinsic properties and synaptic inputs to motoneuron discharge patterns: a simulation study. Journal of neurophysiology. 107 [PubMed]

Powers RK, Heckman CJ. (2015). Contribution of intrinsic motoneuron properties to discharge hysteresis and its estimation based on paired motor unit recordings: a simulation study. Journal of neurophysiology. 114 [PubMed]

Powers RK, Heckman CJ. (2017). Synaptic control of the shape of the motoneuron pool input-output function. Journal of neurophysiology. 117 [PubMed]

Prescott SA, De Koninck Y. (2003). Gain control of firing rate by shunting inhibition: roles of synaptic noise and dendritic saturation. Proceedings of the National Academy of Sciences of the United States of America. 100 [PubMed]

Prescott SA, Ratté S, De Koninck Y, Sejnowski TJ. (2006). Nonlinear interaction between shunting and adaptation controls a switch between integration and coincidence detection in pyramidal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience. 26 [PubMed]

Prescott SA, Ratté S, De Koninck Y, Sejnowski TJ. (2008). Pyramidal neurons switch from integrators in vitro to resonators under in vivo-like conditions. Journal of neurophysiology. 100 [PubMed]

Reinker S, Puil E, Miura RM. (2004). Membrane resonance and stochastic resonance modulate firing patterns of thalamocortical neurons. Journal of computational neuroscience. 16 [PubMed]

Rich S et al. (2019). Inhibitory Network Bistability Explains Increased Interneuronal Activity Prior to Seizure Onset. Frontiers in neural circuits. 13 [PubMed]

Richardson MJ, Gerstner W. (2005). Synaptic shot noise and conductance fluctuations affect the membrane voltage with equal significance. Neural computation. 17 [PubMed]

Rowat P. (2007). Interspike interval statistics in the stochastic Hodgkin-Huxley model: coexistence of gamma frequency bursts and highly irregular firing. Neural computation. 19 [PubMed]

Rudolph M, Destexhe A. (2003). The discharge variability of neocortical neurons during high-conductance states. Neuroscience. 119 [PubMed]

Rudolph M, Destexhe A. (2003). A fast-conducting, stochastic integrative mode for neocortical neurons in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience. 23 [PubMed]

Rudolph M, Destexhe A. (2003). Characterization of subthreshold voltage fluctuations in neuronal membranes. Neural computation. 15 [PubMed]

Rudolph M, Destexhe A. (2004). Inferring network activity from synaptic noise. Journal of physiology, Paris. 98 [PubMed]

Rudolph M, Destexhe A. (2005). An extended analytic expression for the membrane potential distribution of conductance-based synaptic noise. Neural computation. 17 [PubMed]

Rudolph M, Destexhe A. (2006). Analytical integrate-and-fire neuron models with conductance-based dynamics for event-driven simulation strategies. Neural computation. 18 [PubMed]

Rudolph M, Destexhe A. (2006). On the use of analytical expressions for the voltage distribution to analyze intracellular recordings. Neural computation. 18 [PubMed]

Rudolph M, Pelletier JG, Pare D, Destexhe A. (2004). Estimation of synaptic conductances and their variances from intracellular recordings of neocortical neurons in vivo Neurocomputing. 58

Rudolph M, Pospischil M, Timofeev I, Destexhe A. (2007). Inhibition determines membrane potential dynamics and controls action potential generation in awake and sleeping cat cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience. 27 [PubMed]

Rössert C, Solinas S, D'Angelo E, Dean P, Porrill J. (2014). Model cerebellar granule cells can faithfully transmit modulated firing rate signals. Frontiers in cellular neuroscience. 8 [PubMed]

Santhakumar V, Aradi I, Soltesz I. (2005). Role of mossy fiber sprouting and mossy cell loss in hyperexcitability: a network model of the dentate gyrus incorporating cell types and axonal topography. Journal of neurophysiology. 93 [PubMed]

Schmidt-Hieber C et al. (2017). Active dendritic integration as a mechanism for robust and precise grid cell firing. Nature neuroscience. 20 [PubMed]

Shu Y, Duque A, Yu Y, Haider B, McCormick DA. (2007). Properties of action-potential initiation in neocortical pyramidal cells: evidence from whole cell axon recordings. Journal of neurophysiology. 97 [PubMed]

Spain WJ, Fairhall AL, Lundstrom BN, Famulare M, Sorensen LB. (2009). Sensitivity of firing rate to input fluctuations depends on time scale separation between fast and slow variables in single neurons J Comput Neurosci. in press

Stiefel KM, Englitz B, Sejnowski TJ. (2013). Origin of intrinsic irregular firing in cortical interneurons. Proceedings of the National Academy of Sciences of the United States of America. 110 [PubMed]

Sun Z, Crompton D, Lankarany M, Skinner FK. (2023). Reduced oriens-lacunosum/moleculare cell model identifies biophysical current balances for in vivo theta frequency spiking resonance Frontiers in Neural Circuits. [PubMed]

Tan AY, Andoni S, Priebe NJ. (2013). A spontaneous state of weakly correlated synaptic excitation and inhibition in visual cortex. Neuroscience. 247 [PubMed]

Thomas EA, Petrou S. (2013). Network-specific mechanisms may explain the paradoxical effects of carbamazepine and phenytoin. Epilepsia. 54 [PubMed]

Tiesinga PH. (2005). Stimulus competition by inhibitory interference. Neural computation. 17 [PubMed]

Tiesinga PH, Fellous JM, José JV, Sejnowski TJ. (2002). Information transfer in entrained cortical neurons. Network (Bristol, England). 13 [PubMed]

Vierling-Claassen D, Cardin JA, Moore CI, Jones SR. (2010). Computational modeling of distinct neocortical oscillations driven by cell-type selective optogenetic drive: separable resonant circuits controlled by low-threshold spiking and fast-spiking interneurons. Frontiers in human neuroscience. 4 [PubMed]

Wenning G, Obermayer K. (2003). Activity driven adaptive stochastic resonance. Physical review letters. 90 [PubMed]

Wolfart J, Debay D, Le Masson G, Destexhe A, Bal T. (2005). Synaptic background activity controls spike transfer from thalamus to cortex. Nature neuroscience. 8 [PubMed]

Wong KF, Wang XJ. (2006). A recurrent network mechanism of time integration in perceptual decisions. The Journal of neuroscience : the official journal of the Society for Neuroscience. 26 [PubMed]

Yu Y, Shu Y, McCormick DA. (2008). Cortical action potential backpropagation explains spike threshold variability and rapid-onset kinetics. The Journal of neuroscience : the official journal of the Society for Neuroscience. 28 [PubMed]

Zang Y, Hong S, De Schutter E. (2020). Firing rate-dependent phase responses of Purkinje cells support transient oscillations. eLife. 9 [PubMed]

Zeldenrust F, Chameau P, Wadman WJ. (2018). Spike and burst coding in thalamocortical relay cells. PLoS computational biology. 14 [PubMed]

This website requires cookies and limited processing of your personal data in order to function. By continuing to browse or otherwise use this site, you are agreeing to this use. See our Privacy policy and how to cite and terms of use.